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Protein Synthesis Inhibitors

5.50 Contact Hours
  • 0% complete
A score of 80% correct answers on a test is required to successfully complete any course and attain a certificate of completion.
Author:    Pamela Downey (MSN, ARNP)

Outcomes

This course concentrates specifically on protein synthesis inhibitors which consist of many different pharmacologic categories with their respective therapeutic agents.

Objectives

After completing this educational program, the learner will be able to:

  1. Describe the mechanism of action for each of the pharmacologic categories discussed under protein synthesis inhibitors.
  2. Discuss the spectrum of activity, indications and usage for each of the pharmacologic categories discussed under protein synthesis inhibitors.
  3. Discuss the specific warnings and precautions for each of the pharmacologic categories discussed under protein synthesis inhibitors and parameters for monitoring.
  4. Describe the specific patient parameters which should be assessed prior to the administration of any therapeutic agent discussed under protein synthesis inhibitors.
  5. Relate the contraindications and limitations of use for any therapeutic agent discussed under protein synthesis inhibitors.
  6. Compare and contrast usage during pregnancy and breastfeeding for each of the pharmacologic categories discussed under protein synthesis inhibitors
  7. Discuss dosing considerations in adults, the geriatric patient, patients with renal and/or hepatic impairment or other special populations in each of the pharmacologic categories discussed under protein synthesis inhibitors.
  8. Relate principles underlying the various routes of administration and any appropriate dietary considerations in each of the pharmacologic categories discussed under protein synthesis inhibitors.

Protein Synthesis Inhibitors

A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins. It usually refers to substances, such as antimicrobial drugs, that act at the ribosome level. The substances take advantage of the major differences between prokaryotic and eukaryotic ribosome structures which differ in their size, sequence, structure and the ratio of protein to RNA. The differences in structure allow some antibiotics to kill bacteria by inhibiting their ribosomes while leaving human ribosomes unaffected.

Key Points

The ribosome is a complex molecular machine, found within all living cells, that serves as the site of biological protein synthesis (translation). Ribosomes link amino acids together in the order specified by messenger RNA (mRNA) molecules. Ribosomes consist of two major components:

  • A small ribosomal subunit called 30S which is an integral part of mRNA translation which reads the RNA. This ensures the ribosome starts translation at the correct location.
  • A large subunit called 50S. The 50S subunit is primarily composed of proteins but also contains single-stranded RNA known as ribosomal RNA (rRNA). rRNA forms secondary and tertiary structures to maintain the structure and carry out the catalytic functions of the ribosome. The large ribosomal subunit (50S) is approximately twice as massive as the small ribosomal subunit (30S).

Protein synthesis inhibitors usually act at the ribosome level, taking advantage of the major differences between prokaryotic and eukaryotic ribosome structures.

  • A prokaryote is a unicellular organism that lacks a membrane-bound nucleus, mitochondria or any other membrane-bound organelle. Prokaryotes can be divided into two domains: archaea and bacteria. In the prokaryotes, all the intracellular water-soluble components (proteins, DNA and metabolites) are located together in the cytoplasm enclosed by the cell membrane, rather than in separate cellular compartments. Bacteria, however, do possess protein-based bacterial microcompartments, which are thought to act as primitive organelles enclosed in protein shells.
  • A eukaryote is any organism whose cells contain a nucleus and other organelles enclosed within membranes. The defining feature that sets eukaryotic cells apart from prokaryotic cells (bacteria and archaea) is that they have membrane-bound organelles, especially the nucleus, which contains the genetic material and is enclosed by the nuclear envelope. Eukaryotic cells also contain other membrane-bound organelles such as mitochondria and the Golgi apparatus. In addition, plants and algae contain chloroplasts. Eukaryotic organisms may be unicellular or multicellular. Only eukaryotes form multicellular organisms consisting of many kinds of tissue made up of different cell types.

Protein synthesis inhibitors work at different stages of prokaryotic messenger RNA (mRNA) translation into proteins like initiation, elongation (including aminoacylation of transfer RNA (tRNA) entry, proofreading, peptidyl transfer and ribosomal translocation) and termination.

  • Translation is a process occurring in the ribosome, in which a strand of messenger RNA (mRNA) guides assembly of a sequence of amino acids to make a protein.
  • Translation, the assembly of amino acids by ribosomes, is an essential part of the biosynthetic pathway, along with generation of messenger RNA (mRNA), aminoacylation of transfer RNA (tRNA), co-translational transport and post-translational modification. Protein biosynthesis is strictly regulated at multiple steps. They are principally present during transcription (phenomena of RNA synthesis from DNA template) and translation (phenomena of amino acid assembly from RNA).
  • By targeting different stages of the mRNA translation, antimicrobial drugs can be changed if resistance develops.

Translation in prokaryotes involves the assembly of the components of the translation system which are: the two ribosomal subunits (the large 50S and small 30S subunits), the mRNA to be translated, the first aminoacyl tRNA, GTP (as a source of energy) and three initiation factors that help the assembly of the initiation complex.

The ribosome contains three RNA binding sites, designated A, P and E (Figure 1). The A site is the point of entry for the aminoacyl tRNA. The P site binds a peptidyl-tRNA (a tRNA bound to the peptide being synthesized). The E site (not shown in Figure 1) binds a free tRNA after it gives its amino acid to the growing peptide chain before it exits the ribosome.

Figure 1

Figure1-Simplified-Diagram-of-Protein-Synthesis

Binding Sites

  • The following antibiotics bind to the 30S subunit of the ribosome thus inhibiting protein synthesis:
    • Aminoglycoside antibiotics such as:
    • Neomycin sulfate
    • Amikacin
    • Gentamicin
    • Kanamycin sulfate
    • Spectinomycin
    • Streptomycin
    • Tobramycin
  • Tetracycline and Glycylcycline antibiotics such as:
    • Chlortetracycline
    • Tetracycline
    • Demeclocycline
    • Doxycycline
    • Minocycline
    • Tigecycline (a tetracycline derivative)
  • The following antibiotics bind to the 50S ribosomal subunit thus inhibiting protein synthesis:
    • Oxazolidinone antibiotics such as:
      • Linezolid
      • Tedizolid phosphate
    • Amphenicol antibiotics such as:
      • Chloramphenicol
      • Azidamfenicol
    • Pleuromutilin antibiotics such as:
      • Retapamulin
    • Macrolide antibiotics such as:
      • Azithromycin
      • Clarithromycin
      • Erythromycin
      • Fidaxomicin
    • Ketolide antibiotics such as:
      • Telithromycin
    • Lincosamide antibiotics such as:
      • Clindamycin
      • Lincomycin
    • Streptogramin antibiotics such as:
      • Pristinamycin
      • Quinupristin/Dalfopristin

Aminoglycoside Antibiotics

Aminoglycoside Antibiotics
Non-Parenteral Aminoglycosides
AgentsCommon Brand Name(s)Route(s)
Neomycin SulfateRibostamycin, Mycifradin, Neo-FradinOral
Parenteral Aminoglycosides
AgentsCommon Brand Name(s)Route(s)*
AmikacinAmikinIM, IV infusion
GentamicinGentamicin InjectionIM, IV infusion
Kanamycin SulfateKantrexNo longer available in the United States
SpectinomycinTrebicinRarely used in the United States
StreptomycinStreptomycin for InjectionIM
TobramycinAkteb, Tobral, Tobrex, NebcinIM, IV infusion
*Aminoglycosides are also available in topical, inhaled, intrathecal, intraventricular, intraperitoneal and impregnated cement formulations for specific indications. Only oral, IM and IV infusions will be considered in this learning module.

Mechanism of Action

The aminoglycosides primarily act by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to a misreading of the genetic code and inhibition of translocation. The initial steps required for peptide syntheses, such as binding of mRNA and the association of the 50S ribosomal subunit, are uninterrupted, but elongation fails to occur due to disruption of the mechanisms for ensuring translational accuracy. The ensuing antimicrobial activity is usually bactericidal against susceptible aerobic gram-negative bacilli.

Aminoglycosides initially penetrate the organism by disrupting the magnesium and calcium bridges between lipopolysaccharide moieties. They are transported across the cytoplasmic membrane in an energy-dependent manner. This step can be inhibited by divalent cations, increased osmolality, acidic pH and an anaerobic environment.

The microbiologic activity of aminoglycosides is pH dependent. As a result, the antimicrobial effect may be reduced at the low pH found in lung and bronchial secretions. Activity may also be reduced in the presence of biofilms, such as those seen with mucoid-producing strains of Pseudomonas aeruginosa commonly isolated in cystic fibrosis patients.

Microbiology

In general, aminoglycosides are active across a broad spectrum of aerobic gram-negative and gram-positive organisms, as well as, mycobacteria. Anaerobic bacteria are intrinsically resistant to aminoglycosides.

Aminoglycosides have antibacterial activity against susceptible:

  • Aerobic gram-negative organisms:
    • Acinetobacter spp
    • Enterobacteriaceae
    • Haemophilus influenza
    • Neisseria gonorrhoeae
    • Pseudomonas aeruginosa
    • Pseudomonas spp
    • Serratia spp
  • Aerobic gram-positive organisms:
    • Staphylococcus aureus
    • Pneumococci - Aminoglycoside activity is generally considered insufficient for clinical application against these organisms.
    • Streptococci and Enterococci - Aminoglycosides are not active alone against these pathogens, although they may have additive or synergistic effects (i.e., antibiotic synergy occurs when multiple antibiotics are used to treat an infection, and their response is stronger or faster than what use of a single antibiotic would be) when combined with other agents and in the absence of high-level resistance to these pathogens.
  • Mycobacteria
    • Mycobacterium abscessus
    • Mycobacterium chelonae
    • Mycobacterium fortuitum
    • Mycobacterium tuberculosis

Indications and Usage

Non-parenteral aminoglycosides i.e. Neomycin sulfate, oral, indications and uses include:

  • Chronic hepatic insufficiency
  • Hepatic encephalopathy
  • Surgical (perioperative) prophylaxis:
    • On the day preceding 8 AM surgery as an adjunct to mechanical cleansing of the bowel along with oral erythromycin   OR
    • On the day preceding 8 AM surgery combined with mechanical cleansing of the large intestine along with oral erythromycin or metronidazole and IV antibiotics on the day of surgery.

The widespread clinical use of parenteral aminoglycosides is generally limited because of the availability of less toxic agents with comparable efficacy and without the need for serum drug concentration monitoring. Aminoglycosides remain important as a second agent in the treatment of serious infections due to aerobic gram-negative bacilli and certain gram-positive organisms and as part of a multi-drug regimen for certain mycobacterial infections. Rarely are their instances (especially outside the urinary tract) in which monotherapy with aminoglycosides is adequate treatment.

Monotherapy

Few indications for monotherapy with systemic aminoglycosides exist. These include:

  • Non-pharyngeal gonococcal infections secondary to Neisseria gonorrhoeae in patients who have a severe penicillin allergy.
  • Plague (Yersinia pestis)
  • Tularemia
  • Urinary tract infections due to multidrug-resistant gram-negative organisms:
    • Aminoglycosides achieve high levels of concentration in the urinary tract and, in some cases, especially with amikacin, retain activity against gram-negative organisms resistant to most other classes of antibiotics.
    • Susceptibility should be confirmed as aminoglycoside resistance is not uncommon among such organisms.

Aminoglycosides should not be relied upon as monotherapy in infections that involve the lungs, abscesses and the central nervous system because of poor activity and/or penetration into these sites.

Combination Therapy

The most frequent clinical use of aminoglycosides most commonly in combination with other antibacterial agents is empiric therapy of serious infections, such as:

  • Anaerobic infections involving Bacteroides fragilis
  • Aerobic gram-negative bacillary meningitis not susceptible to other antibiotics
  • Brucellosis
  • Cholangitis
  • CNS shunt infection (intrathecal) (off-label route)
  • Complicated pulmonary infections
  • Complicated urinary tract infections
  • Complicated intraabdominal infections
  • Diverticulitis, complicated
  • Initial empirical therapy in febrile, leukopenic patients
  • Invasive enterococcal infections (ex. endocarditis)
  • Listeria monocytogenes
  • Meningitis (Enterococcus or Pseudomonas aeruginosa)
  • Nosocomial respiratory tract infections
  • Osteomyelitis caused by aerobic gram-negative bacilli
  • Pelvic inflammatory disease
  • Pneumonia, hospital- or ventilator-associated
  • Prophylaxis against endocarditis (dental, oral, upper respiratory procedures and GI/GU procedures)
  • Prophylactic use of aminoglycosides is usually restricted to select surgical procedures involving the gastrointestinal, urinary tract or female genital tract in patients with beta-lactam allergies
  • Septicemia
  • Serious staphylococcal, Pseudomonas aeruginosa and Klebsiella infections
  • Skin, soft tissue, bone and joint infections
  • Tuberculosis caused by Mycobacteria

Aminoglycosides are usually discontinued in favor of less toxic antibiotics to complete the treatment course once an organism has been identified and its susceptibilities to other agents determined.

Antimycobacterial Therapy

Aminoglycosides are useful for the treatment of drug-resistant tuberculosis and certain nontuberculous mycobacterial infections in combination with other antimycobacterial agents.

Other Clinical Indications

Other clinical indications and routes of administration of aminoglycosides include:

  • External otitis media - topical
  • Chronic pulmonary infections in cystic fibrosis - inhaled
  • Gram-negative bacillary meningitis - intrathecal and intraventricular
  • Continuous or intermittent peritoneal dialysis-associated peritonitis - intraperitoneal
  • Prosthetic joint infections - impregnated cement formulations

Pharmacodynamics and Pharmacokinetics of Non-Parenteral Aminoglycoside

Neomycin Sulfate
AbsorptionOral
Time to Peak, Serum1 to 4 hours
Distribution97% of an orally administered dose remains in the GI tract. Absorbed neomycin distributes to tissues and concentrates in the renal cortex. With repeated doses, accumulation also occurs in the inner ear
Protein Binding0% to 30%
Excretion

Feces (97% or oral dose as unchanged drug)

Urine (30% to 50% of absorbed drug as unchanged drug)

Pharmacodynamics and Pharmacokinetics of Parenteral Aminoglycosides

Aminoglycosides
AbsorptionIM - Rapid and complete
Time to Peak, SerumPeak serum aminoglycoside concentrations are measured approximately 30 to 6- minutes after completion of an intravenous infusion or 30 to 90 minutes after an intramuscular injection. Local instillation into the pleural space or peritoneal cavity can result in significant serum concentrations.
Distribution

Aminoglycosides are systemically distributed to extracellular fluid, including serum, abscesses, ascitic, pericardial, pleural, synovial, lymphatic, and peritoneal fluids

There is a high concentration of aminoglycosides in the renel cortex reaching concentrations in the urine of 25-to 100-fold that of the serum. Small amounts are distributed into bile, sputum, saliva, and tears.

Aminoglycosideshave poor penetration into CSF, eye, bone, biliary tree, bronchial secretions and prostate tissue via the IV route. Aminoglycosides show poor penetration across the blood-brain barrier even when themeninges are inflamed.

Aminoglycoside distribution is increased in patients with edema, ascites, burns, pregnancy, cystic fibrosis and fluid overload and decreased in patients with dehydration.

Protein Binding0 – 34% depending on the agent
Half-life EliminationThe terminal half-life of aminoglycosides ranges from 1.5 to 3.5 hours in adults with normal renal function but is prolonged in patients with decreased renal function.
Excretion
Approximately 99% of the administereddose is eliminated unchanged in the urine primarily by glomerular filtration. A small amount (1%) may be excreted in bile, saliva, sweat and tears.

Definitions to Remember

Post Antibiotic Effect (PAE)

The post antibiotic effect (PAE) refers to the persistent suppression of bacterial growth that occurs after the drug has been removed or cleared by drug metabolism and excretion. The duration of the PAE (approximately 3 hours with a range 1 to 7.5 hours) depends upon the method of evaluation, and the organism studied. In general, the PAE is longer for gram-negative organisms than gram-positive organisms. The duration of the PAE is reduced in the absence of polymorphonuclear leukocytes (PMNs).

Concentration-Dependent Killing

Concentration-dependent killing refers to the ability of higher concentrations of aminoglycosides (relative to the organism's MIC) to induce more rapid and complete killing of the pathogen. Achieving optimal peak concentrations of aminoglycosides with traditional intermittent dosing regimens can be difficult since efforts must be made to avoid sustained elevated trough concentrations (which can predispose to nephrotoxicity). Relative to traditional intermittent methods, the extended-interval dosing approach is more likely to achieve optimal peak concentrations that result in concentration-dependent killing.

Synergistic Effect

A synergistic effect has been demonstrated for selected organisms when aminoglycosides are used in combination with other antibiotics, most often with cell wall-active agents (e.g., beta-lactam antibiotics).

Dosing Considerations

The traditional approach to parenteral aminoglycoside dosing in adults involves the administration of a weight-based dose divided two to three times daily in patients with normal renal function. The dose is reduced and/or dosing interval extended in patients with decreased renal function.

Extended-interval aminoglycoside therapy (also known as once-daily aminoglycosides, single daily aminoglycoside dosing, consolidated or high-dose aminoglycoside therapy) utilizes a higher weight-based dose administered at an extended interval (every 24 hours for those with normal renal function and longer for those with renal dysfunction). Extended-interval aminoglycoside therapy (utilizing higher single doses) should not be confused with traditional intermittent dosing with lower individual doses administered at 24-hour intervals because of renal impairment.

General Principles

Improved patient outcomes have been correlated with the rapid attainment of therapeutic concentrations of aminoglycosides. Dosing should be optimized to achieve this effect. Dosing, also, should be tailored to minimize aminoglycoside toxicity. The following general principles apply to all patients, regardless of whether traditional intermittent versus extended-interval daily dosing strategies are used:

  • The initial dose and frequency of aminoglycosides are based upon the method of administration (i.e., traditional intermittent versus extended-interval daily dosing), indication, dosing weight and renal function.
    • Dosing adjustments should be based upon the results of serum drug concentration monitoring. Targeted peak serum concentrations are intended to take advantage of the pharmacodynamic properties to optimize the potential for efficacy, while specific trough concentrations are targeted to avoid concentration-related toxicity.
    • Intravenous administration of aminoglycosides should occur over at least 30 minutes for traditional intermittent and at least 60 minutes for extended-interval dosing.
  • Determination of the dosing weight regardless of method of administration:
    • Calculation of the dosing weight differs between underweight, average weight and obese patients, as well as, sex.
    • Estimation of creatinine clearance:
    • Since aminoglycosides are eliminated primarily by glomerular filtration, renal function affects the rate of drug clearance and thus affects the optimal dosing interval.
    • The creatinine clearance can be estimated from the serum creatinine concentration using the Cockcroft-Gault formula which takes into account the increase in creatinine production with increasing weight and the decline in creatinine production with age.
    • Any formula estimating the creatinine clearance from the serum creatinine concentration presupposes that the serum creatinine is a stable value. For example, patients who develop acute renal failure have a low glomerular filtration rate which will cause creatinine to be retained leading to an elevation in the serum creatinine concentration. Thus, until a stable serum creatinine level is reached, the above formula might overestimate the creatinine clearance. Alternately, during recovery from acute renal failure, the fall in serum creatinine concentration will lag behind the improvement in glomerular filtration rate due to the time required for excretion of the retained creatinine.
    • Certain disease states or other factors may also alter the relationship between the serum creatinine concentration and creatinine clearance. In particular, creatinine production (and therefore the serum creatinine concentration) is reduced in severe liver disease, malnutrition and significant loss of muscle mass (such as quadriplegia, paraplegia or amputation), possibly resulting in an overestimation of the creatinine clearance with the above formula unless there has been an equivalent reduction in body weight.

Traditional Versus Extended-Interval Dosing Strategy

Parenteral aminoglycosides can be administered using two different dosing strategies:

  • Traditional intermittent dosing strategy which uses smaller doses given several times each day.
  • Extended-interval dosing strategy which uses high doses administered at an extended interval.

Extended-interval aminoglycoside dosing has efficacy comparable with traditional intermittent administration but offers four potential advantages:

  • Possibility of decreased nephrotoxicity
  • Ease of administration and serum concentration monitoring
  • Reduction in administration times and monitoring-related costs
  • May help facilitate the transition from inpatient to outpatient care

Extended-interval dosing of aminoglycosides takes advantage of two pharmacodynamic properties:

  • Post-antibiotic effect which refers to the persistent inhibitory effect against many gram-negative aerobic organisms that is seen after drug clearance.
  • A concentration-dependent killing which refers to the ability to escalate concentrations of aminoglycosides to induce more rapid killing of the pathogen.

Selection of Dosing Strategy

Extended-interval (instead of traditional intermittent) aminoglycoside dosing is often preferred for patients with suspected or documented moderate to severe infections due to gram-negative aerobic bacteria because of comparable efficacy and safety with superior pharmacodynamic profiles and greater ease of administration. These include:

  • Bacteremia
  • Febrile neutropenia patients with malignancy (adults and children)
  • Gynecologic infections (including pelvic inflammatory disease)
  • Immunocompetent, non-pregnant adults and children older than three months of age with:
    • Intraabdominal infections
    • Postpartum endometritis
    • Respiratory tract infections
    • Soft-tissue infections
    • Urinary tract infections

Extended-interval dosing strategies have also been evaluated in patients with cystic fibrosis and for synergistic therapy for patients with select serious gram-positive infections. Typical doses used for these populations are considerably higher and lower (respectively) than those used for other indications.

Use of extended-interval dosing of gentamicin (at 5 mg/kg in adults) is an alternative regimen for surgical prophylaxis in select procedures in patients with beta-lactam allergies.

Extended-interval dosing is not advised for certain patient groups who may have altered aminoglycoside pharmacokinetics (independent of the method of dosing) that render extended-interval dosing less useful and/or who may be more likely to have aminoglycoside toxicity when administered at high doses. These groups include:

  • Patients with burns greater than 20% total body surface area
  • Patients with ascites
  • Pregnant women
  • Patients with creatinine clearance less than 40 mL/min (including patients requiring dialysis) OR greater than 120 mL/min

Gentamicin and Tobramycin Dosing in Adults

Traditional Intermittent Dosing and Monitoring:

  • Administration of an initial loading dose which is determined by type or site of infection, for which different peak serum gentamicin or tobramycin concentrations are desired.
  • Initial maintenance dose and dosing interval
    • For maintenance dosing, a specific percentage of the loading dose is given at a specific dosing interval both of which depend on the creatinine clearance, an estimate of glomerular filtration rate. In those patients in whom a loading dose was not given, the maintenance dose is still determined by the estimated loading dose for the indication.
  • Subsequent monitoring of serum concentrations of gentamicin or tobramycin to guide dose adjustments.
    • In order to meet the desired target concentrations, both the maintenance dose and the dosing interval may need to be adjusted based on the results of drug concentration monitoring.
      • "Target" concentrationswhich are defined as the desired peak concentrations for gentamicin and tobramycin are dependent upon the indication and site of infection.
    • Monitoring of serum aminoglycoside concentrations is essential to ensure efficacy and to avoid toxicity. Routine measurement of serum aminoglycoside concentrations is not necessary with prophylactic therapy given for less than 24 hours.
    • The timing of serum concentrations should be determined when the patient has received therapy for three to five half-lives of the drug (typically around two to three maintenance doses or after adjustment of the dose).
    • The peak levels of gentamicin vary as to the indications for usage i.e. when the drug is being given for synergy, in the treatment of serious, invasive infections, and the susceptibility of the organism in targeted patient populations such as cystic fibrosis.
    • Trough concentrations for gentamicin and tobramycin should be below 2 mcg/mL.
    • Peak concentrations are drawn 30 to 45 minutes after the end of an intravenous infusion or approximately 60 minutes after an intramuscular injection. Trough concentrations are measured within 30 minutes of the next dose.
    • An accurate record of aminoglycoside administration times and the time the samples are obtained is essential in interpreting the results. Thus, sample times should be documented on the laboratory requisition. Drug administration records should be checked to verify that doses have been administered as scheduled.
    • Dosing adjustments
      • In general, changes in the dose will result in proportional changes in both peak and trough concentration values.
      • Changes in the dosing interval while keeping the dose constant will also result in similar directional changes to both peak and trough, although such changes are not proportional. Therefore, calculation of patient-specific pharmacokinetic parameters (most frequently performed by institution-based pharmacists) is the optimal method to determine needed dose and frequency modification based on serum concentration values.
    • Once the desired peak and trough serum concentrations are achieved, serum aminoglycoside concentrations should be re-evaluated throughout therapy when there are any changes in renal function.
      • Serum aminoglycoside monitoring should be repeated at least weekly if therapy will be prolonged beyond 7 to 10 days.

Extended-Interval Dosing and Monitoring

Administration of a higher dose of gentamicin or tobramycin at an extended-interval is dependent on renal function and subsequent monitoring of serum drug concentrations.

  • Calculation of dosing weight and creatinine clearance, both of which are important for dose and dosing interval determination.
  • Administration of a loading dose and dosing interval
    • A loading dose is not needed in the setting of extended-interval aminoglycoside administration.
  • Subsequent monitoring of serum concentrations of gentamicin or tobramycin to guide dose adjustments
    • When an extended-interval daily dosing strategy is employed, the timing and frequency of serum drug concentration monitoring differ from those used in traditional intermittent dosing. Concentrations can be targeted either by using a published nomogram that extrapolates desired dosing interval based on a single drug concentration or by analysis of two or more serum concentrations checked during the dosing cycle.
    • “Target concentrations” for extended-interval aminoglycoside dosing:
      • Targets a peak serum concentration of approximately 15 to 20 mcg/mL for gentamicin and tobramycin in order to target approximately ten times the MIC of the pathogen.
      • Trough serum concentrations should be less than 1 mcg/mL (are most often undetectable) because of the long dosing interval. The estimated drug-free interval (i.e., concentration = 0) is less than 8 hours.
    • Nomogram-based monitoringrequires that a single serum concentration is obtained 6 to 14 hours after the first dose. Results from this measurement are then used to determine the necessary dosing interval.
      • Although unlikely to result in peak serum concentrations below the desired target value when doses of 7 mg/kg are employed, single-concentration serum monitoring requires assumptions that individual patients exhibit kinetic parameters comparable to other patients. Patients not conforming to usual population kinetic parameters may have suboptimal serum aminoglycoside concentrations if doses are calculated from the standard nomogram. Appropriate patient selection should significantly reduce the risk of such variability.
    • Individualized monitoring is used as an alternative to the use of the nomogram in order to obtain a peak serum aminoglycoside concentration (60 minutes post-infusion) and a second level (trough) approximately 6 to 12 hours after the first or second dose.
      • Additional samples may be obtained during the course of therapy (e.g., sample 6 to 12 hours post-infusion after the same dose) to verify that concentrations have not changed significantly. The disadvantage of this method is the requirement of more sophisticated analyses (usually performed by pharmacists).

For either traditional intermittent dosing and monitoring or extended-interval dosing and monitoringindications to repeat the measurement of drug concentrations are changing renal function and duration of therapy beyond 7 to 10 days.

Regardless of the method used to determine patient dosing needs, sampling times must be documented by the phlebotomist for accurate interpretation of results. In addition, requests for laboratory determinations of serum levels should include a provision to indicate that extended-interval dosing is being utilized. Since serum levels obtained (especially the peak levels) will be substantially different from those obtained with traditional intermittent dosing, clinicians, pharmacists and laboratory personnel need to know the dosing method for appropriate interpretation.

Amikacin Dosing in Adults

Traditional Intermittent Dosing and Monitoring:

  • Administration of a loading dose
  • Administration of a subsequent maintenance dose which is typically ordered in divided doses every 8 - 12 hours for patients with normal renal function. Adjustments in the frequency of administration should be made for reductions in renal function.
  • Subsequent monitoring of serum concentrations of amikacin guide dose adjustments
    • Target serum concentration for traditional dosing of amikacin is a peak of 20 to 30 mcg/mL.
    • Higher peak concentrations (up to 40 mcg/mL) are often recommended for serious, life-threatening infections such as nosocomial pneumonia.
    • Trough of less than 8 mcg/mL (often targeted at 1 to 4 mcg/mL).
    • Higher peaks (40 to 50 mcg/mL) are generally achieved with extended-interval dosing.

Extended-Interval Dosing and Monitoring

  • Administration of a loading dose (usually a 15 mg/kg dose is administered).
  • The initial dosing interval is based upon the estimated (or measured) creatinine clearance.
  • Subsequent monitoring of serum concentrations of amikacin guide dose adjustments.
    • Subsequent drug concentration monitoring and dosing interval determination are similar to those for gentamicin and tobramycin without the use of the nomogram.

Streptomycin Dosing in Adults

The dosing of streptomycin varies based on the indications for its use such as:

  • Second-line antituberculous therapy
  • Antimicrobial therapy of native valve endocarditis
  • Treatment of nontuberculous mycobacterial infections of the lung in HIV-negative patients
  • Treatment of tularemia
  • Treatment of plague

Streptomycin is approved for intramuscular administration. Intravenous use is not recommended.

Significant Adverse Reactions to Aminoglycosides

Aminoglycosides
GeneralizedFever
Central Nervous System

Abnormal gait
Ataxia*
Confusion
Depression
Disequilibruim*
Disorientation
Dizziness
Drowsiness
Drug fever
Headache
Lethargy
Lightheadedness*
Seizure activity*
Vertigo*
Myasthenia
Paresthesia of the face
Pseudomotor cerebri

OpthalmicAmblyopia
Visual disturbance
OticAuditory ototoxicity*
Hearing loss*
Tinnitus*
Vestibular ototoxicity*
CardiovascularEdema
Hypertension/Hypotension
RespiratoryDyspnea
Laryngeal edema
Pulmonary fibrosis
Respiratory depression
Neuromuscular and Skeletal

Arthralgia
Muscle cramps
Muscle fatigue (Myasthenia gravis-like symtpoms)
Muscle twitching*
Numbness*
Paresthesia
Perpheal neurophathy
Tremor
Weakness

Endocrine and MetabolicDecreased serum calcium
Decreased serum magnesium
Decreased serum potassim
Decreased serum sodium
Increased lactate dehydrogenase
Increased nonprotein nitrogen
Weight loss
Dermatologic

Alopecia
Angioedema
Erythema
Exfoliative dermatitis
Pruritis
Skin rash
Skin tingling*
Urticaria

GastrointestinalAzotemia
Casts in urine
Changes in distal tubules (dysfunction)
Decreased creatinine clearance
Decreased urine specific gravity
Fanconi-like symptoms
Increased blood urea nitrogen
Increased serum creatinine
Nephrotoxicity
Oliguria
Proteinuria
Polyuria
Renal failure
Renal tubular necrosis
Hematologic and OncologicAgranulocytosis
Anemia
Eosinophilia
Granulocytopenia
Hemolytic anemia
Leukocytosis
Leukopenia
Pancytopenia
Purpura
Reticulocytopenia
Reticulocytosis
Thrombocytopenia
 
Hepatic

Increased serum ALT
Increased serum AST
Increased serum bilirubin
Hepatiomegaly
Splenomegaly

Hypersensitivity 

Anaphylactoid reaction
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Erythema mutiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis

LocalPain at local injection site
Phlebitis
Thrombophlebitis
* US Boxed Warning

Aminoglycoside Toxicity

Aminoglycoside toxicity may cause neurotoxicity:

  • Neurotoxicity may be manifested as both auditory and vestibular ototoxicity:
    • The auditory changes are:
      • Usually irreversible
      • Usually bilateral
      • May be partial or total
    • Risk factors for aminoglycoside-induced hearing loss are:
      • Increased with the degree of exposure to either high peak or high trough serum concentrations.
      • Increased in patients having preexisting renal damage and in those with a healthy renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended.
    • Manifestations of vestibular toxicity include:
      • Ataxia
      • Disequilibrium
      • Lightheadedness
      • Nausea
      • Vertigo
      • Vomiting
    • Manifestations of cochlear toxicity are:
      • Hearing loss
      • Tinnitus
    • Ototoxicity is proportional to the amount of drug given and the duration of treatment.
    • High-frequency deafness usually occurs first and can be detected only by audiometric testing.
    • Tinnitus or vertigo may be indications of vestibular injury and impending bilateral irreversible damage.
    • Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued.
    • Discontinue treatment if signs of ototoxicity occur although the risk of hearing loss continues after drug withdrawal.
  • Neurotoxicity may also be manifested by nephrotoxicity:
    • Usual risk factors include:
      • Patients with pre-existing renal impairment
      • Patients with a healthy renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended.
      • Those patients who are taking concomitant neuro/nephrotoxic medications
      • Advanced age
      • Dehydration
    • Nephrotoxicity may not become apparent until the first few days after cessation of therapy.
    • Aminoglycoside-induced nephrotoxicity usually is reversible.
    • Discontinue treatment if signs of nephrotoxicity occur.
  • Other manifestations of neurotoxicity may include:
    • Numbness
    • Skin tingling
    • Muscle twitching
    • Seizure activity

Aminoglycoside toxicity may cause neuromuscular blockade: 

  • Neuromuscular blockade, respiratory failure and prolonged respiratory paralysis have been reported following parenteral injection, topical instillation (as with orthopedic and abdominal irrigation or with local treatment of empyema) and following oral use of aminoglycosides.
  • Risk factors include:
    • Administration of aminoglycosides by any route, especially in patients:
      • Who have disease states and/or concomitant drug therapy that interfere with neuromuscular transmission
      • Who are receiving anesthetics
      • Receiving neuromuscular blocking agents such as tubocurarine, succinylcholine and decamethonium
      • Receiving massive transfusions of citrate-anticoagulated blood. (If blockade occurs, calcium salts may reverse these phenomena, but mechanical respiratory assistance may be necessary).

Monitoring Parameters Related to Adverse Effects of Aminoglycosides

Patients should be monitored for:

  • Overall Physical Parameters
    • Strict intake and output
    • Vital signs including pulse oximetry
    • Weight
  • Toxicity 
    • Ototoxicity
      • Subjective patient assessment for the presence of auditory and vestibular dysfunction.
      • The use of objective testing, such as audiometry or electronystagmography, is generally reserved for patients who have subjective symptoms or preexisting auditory dysfunction.
      • Baseline and periodic hearing tests (audiograms).
      • Hearing via audiograms should be tested before, during and after treatment especially in patients at risk for ototoxicity or who will be receiving prolonged therapy (greater than 2 weeks).
      • Serial audiograms should be obtained in patients old enough to be tested, particularly high-risk patients.
      • Evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears or hearing loss) or nephrotoxicity requires a dosage adjustment or discontinuance of the drug.
  • Nephrotoxicity
    • Examine urinalysis for:
      • Decreased urine specific gravity
      • Proteinuria
      • Presence of cells or casts
  • Examine creatinine clearance for:
    • Decreased or increased creatinine clearance (CrCL)
  • Examine blood serum at baseline and periodically during chronic therapy for:
    • Increased serum urea nitrogen (BUN)
    • Increased serum creatinine (Cr)
  • Serum Drug Concentrations
    • Monitor initial and appropriately timed periodic serum concentrations of aminoglycosides (e.g., peak and trough with traditional intermittent dosing, post dose level at a prespecified time with extended-interval dosing) particularly in critically-ill patients with serious infections or while in disease states known to significantly alter aminoglycoside pharmacokinetics (e.g., cystic fibrosis, burns or major surgery).
      • When monitoring peak concentrations, the dosage should be adjusted so that prolonged high levels are avoided.
      • When monitoring trough concentrations, the dosage should be adjusted so that high levels are avoided.
      • Excessive peak or trough serum concentrations of aminoglycosides may increase the risk of renal and eighth cranial nerve toxicity.
  • Hypersensitivity Reactions
    • Discontinue use if an allergic reaction occurs.
    • Hypersensitivity: Cross-sensitivity to other aminoglycosides may occur.
  • Superinfections
    • Prolonged use of aminoglycosides may result in fungal or bacterial superinfection, including Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis. CDAD has been observed two months or longer after post antibiotic treatment.
  • Drug-Drug Interactions
    • Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring and/or selection of alternative therapy.

Contraindications

  • Hypersensitivity to aminoglycosides or any component of the formulations.
  • Avoid concurrent and/or sequential use of other neurotoxic or nephrotoxic drugs, particularly other aminoglycosides (e.g., amikacin, streptomycin, neomycin, kanamycin, gentamicin, paromomycin, tobramycin), cephaloridine, cyclosporine, amphotericin B, bacitracin, viomycin, polymyxin B, colistin, cisplatin and vancomycin. The toxicity may be additive. Other factors that may increase patient risk are advanced age and dehydration.
  • Do notgive aminoglycosides concurrently with potent diuretics, such as ethacrynic acid and furosemide. Some diuretics themselves cause ototoxicity and intravenously (IV) administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.
  • Avoid use of aminoglycosides as surgical irrigation due to risks of irreversible deafness, renal failure and death.
  • Myasthenia gravis is an absolute contraindication to aminoglycoside use, regardless of dosing method used.

Other Warnings/Precautions

  • Sulfites: Aminoglycoside preparations may contain sulfites which may cause allergic-type reactions (including anaphylaxis), as well as, life-threatening or less severe asthmatic episodes in certain individuals.
  • Use with caution in patients with pre-existing vertigo, tinnitus or hearing loss.
  • Use with caution in patients with hypocalcemia.
  • Use with caution in patients with neuromuscular disorders, including myasthenia gravis and Parkinson disease.
  • Use with caution in patients with pre-existing renal insufficiency. Dosage modification may be required during systemic therapy.
  • Systemic therapy is not intended for long-term therapy due to toxic hazards associated with extended administration.
  • Some penicillin derivatives may accelerate the degradation of aminoglycosides. This may be clinically significant for certain penicillin (ticarcillin, piperacillin, carbenicillin) and aminoglycoside (gentamicin, tobramycin) combination therapy in patients with significant renal impairment. Close monitoring of aminoglycoside levels is warranted.
  • IM injections should be administered in a large muscle well within the body to avoid peripheral nerve damage and local skin reactions.
  • Small amounts of neomycin are absorbed through intact intestinal mucosa which may result in increases in fecal bile acid excretion and reduction of intestinal lactase activity. Oral doses of greater than12 g/day produce malabsorption of fats, nitrogen, cholesterol, carotene, glucose, xylose, lactose, sodium, calcium, cyanocobalamin and iron. 

Use During Pregnancy and Breastfeeding

Aminoglycosides
AgentsPregnancy Risk FactorBreastfeeding Considerations

Neomycin Sulfate
Amikacin
Gentamicin
Kanamycin Sulfate
Spectinomycin
?Streptomycin
Tobramycin

D*Due to the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother. 
* See Appendix A

Resistance

The aminoglycosides have demonstrated relative stability against the development of resistance compared to other classes of antibiotics. However, both intrinsic and acquired mechanisms of resistance to aminoglycosides have occurred.

Aminoglycoside resistance among gram-negative organisms can occur through acquisition or upregulation of genes that encode inactivating enzymes or efflux systems.

The resistance of gram-negative organisms to aminoglycosides occurs by two major mechanisms:

  • Bacterial production of inactivating enzymes.
  • Methylation of 16S ribosomal RNA. This effect is mediated by an enzyme encoded by the rmtA gene and has been associated with high-level resistance to all parenteral aminoglycosides in current use. Binding to the aminoacyl site on 16S ribosomal RNA is the mechanism by which aminoglycosides normally interfere with protein synthesis.

Enterococci are intrinsically resistant to low to moderate levels of aminoglycosides. The minimum inhibitory concentrations (MICs) of gentamicin are usually 8 to 64 mcg/mL, and those of streptomycin are 64 to 512 mcg/mL. However, the potential for synergy exists when enterococci with low-level resistance to an aminoglycoside are exposed to a combination of the aminoglycoside with a cell wall active agent, such as penicillin or vancomycin. There are increasing reports of acquired high-level enterococcal resistance to aminoglycosides (MIC greater than 2,000 mcg/mL). The significance of such high-level resistance is that it eliminates the synergism expected between an aminoglycoside and a cell wall active agent. Different genetic mutations are responsible for high-level resistance to different aminoglycosides.

While cross-resistance between the specific aminoglycoside agents does occur, it is incomplete. Therefore, individual agents should be tested for susceptibility against the isolated pathogen whenever possible.

Dosing for Special Circumstances

Dose adjustments need to be made in a variety of special populations.

Renal Impaired Patients

  • Peritoneal dialysis
    • Gentamicin and tobramycin are frequently used for empiric treatment of continuous ambulatory peritoneal dialysis (CAPD) related peritonitis. The intraperitoneal concentrations of gentamicin or tobramycin most commonly targeted are 4 to 8 mg/L of dialysate.
    • Patients with systemic illness may receive an intravenous loading dose.
  • Intermittent hemodialysis
    • Intermittent hemodialysis can decrease pre-dialysis concentrations by 50%. Therefore, patients undergoing intermittent hemodialysis generally require supplemental doses of gentamicin or tobramycin after each dialysis (depending on the time lapsed after the first dose and characteristics of the dialysis delivered).
  • Continuous AV hemofiltration
    • Similar to that observed in patients with intermittent hemodialysis, significant inter-patient variability exists among patients undergoing continuous arteriovenous (AV) hemofiltration. Empiric initial daily gentamicin or tobramycin doses of 2.5 mg/kg administered once daily should be followed by serum concentration monitoring to assure adequate peak and trough concentrations.

Cystic Fibrosis Patients

  • Both the volume of distribution and clearance of aminoglycosides are greatly increased in patients with cystic fibrosis, necessitating higher starting doses with both traditional intermittent and extended-interval dosing to achieve target serum concentrations.

Burn Patients

  • Patients with significant burns may exhibit larger volumes of distribution when compared with most patient populations.
  • As a result, larger maintenance doses of gentamicin and tobramycin per day in divided doses may be needed to attain therapeutic serum aminoglycoside concentrations. Serum concentration monitoring and individualized dosing correlates with survival in this patient population.

Septic Patients

  • Septic patients undergoing aggressive fluid resuscitation in the setting of resolving or evolving acute renal failure often warrant especially close monitoring. Some suggest individualized monitoring for such patients.
  • Peak concentrations of aminoglycosides may be affected by high volumes of intravenous fluids or extravascular fluid shifts, requiring adjustments in the determination of pharmacokinetic parameters (such as volume of distribution).

Elderly Patients

  • Since many elderly patients have reduced renal function and/or are receiving concomitant nephrotoxic agents, caution should be used in prescribing aminoglycosides in this patient population.
  • Reduced muscle mass and the resulting reductions in serum creatinine concentration in the elderly may result in overestimation of renal function when formulas such as the Cockcroft-Gault equation are utilized. Therefore, a relatively normal serum creatinine may be associated with a substantial loss of renal function in this patient population. A creatinine increase greater than 50% over baseline requires careful evaluation of urine output and urinalysis for evidence of drug-induced nephrotoxicity.

Synergy for Gram-Positive Infections

  • Lower concentrations of aminoglycosides are targeted when used in combination with other agents to treat serious gram-positive infections, whether traditional intermittent or extended-interval dosing intervals are used.

Dosing: Adult

In underweight and non-obese patients, use of total body weight (TBW) instead of ideal body weight for determining the initial mg/kg/dose is widely accepted. Ideal body weight (IBW) also may be used to determine doses for patients who are neither underweight nor obese.

Dosing: Obesity

In moderate obesity (TBW/IBW ≥1.25) or greater, (e.g., morbid obesity [TBW/IBW >2]), initial dosage requirement may be estimated using a dosing weight of IBW + 0.4 (TBW - IBW).

Dosing: Hepatic Impairment

No dosage adjustment for aminoglycosides is necessary since they do not undergo hepatic metabolism.

Administration

IV Infusion:

  • Administer by intermittent infusion over 30 to 60 minutes.
  • Higher doses are generally administered over 60 minutes.
  • Flush line with appropriate solution both before and after administration of the aminoglycoside.

IM Injection:

  • Inject deep IM into large muscle mass, e.g., mid-lateral thigh muscle or upper outer quadrant of buttocks
  • Rotate injection sites

Summary

Optimal dosing of aminoglycosides should lead to rapid attainment of therapeutic concentrations which has been correlated with improved outcomes while minimizing toxicity. The first steps in aminoglycoside administration include determination of the dosing weight and estimation of renal function.

Parenteral aminoglycosides can be administered using a traditional intermittent dosing strategy which uses smaller doses given several times each day or an extended-interval dosing strategy which uses high doses administered at an extended interval. These two strategies have comparable efficacy and safety. High dose extended-interval administration takes advantage of the pharmacodynamic properties of aminoglycosides and offers greater ease of preparation, administration and monitoring.

For most patients with suspected or documented moderate to severe infections due to gram-negative aerobic bacteria in whom an aminoglycoside is being used and who are expected to exhibit more predictable aminoglycoside pharmacokinetics, extended-interval rather than traditional intermittent dosing is preferred. Certain patient groups may exhibit altered aminoglycoside pharmacokinetics that could render extended-interval dosing less useful or effective. Extended-interval dosing is not advocated for the following patients:

  • Patients with burns (greater than 20% total body surface area)
  • Patients with ascites
  • Pregnant women
  • Patients with creatinine clearance less than 40 mL/min (including patients requiring dialysis, although some institutions use a lower threshold) OR greater than 120 mL/min

Traditional intermittent dosing of gentamicin and tobramycin in adults involves administration of a loading dose based on indication, administration of a maintenance dose at a specific interval several times daily (depending on renal function) and subsequent monitoring of serum concentrations to guide dose adjustments.

Extended-interval dosing of gentamicin and tobramycin in adults involves administration of a higher dose administered at an extended interval based upon the estimated (or measured) creatinine clearance. Extended-interval dosing targets a peak serum concentration of 15 to 20 mcg/mL and trough concentrations less than 1 mcg/mL. Dose adjustments should be made using a published nomogram or through individualized monitoring with the assistance of a pharmacist.

Target serum concentration for amikacin is a peak of 20 to 30 mcg/mL and a trough of at less than 8 mcg/mL (often targeted at 1 to 4 mcg/mL). Higher peak concentrations (up to 40 mcg/mL) are often recommended for serious, life-threatening infections. For patients receiving traditional intermittent dosing of amikacin, the usual loading dose is 7.5 mg/kg, with a subsequent maintenance dose of 15 mg/kg per day in two or three divided doses. For patients receiving extended-interval dosing of amikacin, a 15 mg/kg dose is administered. The initial dosing interval is based upon the estimated (or measured) creatinine clearance.

Specific or additional dosing adjustments are indicated in certain populations, including dialysis patients, burn patients, the elderly and those receiving aminoglycosides as synergistic therapy with beta-lactams for serious gram-positive infections. Septic patients undergoing aggressive fluid resuscitation in the setting of resolving or evolving acute renal failure often warrant especially close monitoring.

For serious infections due to typical gram-negative bacteria, with the exception of uncomplicated lower urinary tract infections, aminoglycosides are generally used in combination with other agents that have gram-negative activity, regardless of dosing method.

Tetracycline and Glycylcycline Antibiotics

Tetracycline Antibiotics
AgentsCommon Brand Name(s)Route(s)*
Chlortetracycline_________________________________Used primarily in veterinary medicine
TetracyclineTetracycline HCIOral
DemeclocyclineDemeclocycline HClOral
Doxycycline

Acticlate, Adoxa, Adoxa Pak 1/100;

Adoxa Pak 1/150, Adoxa Pak 2/100,

Avidoxy, Doryx, Doryx MPC, Doxy100,

Mondoxyne NL, Monodox, Morgidox, Oracea, TargaDOX, Vibramycin

Oral, IV infusion
Minocycline

Dynacin, Minocin, Minocycline HCL, Solodyn

Oral, IV infusion
Glycylcycline Antibiotic
AgentsCommon Brand Name(s)Route(s)
TigecyclineTygacilIV infucion
* Only oral and IV infusion routes will be considered in this learning module

Mechanism of Action

The tetracyclines enter the bacterial cell wall in two ways: passive diffusion and an energy-dependent active transport system, which is probably mediated in a pH-dependent fashion. Once inside the cell, tetracyclines bind reversibly to the 30S ribosomal subunit at a position that blocks the binding of the aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. Protein synthesis is ultimately inhibited leading to a bacteriostatic effect.

Tigecycline is a derivative of minocycline (9-t-butylglycylamido minocycline), and while not classified as a tetracycline, it may share some class-associated adverse effects.  Tigecycline, a glycylcycline antibiotic, binds to the 30S ribosomal subunit of susceptible bacteria, thereby inhibiting protein synthesis. It is generally considered bacteriostatic; however, bactericidal activity has been demonstrated against isolates of Streptococcus pneumoniae and Legionella pneumophila.

Microbiology

The tetracyclines and tigecycline are considered broad-spectrum bacteriostatic antibiotics that are used to treat infection caused by many gram-positive and gram-negative bacteria and many atypical pathogens. These therapeutic agents have little activity against fungi and viruses. Tigecycline has a broader spectrum of activity when compared to the other tetracyclines.

Tetracyclines and tigecycline have antibacterial activity against susceptible:

  • Gram-positive organisms:
    • Actinomyces
      • Actinomyces israelli
    • Bacillus
      • Bacillus anthracis
    • Clostridium
    • Enterococcus
      • Vancomycin-resistant enterococci (VRE)
      • Enterococcus faecalis (vancomycin-susceptible)
    • Listeria
      • Listeria monocytogenes
    • Peptostreptococcus
      • Peptostreptococcus micros
    • Propionibacterium
      • Propionibacterium acnes
    • Staphylococcus
      • Staphylococcus aureus (both methicillin-susceptible and methicillin-resistant)
      • Staphylococcus epidermidis (both methicillin-susceptible and methicillin-resistant
    • Streptococcus
      • Streptococcus anginosus
      • Streptococcus agalactiae
      • Streptococcus intermedius
      • Streptococcus constellatus
      • Streptococcus pneumoniae (penicillin-susceptible)
      • Streptococcus pyogenes
  • Gram-negative organisms:
    • Acinetobacter
      • Actinobacillus actinomycetemcomitans
    • Bacteroides
      • Bacteroides fragilis
      • Bacteroides thetaiotaomicron
      • Bacteroides uniformis
      • Bacteroides vulgatus
    • Bartonella
      • Bartonella bacilliformis
    • Campylobacter
      • Campylobacter fetus
      • Campylobacter pylori (now known as Helicobacter pylori)
    • Citrobacter
      • Citrobacter freundii
    • Clostridium
      • Clostridium perfringens
    • Escherichia
      • Escherichia coli
    • Enterobacter
      • Enterobacter aerogenes
      • Enterobacter cloacae
    • Fusobacteriales
      • Fusobacterium fusiforme
    • Haemophilis
      • Haemophilus ducreyi
      • Haemophilus influenza(upper respiratory tract only)
    • Klebsiella
      • Klebsiella granulomatis
      • Klebsiella oxytoca
      • Klebsiella pneumoniae (lower respiratory tract only)
    • Legionella
      • Legionella pneumophila
    • Neisseria
      • Neisseria meningitides
      • Neisseria gonorrhea
    • Pasteurella
      • Pasteurella multocida
    • Serratia
      • Serratia marcescens
    • Shigella
    • Stenotrophomonas
      • Stenotrophomonas maltophilia
    • Vibrio
      • Vibrio cholera
      • Vibrio vulnificus
  • Atypical pathogens such as:
    • Burkholderia
      • Burkholderia pseudomalle
    • Chlamydia
      • Chlamydia trachomatis
    • Coxiella
      • Coxiella burnetii
    • Entamoeba
      • Entamoeba histolytica
    • Leptospira
    • Mycobacterium
      • Mycobacterium marinum
    • Mycoplasma
      • Mycoplasma pneumoniae (lower respiratory tract only)
    • Plasmodium
    • Rickettsiae
    • Treponema
      • Treponema pallidum
    • Ureaplasma
      • Ureaplasma urealyticum
  • Zoonotic infections such as:
    • Borrelia
      • Borrelia burgdorferi
      • Borrelia recurrentis
    • Brucella
    • Chlamydophila
      • Chlamydophila psittaci
    • Francisella
      • Francisella tularensis
    • Yersinia
      • Yersinia pestis

Indications and Usage

Clinical indications and uses of tetracyclines and tigecycline include:

  • Acne (inflammatory, non-nodular, moderate to severe)
  • Actinomycosis (when penicillin contraindicated)
  • Acute intestinal amebiasis
  • Anthrax (when penicillin contraindicated)
  • Asymptomatic carriers of Neisseria meningitides: To eliminate the meningococci from the nasopharynx of asymptomatic carriers
  • Borrelia recurrentis
  • Campylobacter
  • Cholera (when penicillin contraindicated)
  • Chlamydial or Ureaplasma urealyticum infection
  • Clostridium (when penicillin contraindicated)
  • Gram-negative infections
  • Intra-abdominal infections (complicated)
  • Listeriosis (when penicillin contraindicated)
  • Malaria chemoprophylaxis
  • Meningitis
  • Meningococcal carrier state
  • Mycobacterium marinum
  • Ophthalmic infections:
    • Inclusion conjunctivitis
    • Trachoma
  • Periodontitis
  • Relapsing fever
  • Respiratory tract infections:
    • Bronchitis and/or Pneumonia (community-acquired, bacterial)
  • Rickettsial infections:
    • Rocky Mountain Spotted Fever
    • Tick fever
    • Typhus group infections
    • Q fever
    • Rickettsialpox
  • Rosacea
  • Sexually transmitted diseases:
    • Chancroid caused by Haemophilus ducreyi
    • Granuloma inguinale (donovanosis) caused by Klebsiella granulomatis
    • Infections in women caused by Neisseria gonorrhea
    • Lymphogranuloma venereum caused by Chlamydia trachomatis
    • Nongonococcal urethritis caused by Ureaplasma urealyticum or Chlamydia trachomatis
    • Syphilis caused by Treponema pallidum (when penicillin contraindicated)
    • Uncomplicated urethral, endocervical, or rectal infections in adults caused by Ureaplasma urealyticum or Chlamydia trachomatis
    • Uncomplicated urethritis in men caused by Neisseria gonorrhea and other uncomplicated gonococcal infections (when penicillin contraindicated)
  • Skin and skin structure infections (complicated) caused by:
    • Bacteroides fragilis
    • Enterococcus faecalis (vancomycin-susceptible)
    • Enterobacter cloacae
    • Escherichia coli
    • Klebsiella pneumoniae
    • Staphylococcus aureus (both methicillin-susceptible and methicillin-resistant)
    • Streptococcus agalactiae
    • Streptococcus anginosus
    • Streptococcus constellatus
    • Streptococcus intermedius
    • Streptococcus pyogenes
  • Tularemia (mild to moderate)
  • Urinary tract infections caused by Klebsiella species or Escherichia coli
  • Vincent infection (when penicillin contraindicated)
  • Yaws (when penicillin contraindicated)
  • Zoonotic infections:
    • Bartonellosis caused by Bartonella bacilliformis
    • Brucellosis caused by Brucella species
    • Infections caused by Campylobacter fetus
    • Plague due to Yersinia pestis
    • Psittacosis (ornithosis) caused by Chlamydophila psittaci
    • Tularemia caused by Francisella tularensis

 off-labeluses of tetracyclines and tigecycline include:

  • Acute bacterial rhinosinusitis
  • Bacillary angiomatosis, cutaneous
  • Bartonella infection in HIV-infected patients
  • Bite wounds (animal/human)
  • Cellulitis (purulent) due to community-acquired MRSA
  • Cervicitis due to Chlamydia trachomatis
  • Chronic oral antimicrobial suppression:
    • Propionibacterium (alternative to penicillin or amoxicillin)
    • Staphylococci (oxacillin-resistant)
  • Chronic syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
  • Community-acquired MRSA infection (alternative treatment)
  • Epididymitis (most likely caused by Chlamydia trachomatis or Neisseria gonorrhoeae)  
  • Gonococcal (uncomplicated) infection of the cervix, rectum or urethra
  • Helicobacter pylori eradication
  • Lyme disease
  • Malaria (uncomplicated, severe)
  • Necrotizing infection due to Aeromonas hydrophila or Vibrio vulnificus
  • Nocardiosis, cutaneous (non-CNS)
  • Pelvic inflammatory disease
  • Periodontitis (refractory)
  • Proctitis, proctocolitis, enteritis
  • Prosthetic Joint Infection
    • Staphylococci (oxacillin-sensitive or oxacillin-resistant)
    • Total ankle, elbow, hip or shoulder arthroplasty
    • Total knee arthroplasty
  • Rheumatoid arthritis
  • Sclerosing agent for pleural effusion
  • Skin and soft tissue infections due to MSSA or MRSA

Pharmacodynamics and Pharmacokinetics of Tetracyclines and Tigecycline

Tetracyclines and Glycylcycline
Absorption

Oral: 66% to 88% depending on the therapeutic agent.

Absorption of the oral tetracyclines occurs primarily in the proximal small intestine and the stomach.

The extent of absorption is reduced by food and by certain antacids and dairy products containing aluminum, calcium, magnesium, and iron.

Time to Peak, Serum

Oral: 1 50 4 hours depending on the therapeutic agent.

IV infusion: 30 minutes to 1 hour depending on the therapeutic agent.

Distribution

In general, tetracyclines penetrate into tissues and body fluids fairly well. Among the following therapeutic agents, the degree of tissue penetration correlates to liquid solubility: minocycline> doxydycline >tetracycline.

Tetracycline: distributes well into most body fluids and tissues including ascetic, synovial, and pleural fluids and bronchial secretions. Poor penetration into CSF.

Doxycycline: therapeutic concentrations have been widely distributed in the body tissues and fluids including synovial, pleural, prostatic, seminal fluids, bronchial secretions, saliva and aqueous humor. CSF penetration is poor.

Minocycline: therapeutic concentrations have been found in the aqueous humor, bile, duodenum, fallopian tubes/ovaries, liver, lung, sinuses, saliva, sputum, tears, and thyroid gland. Minocycline distributes in lower concentrations to the bladder, breast, lymph nodes, prostate, and skin. Poor CSF penetration. Deposits in fat or extended periods.

Tigecycline: therapeutic concentrations have been widely distributed in tissues, gallbladder, lung and colon.

All the tetracyclines and tigecycline cross the placenta and accumulate in the gone and teeth of the fetus. They are also excreted in breast milk.

Protein Binding40% to 90% depending on the therapeutic agent.
Metabolism

Demeclocycline: None

Doxycycline: Not hepatic. Partially inactivated in the GI tract by chelateformation

Minocycline: Hepatic to inactive metabolites

Tigecycline: Hepatic, via glucuronidation, N-acetylation, and epimerzation to several metabolites, each less than 10% of the dose.

Half-life Elimination

Tetracycline oral: 6 to 11 hours.

Demeclocycline oral: 10 to 16 hours.

Doxycycline: Single does: 12 to 15 hours (usually increases to 22 to 24 hours with multiple doses); 18 to 25 hours in ESRD.

Minocycline oral: 16 hours (range: 11 to 17 hours).

MinocyclineIV infusion: 15 to 23 hours; 11 to 16 hours (hepatic impairment); 18 to 69 hours (renal impairment).

Tigecycline: Single dose: 27 hours; following multiple doses: 42 hours; increased by 23% in moderate hepatic impairment and 43% in severe hepatic impairment.

Excretion

Tetracycline: Urine (30%); Feces (20% to 60%).

Demeclocyline: Urine (44% as unchanged drug); Feces (13% to 46% as unchanged drug).

Doxycycline: Urine (23%); Feces (30%)

Minocycline: Urine (5% to 12% excreted unchanged); Feces (20% to 34%).

Tigecycline: Urine (33% with 22% of the total dose as unchanged drug); Feces 59% (primarily as unchanged drug).

Significant Adverse Reactions to Tetracyclines and Tigecycline

Tetracyclines and Tigecycline
Generalized

Common cold
Fatigue
Malaise

Central Nervous System

Anxiety
Ataxia
Dizziness
Drowsiness
Headache
Lightheadedness
Paresthesia
Pseudotumor cerebri (Increased intracranial pressure)
Vertigo

Ophthalmic

Permanent vision loss
Visual disturbances

Otic

Hearing loss
Tinnitus

Cardiovascular

Flushing
Hypertension/Hypotension
Myocarditis
Peripheral edema
Pericarditis
Pericardial effusions
Tachycardia

Respiratory

Bronchitis
Dyspnea
Nasal congestion
Nasopharyngitis
Pneumonia
Pneumonitis
Pulmonary infiltrates
Sinus headache
Sinusitis

Neuromuscular and Skeletal

Arthralgia
Back pain
Exacerbation of systemic lupus erythematosus
Lambert-Eaton syndrome
Myalgia
Polyarthralgia
Weakness

Endocrine and Metabolic

Hypocalcemia
Hypoglycemia/Hyperglycemia
Hyponatremia
Increased amylase
Increased lactate dehydrogenase
Malignant neoplasm of the thyroid
Microscopic thyroid discoloration (brown/black)
Nephrogenic diabetes insipidus
Thyroid dysfunction

Dermatologic

Erythema multiforme
Erythematous rash
Exfoliative dermatitis
Maculopapular rash
Pruritus
Skin photosensitivity
Skin hyperpigmentation/Mucous membrane pigmentation/Pigmentation of the nails
Skin rash
Toxic epidermal necrolysis
Urticaria

Gastrointestinal

Abdominal cramps/discomfort/distention/pain
Acid indigestion
Acute pancreatitis
Anorexia
Antibiotic-associated pseudomembranous colitis
Diarrhea
Diarrhea caused by Clostridium difficile
Dysgeusia
Dyspepsia
Dysphagia
Enterocolitis
Epigastric pain
Esophageal ulcerations and strictures
Esophagitis
Glossitis
Large bulky stools
Nausea
Pancreatitis
Proctitis
Pseudomembranous colitis
Staphylococcal enterocolitis
Stomatitis
Vomiting
Xerostomia

Genitourinary

Acute renal failure
Azotemia
Balanitis
Dysmenorrhea
Increased blood urea nitrogen (BUN)/Creatinine (Cr)
Fanconi-like syndrome
Inflammatory anogenital lesion (with monilial overgrowth)
Nephrogenic diabetes insipidus
Renal tubular acidosis
Vaginitis
Vaginal moniliasis
Vulvovaginal candidiasis

Hematologic and Oncologic

Anemia
Eosinophilia
Hemolytic anemiaHypoproteinemia
IgA vasculitis
Leukopenia
Neutropenia
Thrombocytopenia

Hepatic

Autoimmune hepatitis
Cholestasis
Hepatic insufficiency/failure
Hepatitis
Hepatotoxicity
Hyperbilirubinemia
Increased liver enzymes (PT/INR, aPTT, Albumin, Bilirubin-both direct and indirect)
Increased liver transaminases (AST or SGOT and ALT or SGPT)
Increased serum alkaline phosphatase

Hypersensitivity

Anaphylactoid reaction
Anaphylaxis
Angioedema
DRESS syndrome
Hypersensitivity reactions
Stevens-Johnson syndrome

Local

Localized phlebitis
Swelling at injection site
Thrombophlebitis
Vasculitis

Others

Abnormal healing
Abscess
Candidal superinfection
Fixed drug eruption
Fungal infection
Infection
Influenza
Lupus-like syndrome
Septic shock
Serum sickness
Superinfection

*US Boxed Warning: Tigecycline has been associated with an overall increase in mortality. Its use should be reserved for situations when alternative treatments are not suitable.

Warnings/Precautions Related to Tetracyclines and Tigecycline

Patients should be monitored for:

1. Concerns Related to Adverse Reactions

  • Anaphylactic/Hypersensitivity Syndromes
    • Anaphylactic/Hypersensitivity Syndromes including drug rash with eosinophilia and systemic symptoms (DRESS), skin rash, erythema multiforme, Stevens-Johnson syndrome or eosinophilia, fever and organ failure, urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis and systemic lupus erythematosus exacerbation have been reported.
    • Discontinue therapeutic agent immediately and institute supportive measures.
    • Because tigecycline is structurally similar to the tetracyclines, its use in patients with known hypersensitivity to tetracycline-class antibiotics should be avoided.
    • Onset of symptoms may be delayed up to several weeks.
    • Can be fatal in up to 10% of cases.
  • Antianabolic Effects
    • Tetracyclines inhibit protein synthesis and may exacerbate preexisting renal failure by increasing the azotemia from amino acid metabolism.
    • Increased BUN may be secondary to antianabolic effects.
    • Use caution in patients with renal impairment as this may lead to azotemia, hyperphosphatemia, acidosis and possibly to drug accumulation and potential hepatotoxicity.
    • Demeclocycline can cause a nephrogenic diabetes insipidus, a side effect that is used therapeutically to treat the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
      • Diabetes insipidus syndrome: Dose-dependent nephrogenic diabetes insipidus is common with the use of demeclocycline but is reversible on discontinuation of the therapeutic agent. This adverse reaction of demeclocycline has been used as a therapeutic advantage in the off-label use of hyponatremia associated with SIADH.
  • Autoimmune Syndromes
    • Lupus-like, hepatitis and vasculitis autoimmune syndromes (including serum sickness [e.g. fever, arthralgia and malaise]) have been reported.
    • Discontinue therapeutic agent if symptoms occur and assess liver function tests, ANA and CBC.
  • CNS Effects
    • If dizziness, blurred vision, lightheadedness or vertigo occur, physical or mental abilities may be impaired:
      • Caution patients about performing tasks that require mental alertness (e.g., operating machinery or driving).
      • Symptoms usually disappear with continued therapy or when the therapeutic agent is discontinued.
    • Vertigo has been associated with minocycline and appears to be dose-related.
      • More common in women than men, this may appear during the second or third day of therapy and usually resolves in one to two days after discontinuing the minocycline.
      • Complaints consist of dizziness, ataxia, nausea, vomiting and tinnitus.
    • Intracranial Hypertension (e.g., pseudotumor cerebri): Intracranial hypertension (headache, blurred vision, diplopia, vision loss and/or papilledema) has been associated with use.
      • Usually, resolves after discontinuation of treatment but permanent visual loss may occur.
      • If visual symptoms develop during treatment, prompt ophthalmologic evaluation is warranted.
      • Women of childbearing age who are overweight or have a history of intracranial hypertension are at greater risk.
      • Intracranial pressure can remain elevated for weeks after the therapeutic agent has been discontinued thus patients need to be monitored until they stabilize.
  • Gastrointestinal Inflammation/Ulceration
    • Esophagitis and ulcerations (sometimes severe) may occur.
    • Patients with dysphagia and/or retrosternal pain may require assessment for esophageal lesions.
    • Discontinue therapy during the assessment period.
    • Avoid use in patients with obstructive esophageal conditions (e.g., stenosis, achalasia).
  • Hepatotoxicity
    • Abnormal liver function tests (increased total bilirubin, prothrombin time, transaminases) have been reported.
    • Isolated cases of significant hepatic dysfunction and hepatic failure have occurred.
    • Closely monitor for worsening hepatic function in patients who develop abnormal liver function tests during therapy.
    • Adverse hepatic effects may occur after the therapeutic agent has been discontinued.
    • Serious liver injury, including irreversible drug-induced hepatitis and fulminant hepatic failure (sometimes fatal), have been reported with use of minocycline for acne treatment.
  • Hyperpigmentation
    • Hyperpigmentation may occur in nails, bone, skin (including scar and injury sites), eyes, sclerae, thyroid, oral cavity (teeth, mucosa, alveolar bone), visceral tissue and heart valves.
    • Skin and oral hyperpigmentation are independent of dose or administration duration.
  • Pancreatitis
    • Acute pancreatitis (including fatalities) has been reported, including patients without known risk factors.
    • Discontinue therapeutic agent when suspected.
  • Photosensitivity
    • May cause photosensitivity.
    • Discontinue therapeutic agent if skin erythema occurs.
    • Use sunscreen and avoid prolonged exposure to sunlight by wearing protective clothing.
    • Do not use tanning equipment or UVA/B treatment.
  • Superinfection
    • Prolonged use may result in fungal or bacterial superinfection, including Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis.
    • CDAD has been observed greater than two months post antibiotic treatment.
    • A patient with continued diarrhea, fever and a rising white blood count should be evaluated for Clostridium difficile-associated diarrhea (CDAD).

2. Laboratory/Diagnostic Results

  • Perform culture and sensitivity testing prior to initiating therapy and where appropriate during treatment.
  • Monitor patient’s temperature.
  • Monitor liver function tests, renal function tests, CBC, WBC prn and periodically with prolonged therapy.
  • If symptomatic for an autoimmune disorder, monitor ANA and CBC.
  • Ophthalmologic evaluation if visual disturbances occur.
  • If therapeutic agents prescribed as part of alternative treatment for gonococcal infection, test for cure seven days after treatment.
  • If therapeutic agents prescribed for syphilis, obtain follow-up serologic tests three months after treatment.
  • Patients with no risk factors for chronic Q fever should undergo clinical and serological evaluation six months after diagnosis of acute Q fever to identify possible progression to chronic disease.
  • Some parenteral (IV) formulations contain magnesium.
    • Monitor serum magnesium in patients with renal impairment and signs of magnesium intoxication (e.g., flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and CNS depression leading to respiratory paralysis).
    • Use parenteral (IV) formulations with caution and closely monitor patients with heart block or myocardial damage.

3. Hypersensitivity Reactions

  • Discontinue use if allergic reactions occur.

4. Drug-Drug Interactions

  • Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring and/or selection of alternative therapy.

5. Disease-Related Concerns

  • Hepatic impairment
    • Hepatotoxicity and hepatic failure have rarely been reported with use.
    • Dose adjustment and/or adjustment in interval frequency recommended.
    • The risk may be increased in patients with preexisting hepatic or renal impairment.
    • Use with caution in patients with hepatic impairment or in conjunction with other hepatotoxic drugs.
  • Renal impairment
    • Nephrotoxicity has also been reported with use, particularly in the setting of cirrhosis.
    • Use with caution in patients with renal impairment (CrCl <80 mL/minute).
    • Dosage adjustment and/or adjustment in interval frequency is recommended.

6. Concerns Related to Special Populations

  • Pregnancy
    • Do not use during pregnancy.
    • In addition to affecting tooth development of the fetus, tetracycline use has been associated with retardation of skeletal development and reduced bone growth.
    • As a class, tetracyclines are generally considered second-line antibiotics in pregnant women, and their use should be avoided.
    • The decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
  • Pediatric
    • Safety and efficacy in children and adolescents less than 18 years of age have not been established due to increased mortality observed in trials of adult patients.
    • Use is only restricted if no alternative antibiotics are available.
    • Because of effects on tooth development (yellow-gray-brown discoloration), use in patients 8 years of age or younger is not recommended.

Contraindications

  • Hypersensitivity to any of the tetracyclines or any component of the formulation.
  • Tetracyclines and tigecycline use should be avoided in pregnant or lactating women.

Other Warnings/Precautions

  • Limitations of use:
    • When used for malaria prophylaxis, doxycycline does not completely suppress Plasmodium falciparum’s sexual blood stage gametocytes. Patients completing a regimen may still transmit the infection to mosquitoes outside endemic areas.
    • Periodontitis: Effectiveness of doxycycline has not been established in patients with coexistent oral candidiasis.
      • Use with caution in patients with a history or predisposition to oral candidiasis.
  • The absorption of tetracyclines can be impaired by co-administered minerals and antacids (e.g., aluminum, calcium, magnesium and iron), lanthanum and dairy including milk.
  • Tetracyclines can interact with oral isotretinoin, beta-lactams and a variety of other drugs.
  • Minocycline should not be used for the treatment of acne in pregnant women or in males or females attempting to conceive a child.
  • Do not use tigecycline for diabetic foot infections, healthcare-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP).
    • Increased mortality and decreased efficacy have been reported in HAP and VAP trials.
  • The combination of tetracyclines and penicillins should be avoided due to the diminished bactericidal activity of the penicillin.

Use During Pregnancy and Breastfeeding

Tetracyclines and Tigecycline Antibiotics
AgentPregnancy Risk Factor*Breastfeeding Considerations

Tetracycline
Demeclocycline
Doxycycline
Minocycline

DTetracyclines are excreted in breast milk.
*See Appendix A
Glycylcycline Antibiotic
AgentPregnancy Risk Factor*Breastfeeding Considerations
TigecyclineDIt is not known if tigecycline is found in breast milk.
* See Appendix A

Resistance

In contrast to many other antibiotics, tetracyclines are infrequently inactivated biologically or altered chemically by resistant bacteria. Resistance to these agents develops primarily by preventing accumulation of the drug inside the cell either by decreasing influx or increasing efflux. Once resistance develops to one of the drugs in this class, it is typically conferred to all tetracyclines.

However, there are differences in resistance among species of bacteria. Resistance genes to tetracyclines often occur on plasmids or other transferable elements such as transposons. Bacteria carrying a ribosome protection type of resistance gene produce a cytoplasmic protein that interacts with the ribosomes and allows the ribosomes to proceed with protein synthesis even in the presence of high intracellular levels of the drug.

Tigecycline has a reduced potential for resistance since it is not affected by the two major mechanisms of tetracycline resistance: ribosomal protection proteins and efflux pumps. Thus, tigecycline may have activity against tetracycline-resistant organisms.

Dosing Considerations

Dosing: Adult

Dosing of each tetracycline and tigecycline antibiotic is dependent upon the susceptible infection and the therapeutic agent appropriate for that infection. Refer to each therapeutic agent for usual dosage range and dosage intervals appropriate for adults.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

  • There are no specific dosage adjustments provided in the manufacturer’s labeling.
  • Monitor creatinine clearance (CrCl).
  • End-stage renal disease (ESRD) on dialysis:
    • The tetracyclines are minimally removed by hemodialysis, peritoneal dialysis or hemofiltration.
    • No supplemental dose or dosage adjustment is necessary post-dialysis.
    • With the possible exception of doxycycline and tigecycline, tetracycline antibiotics should generally not be used in patients with end-stage renal disease.

Dosing: Hepatic Impairment

  • Dose adjustment is only required in severe hepatic dysfunction for doxycycline and tigecycline (maintenance dose 25 mg IV every 12 hours).
  • Hepatotoxicity has been reported.
  • Use with caution.

Oral Administration

  • Administer oral tetracyclines on an empty stomach (i.e., 1 hour before or 2 hours after food, milk or dairy products) to increase total absorption and with an adequate amount of fluid to reduce the risk of esophageal irritation and ulceration.
  • Administer at least 1 to 2 hours prior to, or 4 hours after antacid because aluminum and magnesium cations may chelate with tetracyclines and reduce total absorption.
  • Serum concentrations may be decreased if taken with food, milk or other dairy products.
  • Administer around-the-clock to promote less variation in peak and trough serum levels.
  • Minocycline serum concentrations are not significantly altered if taken with food or dairy products so it may be taken without regard to food.
    • Swallow pellet-filled capsule and extended-release tablet or capsule whole. Do not chew, crush or split.
  • For doxycyclines, follow the directions for taking the specific therapeutic agent on an empty stomach or with food.

IV Infusion Administration

  • Infuse over 30 to 60 minutes up to 4 hours (depending on the therapeutic agent) through a dedicated line or via Y-site.
  • If the same IV line is used for sequential infusion of several drugs, flush the line with an appropriate compatible solution both before and after administration.
  • Avoid rapid administration and extravasation.
  • IV administration should be used only if the oral route is not feasible or adequate.
  • Prolonged intravenous therapy may be associated with thrombophlebitis.

Dietary Considerations

  • Ethanol: Chronic ethanol ingestion may reduce the serum concentration of doxycycline.
  • Tetracyclines (in general): Take with food if gastric irritation occurs
  • Doxycycline serum levels may be slightly decreased if taken with food or milk.
    • Administration with iron or calcium may decrease doxycycline absorption. May decrease absorption of calcium, iron, magnesium, zinc and amino acids.
    • Administration on an empty stomach is not recommended due to GI intolerance.

Summary

The Tetracycline and Glycylcycline class of antibiotics is a large family of broad-spectrum, bacteriostatic therapeutic agents that have a limited but important role in the armamentarium of antibacterial agents. The first tetracycline was the product of a soil-screening program to detect antimicrobials in the 1950’s.

Tetracyclines and tigecycline inhibit bacterial protein synthesis by binding reversibly to the 30S ribosomal subunit preventing binding of aminoacyl tRNA to the acceptor (A) site on mRNA.

The tetracyclines and tigecycline have gram-positive activity, including Staphylococci, Streptococci and Enterococci but are rarely used because of resistance. They have activity against gram-negatives such as E. coli, but only some Enterobacteriaceae, Neisseria, Haemophilus and Shigella. They are also active against atypical pathogens such as Mycoplasma, Rickettsiae and Chlamydia. Some zoonotic infections also can be treated with tetracyclines.

Their principal indications for use is in the treatment of Lyme disease, community- acquired pneumonia and acne.

Tetracyclines are most frequently administered orally. There are both short and long-acting therapeutic agents. Most are lipophilic and have excellent tissue distribution. The most commonly used tetracycline, minocycline (metabolized in the liver) and doxycycline (inactivated in the intestine), are cleared by nonrenal routes.

Although generally well tolerated, tetracyclines have a long list of potential side effects. These include photosensitivity, discoloration of children’s teeth, hepatotoxicity and hypersensitivity reactions. Tetracyclines are generally safe. The most common adverse events are related to gastrointestinal symptoms (e.g., epigastric discomfort and nausea).

Tetracyclines should generally not be used in pregnant women or children under the age of eight years unless other appropriate therapeutic agents are ineffective or contraindicated.

The primary mechanism of resistance to tetracyclines is decreasing penetration or increasing export of the therapeutic agent via an efflux pump. This mechanism may be plasmid mediated and also confers resistance to all members of the class.

Oxazolidinones

Oxazolidinones
AgentCommon Brand Name(s)Route(s)*
LinezolidLinox, ZyvoxOral, IV infusion
Tedizolid PhosphateSivextroOral, IV infusion
* Only oral and IV infusion routes will be considered in this learning module.

Mechanism of Action

Linezolid is a synthetic antibacterial agent of the oxazolidinones. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. Linezolid is bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal in most isolates.

Tedizolid, after conversion from the prodrug tedizolid phosphate, binds to the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, resulting in inhibition of bacterial protein synthesis. It is considered bacteriostatic against enterococci, staphylococci and streptococci.

Microbiology

Linezolid is a synthetic oxazolidinone that has activity against a variety of predominantly gram-positive organisms which are often the causative agent in nosocomial pneumonia, community-acquired pneumonia and complicated skin and skin structure infections.

Tedizolid is an oxazolidinone antibiotic with a spectrum of activity similar to that of linezolid although it may have activity against some linezolid-resistant gram-positive cocci. Tedizolid has activity against a variety of predominantly gram-positive organisms which are often the causative agent of acute bacterial skin and skin structure infections (ABSSSI).

Linezolid and tedizolid have antibacterial activity against susceptible:

  • Gram-positive organisms:
  • Enterococcus
    • Enterococcus faecalis (aka, group D streptococcus or GDS) (including vancomycin-resistant isolates)
    • Enterococcus faecium (vancomycin-resistant isolates only)
  • Staphylococcus
    • Staphylococcus aureus (including methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) isolates)
    • Staphylococcus epidermidis (including MRSA isolates)
  • Streptococcus
    • Streptococcus agalactiae (aka, group B streptococcus or GBS)
    • Streptococcus anginosus group including:
      • Streptococcus anginosus
      • Streptococcus intermedius
      • Streptococcus constellatus
    • Streptococcus pneumoniae (aka, pneumoccus)
    • Streptococcus pyogenes (aka, group A streptococcus or GAS)
    • Viridans streptococci
  • Gram-negative organisms:
    • Pasteurella
      • Pasteurella multocida

Indications and Usage

Clinical indications and uses of oxazolodinones include:

  • Enterococcal infections, vancomycin-resistant
    • Treatment of vancomycin-resistant Enterococcus faecium infections with or without bacterial invasion of the bloodstream.
  • Pneumonia
    • Community-acquired pneumonia (CAP)
      • Treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only).
      • Linezolid is also an acceptable second-line treatment for community-acquired pneumococcal pneumonia when penicillin resistance is present.
    • Hospital-acquired or healthcare-associated pneumonia
      • Treatment of hospital-acquired, healthcare-associated and ventilator-associated pneumonia caused by Staphylococcus aureus (methicillin-susceptible and resistant isolates) or Streptococcus pneumoniae.
      • U.S. guidelines recommend either linezolid or vancomycin as the first-line treatment for hospital-acquired (nosocomial) MRSA pneumonia.
      • Linezolid's advantages include its high bioavailability because it allows easy switching to oral therapy and the fact that poor kidney function is not an obstacle to use, whereas achieving the correct dosage of vancomycin in patients with renal insufficiency is very difficult.
      • Some studies have suggested that linezolid is better than vancomycin against nosocomial pneumonia, particularly ventilator-associated pneumonia caused by MRSA, perhaps because the penetration of linezolid into bronchial fluids is much higher than that of vancomycin.
      • Linezolid is reserved for cases in which MRSA has been confirmed as the causative organism or when MRSA infection is suspected based on the clinical presentation.
  • Skin and Skin Structure Infections (SSSI’s)
  • Complicated
    • Linezolid is prescribed for the treatment of complicated skin and skin structure infections (cSSSI’s), including diabetic foot infections, unless complicated by osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and resistant isolates), Streptococcus pyogenes or Streptococcus agalactiae.
  • Uncomplicated
    • Linezolid is prescribed for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible [MSSA] isolates) or Streptococcus pyogenes.
    • The manufacturer advises against the use of linezolid for uncomplicated skin and soft tissue infections caused by MRSA.
    • Tedizolid is prescribed for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI’s) caused by susceptible isolates of the following Gram-positive microorganisms:
      • Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates)
      • Streptococcus pyogenes
      • Streptococcus agalactiae
      • Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius)
      • Streptococcus constellatus)
      • Enterococcus faecalis
  • Other uses of oxazolodinones may include:
    • Bone and joint infections, including chronic osteomyelitis.
    • Linezolid has been used to treat tuberculosis in combination with other drugs.
    • Linezolid has been studied as an alternative to vancomycin in the treatment of febrile neutropenia in cancer patients when gram-positive infection is suspected.
    • Linezolid is also one of few antibiotics that diffuse into the vitreous humor and may, therefore, be effective in treating endophthalmitis (inflammation of the inner linings and cavities of the eye) caused by susceptible bacteria.
    • Linezolid appears superior to vancomycin in treating community-acquired MRSA infections of the central nervous system.

Some off-label uses of oxazolidinones include:

  • Brain abscess, subdural empyema and spinal epidural abscess (Staphylococcus aureus [methicillin-resistant])
  • Infective endocarditis
  • Meningitis caused by:
    • Staphylococcus aureus (methicillin-resistant)
    • VRE: Linezolid is the first-line drug of choice.
    • MRSA: Linezolid is an alternative to vancomycin.
  • Osteomyelitis (Staphylococcus aureus [methicillin-resistant])
  • Prosthetic joint infections
  • Septic arthritis (Staphylococcus aureus [methicillin-resistant])
  • Septic thrombosis of cavernous or dural venous sinus (Staphylococcus aureus [methicillin-resistant])

Linezolid is not approved for the treatment of catheter-related bloodstream infections.

Pharmacodynamics and Pharmacokinetics of Oxazolidinones

Oxazolidinones
Absorption

Oral: The systemic absorption of linezolid approaches 100% following oral administration.

Tedizolid phosphate is an inactive prodrugconverted by serum phosphatases to the active form, tedizolid. It exhibits excellent bioavailability (91%) after oral administration.

Time to Peak, Serum

Oral: 1 to 3 hours depending on the therapeutic agent.

IV infusion: 1 to 1.5 hours depending on the therapeutic agent.

DistributionLinezolidbinds poorly to serum protiens (31%), and thus it penetrates well into most body compartments including bone, alveoli and the cerbrospinal space. The overall tissue distribution of linezolid is stable and is not adversely affected by sepsis or peripheral vascular disease.
Protein Binding

Protein binding: 31% for linezolid.

Protein binding: 70% to 90% for tedizolid.

Metabolism

Linezolid does not interact weth the cytochrome P450 oxidative system but rather undergoes hepatic oxidative metabolism into two inactive metabolites. its metabolites are eliminated predominantly in the urine.

Tedizolid phosephate is converted by phoshatases to tedizolid(active, parent drug). There are no other significant circulatingmetabolites

Half-life Elimination

Adults: 4.9 to 7 hours for linezolid

Adults: approximately 12 hours for tedizolid

Excretion

Linezolid: Urine (~30% of total dose as parent drug, ~50% of total dose as metabolites). Two metabolites of linezolid may accumulate in patients with severe renal impairment. Feces: (~9% of total dose as metabolites).

Tedizolid: Urine (18%); Feces (82%) as inactive sulfate conjugates.

Significant Adverse Reactions to Oxazolidinones

Oxazolidinones
GeneralizedFever
Central Nervous System

"Glove and stocking" sensory impairment
Dizziness
Facial paralysis
Headache
Hypoesthesia
Insomnia
Paresthesia
Peripheral Neuropathy*
Seizures activity*
Vertigo

Ophthalmic

Asthenopia
Blurred vision
Decreased visual acuity
Decreased visual perception
Optic neuropathy*
Scotomas
Vision loss*
Vitreous Opacity

Cardiovascular

Flushing
Hypertension*
Palpitations
Tachycardia

RespiratoryNone
Neuromuscular and SkeletalGeneralized weakness
Endocrine and MetabolicHypoglycemia in diabetes mellitus patients receiving oral hypoglycemic agents or insulin*
Decreased amylase
Increased lactate dehydrogenase
DermatologicBullous skin disease*
Dermatitis
Pruritus
Skin rash
Urticaria
Gastrointestinal

Abdominal pain
Constipation
Diarrhea
Clostridium difficile associated diarrhea*
Dysgeusia
Increased serum lipase
Nausea
Oral Candidiasis
Pancreatitis
Pseudomembranouscolitis
Tongue discoloration
Vomiting

GenitourinaryIncreased blood urea nitrogen (BUN)/Creatinine (Cr)
Vaginal candidiasis
Vulvovaginal candidiasis
Hematologic and OncologicAnemia
Decrease in absolute neutrophil count*
Eosinophilia
Leukopenia
Pancytopenia*
Neutropenia
Thrombocytopenia
Hepatic

Increased bilirubin
Increased serum alkaline phophatase
Increased serum transaminases (AST or SGOT and ALT or SGPT)

Hypersensitivity

Anaphylaxia*
Angioedema"
Hypersensitiity reactions
Steven-Johnson syndrome*

LocalLocalized Phlebitis
OthersFungal infection
Infusion related reaction*
Lactic acidosis*
Rhabdomyolysis*
Serotonin syndrome (with concurrent use of other serotonergic agents)*
* US boxed Warning: Limited to important or life-threatening.

Warnings/Precautions Related to Oxazolidinones

Patients should be monitored for:

1. Concerns Related to Adverse Reactions

  • Linezolid
    • Lactic Acidosis
      • Lactic acidosis usually occurs after 40 to 50 days on linezolid therapy and is usually associated with nausea, vomiting, generalized weakness, unexplained acidosis or low bicarbonate levels.
      • Discontinuation of linezolid usually results in resolution of lactic acidemia.
      • It has been postulated that linezolid cross-interacts with human mitochondrial 16S RNA because of its resemblance to bacterial 23S rRNA.
    • Reversible Myelosuppression
      • Use with caution in patients with preexisting myelosuppression, in patients receiving other drugs which may cause bone marrow suppression or in chronic infection (previous or concurrent antibiotic therapy).
      • Linezolid-induced thrombocytopenia is the most frequently observed blood dyscrasia occurring in up to one-third of patients.
      • Leukopenia and anemia may also occur although all blood cell lineages may be depressed with prolonged and high cumulative doses of the drug.
      • Risk factors for linezolid-induced myelosuppression include:
        • Low baseline blood cell counts
        • Duration of therapy greater than14 days
        • Renal impairment
      • Administration of pyridoxine (B6) successfully reversed linezolid-induced thrombocytopenia in one report but did not prevent myelosuppression for treatment exceeding two weeks.
      • Weekly CBC monitoring is recommended.
      • Discontinue linezolid in patients developing myelosuppression (or in whom myelosuppression worsens during treatment).
    • Linezolid-Induced Reversible Optic Neuropathy including:
      • Decreased visual acuity
      • Development of scotomas, i.e., area of partial alteration in the field of vision consisting of a partially diminished or entirely degenerated visual acuity that is surrounded by a field of normal – or relatively well-preserved – vision.
      • Diminished color perception
      • Any symptoms of visual change or impairment warrant immediate ophthalmic evaluation and possible discontinuation of therapy.
    • Irreversible Peripheral Neuropathy
      • Usually manifesting as a "glove and stocking" sensory impairment with a sensory-motor axonal pattern on nerve conduction studies.
      • This adverse effect is time and dose dependent with the use of linezolid and may not resolve after discontinuation of the drug.
    • Serotonin Syndrome
      • Linezolid is a reversible, nonselective monoamine oxidase inhibitor (MAOI). MAO inhibition causes levels of the neurotransmitter serotonin to increase. Thus, linezolid has the potential for causing serotonin syndrome, i.e., a hyper serotonergic state characterized by:
        • Mental status changes such as agitation, confusion, hallucinations
        • Neurologic abnormalities such as hyperreflexia, myoclonus
        • Autonomic instability such as shivering and tachycardia
      • These symptoms may occur when linezolid is used in patients with either endocrinologically active carcinoid tumors or patients who are using linezolid with concomitant pro serotonergic drugs which reduce linezolids metabolism or in patients with carcinoid syndrome drugs.
      • Risk factors for serotonin syndrome include patients who are taking:
        • SSRIs (e.g., Citalopram (Celexa), Escitalopram (Lexapro), Paroxetine (Paxil) (Pexeva), Fluoxetine (Prozac), Sertraline (Zoloft)
        • MAOIs (e.g., Phenelzine (Nardil), Isocarboxazid (Marplan), Tranylcypromine (Parnate), Selegiline (Eldepryl) (Zelapar)
        • Tricyclic antidepressants: (e.g., Amitriptyline, Amoxapine, Desipramine (Norpramin), Doxepin, Imipramine (Tofranil), Nortriptyline (Pamelor), Protriptyline (Vivactil), Trimipramine (Surmontil)
        • Serotonin 1B,1D receptor agonists (Triptans)
        • Meperidine (e.g., Demerol, Meperitab)
        • Bupropion (e.g., Wellbutrin, Aplenzin, Budeprion, Zyban)
        • Buspirone (e.g., Buspar, Vanspar)
      • Avoid the use of linezolid in such patients unless clinically appropriate and under close monitoring for signs/symptoms of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
      • Patients taking serotonergic antidepressants should receive linezolid only if the benefit is thought to outweigh the risk and no other therapies are available.
        • The serotonergic antidepressants should be discontinued, and the patient monitored for signs and symptoms of both serotonin syndrome and antidepressant discontinuation.
    • General protocols used to monitor for the development of serious adverse reactions to linezolid include:
      • Weekly monitoring of CBC for possible bone marrow suppression especially when therapy lasts longer than two weeks.
      • Twice-weekly liver function tests.
      • Measurement of serum lactate levels for early detection of lactic acidosis.
      • A review of all medications taken by the patient, interrupting the use of those that may interact with linezolid.
      • Periodic eye and neurological examinations in patients set to receive linezolid for longer than four weeks.
  • Linezolid and tedizolid
    • Superinfection
      • Prolonged use may result in fungal or bacterial superinfection, including Clostridium difficile associated diarrhea (CDAD) and pseudomembranous colitis.
      • CDAD has been observed greater than two months post antibiotic treatment.
      • Evaluate all patients who present with diarrhea following antibiotic use. If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.

2. Disease-Related Concerns

  • Linezolid
    • Carcinoid Syndrome
      • Use with caution and closely monitor for serotonin syndrome in patients with carcinoid syndrome.
      • Do not use in the absence of close monitoring.
    • Diabetes mellitus
      • Hypoglycemic episodes have been reported.
      • Use with caution and closely monitor glucose in diabetic patients.
      • Dose reductions/discontinuation of concurrent hypoglycemic agents or discontinuation of linezolid may be required.
    • Hypertension
      • Use with caution and closely monitor blood pressure in patients with uncontrolled hypertension.
      • Those patients taking any of the following:
        • Sympathomimetic drugs (e.g., Pseudoephedrine)
        • Vasopressors (e.g., Epinephrine, Norepinephrine)
        • Dopaminergic drugs (e.g., Dopamine, Dobutamine)
    • Hyperthyroidism
      • Use with caution and closely monitor blood pressure in patients with untreated hyperthyroidism.
    • Pheochromocytoma
      • Use with caution and closely monitor blood pressure in patients with pheochromocytoma.
    • Seizure disorder
      • Seizures have been reported.
      • Use with caution in patients with a history of seizures.
  • Tedizolid
    • Neutropenia
      • Not recommended for use in patients with neutrophil counts less than 1000 cells/mm3.
      • Alternative therapies should be considered when treating patients with neutropenia and acute bacterial skin and skin structure infections (ABSSI’s).

3. Patient Health History

  • Ascertain all medications taken by the patient.
  • Medications which may interact with oxazolidinones should be discontinued.

4. Laboratory/Diagnostic Results

  • Perform culture and sensitivity testing prior to initiating therapy and where appropriate during treatment.
  • When taking linezolid, monitor baseline CBC with differential then twice weekly, particularly in patients:
    • At increased risk of bleeding.
    • With pre-existing myelosuppression.
    • Individuals who are taking concomitant medications that cause bone marrow suppression.
    • Individuals who require greater than two weeks of therapy.
    • With chronic infection who have received previous or concomitant antibiotic therapy.
    • Whose visual function may become impaired with extended therapy lasting three months or longer.
    • With new onset visual symptoms, regardless of therapy length.
    • With renal impairment, monitor for hematopoietic (e.g., anemia, leukopenia, thrombocytopenia) and neuropathic (e.g., peripheral neuropathy) adverse reactions when administering for extended periods.
  • Monitor baseline and twice weekly liver function tests.
  • Monitor baseline and serum lactate levels for early detection of lactic acidosis.
  • Ophthalmologic evaluation if visual disturbances occur.
  • Neurologic examinations if linezolid will be taken for longer than four weeks.

5. Hypersensitivity Reactions

  • Discontinue use if allergic reactions occur.

6. Drug-Drug Interactions

  • Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy.

7. Concerns Related to Special Populations

  • Linezolid
    • No dosage adjustments are required in the elderly, in people with mild-to-moderate liver failure or those with impaired kidney function.
    • Hemodialysis Patients:
      • Care should be taken to give linezolid after hemodialysis because dialysis removes 30–40% of a dose from the body.
      • No dosage adjustments are needed for patients undergoing continuous hemofiltration, although more frequent administration may be warranted in some cases.
  • Pregnancy
    • Do not use during pregnancy.
  • Pediatric
    • The manufacturer does not recommend the use of linezolid for empiric treatment of pediatric CNS infections since therapeutic linezolid concentrations are not consistently achieved or maintained in the CSF of patients with ventriculoperitoneal shunts. Limited data in the form of case reports in pediatric and adult patients suggest that linezolid may be useful in treating gram-positive CNS infections that have failed to respond to other treatment options describing successful treatment of documented VRE and Staphylococcus aureus CNS and shunt infections in the literature.

Contraindications

  • Linezolid is contraindicated in the following situations:
    • Patients who have had a prior allergic reaction to linezolid.
    • Hypersensitivity to linezolid or any of the other components of the formulation.
    • Concurrent use of or within two weeks of taking MAO inhibitors.
    • Patients who have risk factors for serotonin syndrome.
  • Tedizolid
    • There are no contraindications listed in the manufacturer's labeling.

Use During Pregnancy and Breastfeeding

Oxazolidinone
AgentsPregnancy Risk Factor*Breastfeeding Considerations
Linezolid
Tedizolid
CWhether linezolid and tedizolid are excreted in breast milk or are safe to use during breastfeeding is unknown
* See Appendix A

Resistance

Resistance to linezolid has occurred in patients infected with:

  • Enterococcus faecium (vancomycin-resistant)
  • Enterococcus faecalis
  • Staphylococcus aureus (methicillin-resistant) (MRSA)
  • The linezolid resistance in the enterococcus organisms is associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism.
  • Linezolid resistance in staphylococci is mediated by the enzyme methyltransferase. This resistance is mediated by the cfr (chloramphenicol-florfenicol) gene located on a plasmid which is transferable between staphylococci.

Resistance to tedizolid has occurred with isolates exhibiting elevated tedizolid minimum inhibitory concentration values generally carrying the cfr multidrug-resistance gene or mutations in the genes encoding 23S rRNA or those encoding ribosomal proteins L3 or L4 and 5.

Dosing Considerations

Dosing: Adult

Dosing of each oxazolidinone antibiotic is dependent upon the susceptible infection and the therapeutic agent appropriate for that infection. Refer to each therapeutic agent for usual dosage range and dosage intervals appropriate for adults.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment
  • Linezolid
    • Mild to severe renal impairment:
      • No dosage adjustment necessary.
      • The two primary metabolites of linezolid may accumulate in patients with renal impairment, but the clinical significance is unknown.
      • Use with caution.
  • End-stage renal disease (ESRD) on intermittent hemodialysis (IHD):
    • Dialyzable (approximately 30% removed during 3-hour dialysis session):
    • Administer after hemodialysis on dialysis days.
  • Peritoneal dialysis:
    • No supplemental dose or dosage adjustment needed.
  • Continuous renal replacement therapy (CVVH, CVVHD, CVVHDF):
    • Some have suggested no supplemental dose or dosage adjustment needed Others have postulated that achievement of MIC 2 mg/L may be suboptimal in ~30% of patients undergoing CVVHD or CVVHDF given 600 mg every 12 hours. However, no alternative dosing recommendations suggested.
  • Tedizolid
    • No dosage adjustment necessary.

Dosing: Hepatic Impairment

  • Linezolid
    • Mild to moderate hepatic impairment (Child-Pugh class A or B):
      • No dosage adjustment necessary.
    • Severe impairment (Child-Pugh class C):
      • Has not been studied.
  • Tedizolid
    • No dosage adjustment necessary.
Oral Administration
  • Oral: Administer without regard to meals i.e. with or without food.
  • Oral linezolid suspension: Invert gently to mix prior to administration, do not shake.

IV Infusion Administration

  • IV infusion:
    • Administer intravenous infusion over 30 to 120 minutes depending on the therapeutic agent.
    • Do not mix or infuse with other medications.
    • Do not administer as an IV push or bolus.
    • Not for intra-arterial, IM, intrathecal, intraperitoneal or subcutaneous administration.
    • If the same IV line is used for sequential infusion of other drugs, flush the line with an appropriate compatible solution both before and after administration.

Dietary Considerations

  • Linezolid
    • Avoid tyramine-containing foods/beverages (pork, aged or matured cheese, air-dried or cured meats including sausages and salamis, fava or broad bean pods, smoked or pickled foods, tap/draft beers, hearty red wine, Marmite concentrate, sauerkraut, soy sauce and other soybean condiments).
    • Food/beverages containing dopamine, tyrosine, phenylalanine, tryptophan or caffeine may cause sudden and severe high blood pressure (hypertensive crisis or serotonin syndrome).
    • Food’s freshness is also an important concern since improperly stored or spoiled food can create an environment in which tyramine concentrations may increase.

Summary

Linezolid and tedizolid are oxazolidinone antibiotics that have a spectrum of activity against a variety of predominantly gram-positive organisms and a few gram-negative organisms. Both therapeutic agents are primarily prescribed to treat enterococcal infections (usually vancomycin-resistant), community-acquired pneumonia (CAP), hospital-acquired or healthcare-associated pneumonia, complicated and uncomplicated skin and skin structure infections (SSSI’s), as well as, a variety of miscellaneous indications for usage.

Significant adverse reactions to oxazolidinones may occur especially to linezolid which has been more extensively studied. The potential for adverse reactions to these therapeutic agents to occur dictates close clinical monitoring and extensive patient education to aid in the prevention of the adverse reactions especially in the setting of drug interactions.

Linezolid is a weak inhibitor of monoamine oxidase (MAO) and can precipitate serotonin toxicity when coadministered with nonselective MAO inhibitors, selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants, serotonin 1B, 1D receptor agonists, meperidine, bupropion and buspirone. Most case reports of linezolid-induced serotonin syndrome occurred within one week of starting linezolid therapy in conjunction with the administration of an SSRI. Deaths from this interaction have been reported. Linezolid-related serotonin toxicity can usually be managed by discontinuing linezolid, the coadministered suspected drug or both. The median time to resolution of symptoms is usually 48 hours from the time of adjusting medications. Close monitoring for signs and symptoms of serotonin syndrome is critical.

Tedizolid is a reversible inhibitor of monoamine oxidase in vitro. Potential drug interactions resulting from such activity (such as interactions with select serotonin reuptake inhibitors [SSRIs] and others) have not been evaluated in clinical trials. In theory, such effects might occur less frequently with tedizolid than linezolid, due (in part) to the differing pharmacokinetic profiles of these agents.

Resistance to the causative organism may evolve when taking either linezolid or tedizolid via differing mechanisms. So, repeat culture and sensitivities when appropriate should be performed to evaluate the effectiveness of either therapeutic agent.

Remember, in both the popular press and the scientific literature, linezolid has been called a "reserve antibiotic" i.e. one that should be used sparingly so that it will remain effective as a drug of last resort against potentially intractable infections.

Amphenicols and Pleuromutilins

Amphenicols
AgentsCommon Brand Name(s)Route(s)
Chloramphenicol*Chloromycetin; Choromycetin SuccinateOphthalmic, IV infusion
AzidamfenicolAzidoamphenicolophthalmic
* The manufacture of oral chloramphenicol in the United States stopped in 1991 because of a large number of chloramphenicol-associated causes of aplastic anemia associated with oral preparations.
Pleuromutilins
AgentsCommon Brand Name(s)Route(s)
RetapamulinAltabaxTopical

Mechanism of Action

Amphenicols are a class of antibiotics with a phenylpropanoid structure. Amphenicols are bacteriostatic by inhibiting protein synthesis. They prevent protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome. It specifically binds to A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal subunit thus preventing peptide bond formation.

The pleuromutilin class of antibiotics has a unique mode of action which involves inhibition of bacterial protein synthesis at the level of the bacterial 50S ribosome. It binds to domain V of 23S rRNA, inhibits ribosomal peptidyl transferase activity and partially inhibits the binding of the initiator tRNA substrate to the ribosomal P-site. An example of a pleuromutilin is retapamulin which is primarily bacteriostatic. It selectively inhibits bacterial protein biosynthesis by binding at a unique site (protein L3) on the ribosomal 50S subunit which prevents the formation of active 50S ribosomal subunits by inhibiting peptidyl transfer and blocking P-site interactions at this site.

Microbiology

Chloramphenicol and azidamfenicol are used to treat serious infections due to organisms resistant to other less toxic antibiotics or when its penetrability into the site of infection is clinically superior to other antibiotics to which the organism is sensitive. Retapamulin is often indicated for the treatment of impetigo where common bacteria typically found in skin and soft tissue infections (SSTI’s) have become resistant to the leading topical antimicrobials used in clinical practice.

Amphenicols and pleuromutilins have antibacterial activity against susceptible:

  • Gram-positive organisms:
    • Enterococcus
      • Enterococcus faecium (vancomycin-resistant)
    • Propionibacterium spp
      • Propionibacterium acnes
    • Staphylococcus (coagulase-negative)
      • Staphylococcus aureus (methicillin-susceptible isolates [MSSA])
      • Staphylococcus epidermidis
      • Staphylococcus haemolyticus
      • Staphylococcus lugdunensis
      • Staphylococcus saprophyticus
    • Streptococcus
      • Streptococcus agalactiae
      • Streptococcus pneumoniae
      • Streptococcus pyogenes (Group A β- hemolyticStreptococci (GABHS) and Group A Streptococcus (GAS)
      • Streptococcus viridans
  • Gram-negative organisms:
  • Bacteroides spp
  • Clostridium spp
  • Escherichia
    • Escherichia coli
  • Fusobacterium spp
  • Haemophilus
    • Haemophilus influenza
  • Neisseria
    • Neisseria meningitides
  • Porphyromonas spp
    • Porphyromonas gingivalis
  • Prevotella spp
  • Rickettsia
  • Salmonella
  • Vibrio
    • Vibrio cholera (tetracycline-resistant)

Indications and Usage

Chloramphenicol is used to treat serious infections due to organisms resistant to other less toxic antibiotics or when its penetrability into the site of infection is clinically superior to other antibiotics to which the organism is sensitive. It is useful in infections caused by:

  • Bacteroides
  • Enterococcus faecium (vancomycin-resistant)
  • Haemophilus influenza
  • Neisseria meningitides
  • Rickettsia
  • Salmonella
  • Vibrio cholera (tetracycline-resistant)

Chloramphenicol remains the first-choice in the treatment of staphylococcal brain abscesses because of its excellent blood-brain barrier penetration (far superior to any of the cephalosporins). It is also useful for the treatment of brain abscesses due to mixed organisms or when the causative organism is not known.

Chloramphenicol is active against the three main bacterial causes of meningitis:

  • Neisseria meningitidis
  • Streptococcus pneumoniae
  • Haemophilus influenzae

Chloramphenicol remains the drug of choice in the treatment of meningitis in patients with severe penicillin or cephalosporin allergies.

Chloramphenicol and azidamfenicol have a broad spectrum of activity and have been effective in treating ocular infections caused by a number of bacteria including:

  • Escherichia coli
  • Staphylococcus aureus
  • Streptococcus pneumoniae

Retapamulin is often indicated for the treatment of impetigo which is a skin infection for which patients seek care from dermatologists. The most common bacteria found in skin and soft tissue infections (SSTI’s) which have become resistant to the leading topical antimicrobials used in clinical practice include gram-positive and some gram-negative organisms such as:

  • Bacteroides
  • Clostridium
  • Coagulase-negativeStaphylococci
  • Fusobacterium spp
  • Porphyromonas spp
  • Prevotella spp
  • Propionibacterium spp (including P acnes)
  • Staphylococcusaureus (methicillin-susceptible isolates only) (MSSA)
  • Streptococcus agalactiae
  • Streptococci viridans
  • Streptococcuspyogenes (aka, Group A β- hemolyticStreptococci (GABHS) and Group A Streptococcus (GAS)

Pharmacodynamics and Pharmacokinetics of Amphenicols and Pleuromutilins

Amphenicols and Pleuromutilins
Absorption

Azidamfenicol is absorbed intraocular with some systemic absorption after topical application to the eye.

The absorption of topical retapamulin is low. Thus, systemic exposure is minimal following topical application to intact but increased when applied to abraded skin. Absorption is highest in younger patients.
Time to Peak, SerumChloramphenicol succinate: IV infusion: ~70%; highly variable, dependent upon rate and extent of metabolism to chloramphenicol.
DistributionChloramphenicol is extremely lipid-soluble. It remains relatively unbound to protein and is a small molecule. It has a large apparent volume of distribution and penetrates effectively into all tissues of the body, including the brain. Distribution is not uniform with the highest concentrations found in the liver and kidney and the lowest in the brain and cerebrospinal fluid. The concentration achieved in brain and cerebrospinal fluid is around 30 to 50% of the overall average body concentration, even when the meninges are not inflamed. When the meninges are inflamed, the concentration increases to as high as 89%.
Protein Binding

Chloramphenicol is about 60% bound to protein but decreased with hepatic or renal dysfunction.

Retapamulin is about 94% protein bound.

Metabolism

Chloramphenicol: Hepatic to metabolites (inactive).

Chloramphenicol succinate: Hydrolyzed in the liver, kidney and lungs to chloramphenicol.

Metabolism of retapamulin is via the hepatic CYP3A4 pathway which extensively metabolizes it by mono-oxygenation and di-oxygenation to multiple metabolites.
Half-life EliminationHalf-life elimination of chloramphenicol in adults with normal renal function is about 3 - 4 hours, but in end-stage renal failure, its half-life is 3 - 7 hours. With hepatic disease, the half-life is prolonged.
ExcretionChloramphenicol succinate is excreted 30% unchanged in the urine.

Significant Adverse Reactions to Amphenicols and Pleuromutilins

Amphenicols and Pleuromutilins
GeneralizedFever
Central Nervous SystemConfusion
Delirium
Depression
Headache
OphthalmicMacular rashes
Optic neuritis
RespiratoryEpistaxis
Nasopharyngitis
DermatologicContact dermatitis
Eczema
Skin rash
Urticaria
GastrointestinalC. difficile-associated diarrhea (DCAD)*
Diarrhea
Enterocolitis
Glossitis
Nausea
Pseudomembranous colitis*
Stomatitis
Vomiting
Hematologic and OncologicAplastic anemia*
Bone marrow depression*
Granulocytopenia*
Hypoplastic anemia*
Pancytopenia*
Thrombocytopenia*
HypersensitivityAnaphylaxis
Angioedema
Hypersensitiviy reactions
LocalApplication site irriation: blisters, burning, redness, swelling and oozing at the site where ointment is applied.
OthersGray Baby Syndrome*
Increased creatine phosphokinase (CPK)
* U.S. Boxed Warning

Warnings/Precautions Related to Amphenicols and Pleuromutilins

Patients should be monitored for:

  1. Concerns Related to Adverse Reactions (Amphenicols only)
  • Hematologic and Oncologic:
    • Blood Dyscrasias – may occur after both short-term and prolonged therapy.
      • Aplastic Anemia
        • Aplastic anemia usually occurs weeks or months after treatment has been stopped and a genetic predisposition may be involved.
        • This effect is rare and sometimes fatal.
        • Patients are recommended to have a baseline CBC with a repeat CBC every few days while on treatment.
        • Chloramphenicol should be discontinued if the complete blood count drops below 2.5 x 10 cells/l.
        • The lowest risk of developing aplastic anemia occurs with eye drops.
        • There have been reports of aplastic anemia attributed to chloramphenicol which later terminated in leukemia.
        • Discontinue chloramphenicol if there is evidence of myelosuppression.
        • Irreversible bone marrow suppression may occur weeks or months after therapy.
        • Avoid repeated courses of treatment with chloramphenicol.
        • Chloramphenicol should not be used for minor infections or when less potentially toxic agents are effective.
      • Granulocytopenia
      • Hypoplastic anemia
      • Pancytopenia
      • Thrombocytopenia
  • Miscellaneous:
    • Gray Baby Syndrome
      • Gray Baby Syndrome is characterized by circulatory collapse, cyanosis, acidosis, abdominal distention, myocardial depression, coma and death.
      • Reaction appears to be associated with serum chloramphenicol levels ≥50 mcg/mL.
      • Gray Baby Syndrome has been associated with intravenous chloramphenicol use.
      • This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes (i.e. UDP-glucuronyl transferase), so chloramphenicol remains unmetabolized in the body.
    • Superinfection
      • Prolonged use may result in fungal or bacterial superinfection, including Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis.
      • CDAD has been observed greater than 2 months post antibiotic treatment.
      • A patient with continued diarrhea, fever and a rising white blood count should be evaluated for Clostridium difficile-associated diarrhea (CDAD).
  1. Laboratory/Diagnostic Results
  • Perform culture and sensitivity testing where possible prior to initiating therapy and where appropriate during treatment.
  • Monitor CBC with differential at baseline and every two days during therapy.
  • Monitor periodic liver and renal function tests.
  • Monitor serum chloramphenicol drug concentrations both peak and trough.
  • Monitor for superinfections.
  • If using retapamulin, monitor for creatine phosphokinase (CPK) elevation where appropriate.
  1. Hypersensitivity Reactions
  • Discontinue use if allergic reactions occur.
  1. Drug-Drug Interactions
  • Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring and/or selection of alternative therapy.
    • Drug Interactions with Chloramphenicol
      • Chloramphenicol is a potent inhibitor of the cytochrome P450 isoforms CYP2C19 and CYP3A4 in the liver.
        • Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of:
          • Antidepressants
          • Anticoagulants
          • Antiepileptics
          • Proton pump inhibitors
        • Inhibition of CYP3A4 causes increased levels of:
          • Anticoagulants
          • Antivirals
          • Azole antifungals
          • Benzodiazepines
          • Calcium channel blockers
          • Cardiac antiarrhythmics
          • Chemotherapeutic drugs
          • Immunosuppressants
          • Macrolide antibiotics
          • PDE5 inhibitors
          • SSRI’s
          • Statins
          • Tricyclic antidepressants
  • Drug Interactions to Retapamulin
    • Multiple drug interactions with retapamulin may occur including those that may increase the serum concentration of retapamulin especially in young patients such as CYP3A4 inhibitors:
      • Atazanavir
      • Clarithromycin
      • Darunavir
      • Indinavir
      • Itraconazole
      • Ketoconazole
      • Lopinavir
      • Nefazodone
      • Nelfinavir
      • Ritonavir
      • Telithromycin
      • Tipranavir.
      • Saquinavir
  1. Disease-Related Concerns
  • Hepatic impairment
    • Use amphenicols with caution in patients with hepatic impairment.
    • Reduced dosage and serum concentration monitoring both peak and trough are recommended.
  • Renal impairment
    • Use amphenicols with caution in patients with renal impairment.
    • Reduced dosage and serum concentration monitoring both peak and trough are recommended.

6.Concerns Related to Special Populations (Chloramphenicol only)

  • Glucose 6-phosphate dehydrogenase deficiency
    • Use with caution in patients with glucose 6-phosphate dehydrogenase deficiency.
  • Neonates
    • Use in neonates (including premature) has resulted in “Gray Baby Syndrome" characterized by cyanosis, abdominal distention (with or without emesis), vasomotor collapse (often with irregular respiration) and death.
      • Progression of symptoms is rapid.
      • Prompt termination of therapy is required.
      • Reaction may result from drug accumulation caused by the impaired neonatal hepatic or renal function.

Contraindications

  • Hypersensitivity to chloramphenicol or any component of the formulation.
  • Chloramphenicol is contraindicated in the treatment of trivial infections or viral infections.
  • Chloramphenicol is contraindicated for use as bacterial prophylaxis.
  • No contraindications are listed in the manufacturers’ labeling

Use During Pregnancy and Breastfeeding

Amphenicol Antibiotics
AgentPregnancy Risk Factor*Breastfeeding Considerations
Chloramphenicol
?Azidamfenicol
CChloramphenicol and its inactive metabolites are excreted in breast milk. The half-life is also significantly prolonged in low birth weight infants. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends that caution is exercised when administering chloramphenicol to nursing women
* See Appendix A
Pleuromutilin Antibiotics
AgentPregnancy Risk Factor*Breastfeeding Considerations
RetapamulinBIt is not known if retapamulin is excreted in breast milk. The manufacturer recommends that caution is exercised when administering retapamulin to nursing women
* See Appendix A

Resistance

Three mechanisms of resistance to chloramphenicol are known:

  • Reduced membrane permeability
    • Most common mechanism of low-level chloramphenicol resistance.
  • Mutation of the 50S ribosomal subunit
    • Resistance-conferring mutations of the 50S ribosomal subunit are rare.
  • Elaboration of chloramphenicol acetyltransferase
    • High-level resistance is conferred by the cat-gene which codes for an enzyme called chloramphenicol acetyltransferase, which inactivates chloramphenicol by covalently linking one or two acetyl groups, derived from acetyl-S-coenzyme A, to the hydroxyl groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome.

Retapamulin has demonstrated excellent activity in vitro against Staphylococcus aureus, irrespective of their level of resistance to other antimicrobials. One study has shown that bacterial resistance in vitro is through two mechanisms:

  • Mutation in protein L3 close to the peptidyl transferase center and the development of drug efflux mechanisms. Mutation in L3 is a multi-step process which appears to be slow to emerge.
  • A stepwise reduction in pleuromutilin susceptibility occurring concurrently with stepwise acquisition of mutations in rplC.
  • A potential clinical threat of cross-resistance in the antibiotics that target the ribosomal peptidyl transferase center (PTC) is the multidrug resistance phenotype mediated by the cfr rRNA methyltransferase. This gene encodes a methyltransferase that modifies the PTC nucleotide A2503 and is responsible for resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin antibiotics.

Dosing Considerations

Dosing: Adult

Serious infections:

  • Chloramphenicol IV infusion: 50 to 100 mg/kg/day in divided doses every 6 hours to a maximum daily dose: 4 g/day.

Dosing: Geriatric

Refer to adult dosing.

Dosing of Retapamulin

A thin layer of retapamulin should be applied to the affected area (up to 100 cm 2 in total area in adults) twice daily for five days.

Dosing: Renal Impairment

  • Most the chloramphenicol dose is excreted by the kidneys as the inactive metabolite, chloramphenicol glucuronate. Only a tiny fraction of the chloramphenicol is excreted by the kidneys unchanged.
  • Plasma chloramphenicol levels should be monitored in patients with renal impairment.
  • Dose monitoring
    • Plasma levels of chloramphenicol must be monitored in the elderly and patients with abnormal liver and/or kidney function.
    • Because efficacy and toxicity of chloramphenicol are associated with a maximum serum concentration, peak levels (one hour after the intravenous dose is given) should be 10 - 20µg/ml with toxicity greater than 40 µg/ml. Trough levels (taken immediately before a dose) should be 5 - 10µg/ml.
  • There are no dosage adjustments provided for renal impairment in the manufacturer's labeling for retapamulin. However, dosage adjustment is unlikely due to low systemic absorption.

Dosing: Hepatic Impairment

  • Chloramphenicol is metabolized by the liver to chloramphenicol glucuronate (which is inactive).
  • In liver impairment, the dose of chloramphenicol must, therefore, be reduced.
  • No standard dose reduction exists for chloramphenicol in liver impairment, and the dose should be adjusted according to measured plasma chloramphenicol concentrations.
  • There are no dosage adjustments provided for hepatic impairment in the manufacturer's labeling for retapamulin. However, dosage adjustment is unlikely due to low systemic absorption.

Topical Administration of Retapamulin

  • For external use only.
  • Not for intranasal, intravaginal, ophthalmic, oral or mucosal application.
  • May cover treatment area with sterile bandage or gauze dressing if needed.
  • Wash hands after application if the hands are not the area for treatment.
  • If sensitization or severe local skin irritation occurs, wipe ointment off and discontinue use.

IV Infusion Administration

  • Do not administer chloramphenicol IM.
  • Chloramphenicol is administered IV infusion over 15 to 30 minutes at a final concentration for administration of less than or equal to 20 mg/ml.

Dietary Considerations

  • Patients may have increased dietary need for riboflavin, pyridoxine and vitamin B12.
  • Some products may contain sodium.
  • Chloramphenicol increases the absorption of iron.

Summary

Amphenicols are bacteriostatic by inhibiting protein synthesis. They prevent protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial 50S ribosome. The pleuromutilin class of antibiotics has a unique mode of action which involves inhibition of bacterial protein synthesis at the level of the bacterial 50S ribosome. It binds to domain V of 23S rRNA, inhibits ribosomal peptidyl transferase activity and partially inhibits the binding of the initiator tRNA substrate to the ribosomal P-site.

Chloramphenicol and azidamfenicol are used to treat serious infections due to organisms resistant to other less toxic antibiotics or when its penetrability into the site of infection is clinically superior to other antibiotics to which the organism is sensitive. Retapamulin is often indicated for the treatment of impetigo where common bacteria typically found in skin and soft tissue infections (SSTI’s) have become resistant to the leading topical antimicrobials used in clinical practice. 

Chloramphenicol remains the first-choice in the treatment of staphylococcal brain abscesses because of its excellent blood-brain barrier penetration (far superior to any of the cephalosporins). It is also useful for the treatment of brain abscesses due to mixed organisms or when the causative organism is not known. It is also active against meningitis. Chloramphenicol and azidamfenicol have a broad spectrum of activity and have been effective in treating ocular infections caused by several bacteria. Retapamulin is often indicated for the treatment of impetigo.

US Boxed warnings/precautions related to amphenicols and pleuromutilins include blood dyscrasias. Gray Baby Syndrome and superinfections. Multiple drug-drug interactions may occur. Caution should be used in patients who have preexisting hepatic and/or renal impairment or have glucose 6-phosphate dehydrogenase deficiency. Use during pregnancy and breastfeeding should occur only when the benefits far outweigh the risks and no other suitable therapeutic agent is available. Resistance to amphenicols and pleuromutilins has been known to occur.

Dosing and routes of administration in adults and geriatric populations with or without renal or hepatic impairment, as well as dietary considerations, should always be considered prior to initiation of treatment and during treatment.

Macrolides and Ketolides

Macrolide Antibiotics
AgentsCommon Brand Name(s)Route(s)
Azithromycin

Ophthalmic: AzaSite
Oral: Zithromax; Zithromax Tri-Pak; Zithromax Z-Pak; Zmax
IV infusion: Zithromax

Ophthalmic solution, oral, IV infusion
ClarithromycinBiazin; Biaxin XL; Biazin XL PacOral
Erythromycin

Ophthalmic: Ilotycin
Oral: E.E.S. 400; E.E.S. Granules; Ery-Tab; EryPed 200; EryPed 400; Erythrocin Stearate; PCE; Ery-tab
IV infusion: Erthrocin Lactobionate
Topical: Erygel

Ophthalmic ointment,oral, IV infusion, Topical
FidaxomicinDificidOral
Ketolide Antibiotics
AgentCommon Brand Name(s)Route(s)
TelithromycinKetekOral

Mechanism of Action

Macrolides are antibiotics whose mechanism of action is primarily bacteriostatic. They bind to the P site on the 50S subunit of the ribosome, therefore, inhibiting bacterial protein synthesis. They are believed to do this by:

  • Preventing peptidyltransferase from adding the growing peptide attached to tRNA to the next amino acid
  • Inhibiting ribosomal translation or
  • By premature dissociation of the peptidyl-tRNA from the ribosome

Macrolides are actively concentrated within leukocytes, and are, therefore, transported into the site of infection.

Ketolides are a class of antibiotics that are structurally related to the macrolides. Ketolides block protein synthesis by binding to ribosomal subunits and may also inhibit the formation of newly forming ribosomes. They are used to treat respiratory tract infections caused by macrolide-resistant bacteria due to their ability to bind at two sites at the bacterial ribosome, as well as, having a structural modification that makes them poor substrates for efflux pump mediated resistance.

Microbiology

Macrolides and ketolides have antibacterial activity against susceptible:

  • Gram-positive organisms:
    • Clostridium
      • Clostridium difficile
      • Clostridium perfringens
    • Corynebacterium
      • Corynebacterium diphtheria
    • Enterococcus spp
    • Propionibacterium
      • Propionibacterium acnes (use topical erythromycin)
    • Staphylococcus
      • Staphylococcus aureus (except for methicillin-resistant Staphylococcus aureus)
      • Staphylococcus epidermidis
    • Streptococcus
      • Group A streptococcal (GAS) infection caused by Streptococcus pyogenes in penicillin-sensitive patients (use azithromycin or use telithromycin if erythromycin-resistant)
      • Group B streptococcal (GBS) infection caused by Streptococcus agalactiae
      • Group C streptococcal (GCS) infection caused by Streptococcusdysgalactiae
      • Group G streptococcal (GGS) infection caused by Streptococcusdysgalactiae
      • Streptococcus pneumonia
  • Gram-negative organisms:
    • Bartonella
      • Bartonella henselae
    • Bordetella
      • Bordetella pertussis
    • Campylobacter spp
      • Campylobacter jejuni
    • Chlamydophila
      • Chlamydophila pneumoniae
    • Clostridium
      • Clostridium difficile
    • Escherichia
      • Escherichia coli
    • Haemophilis
      • Haemophilus influenzae
      • Haemophilis parainfluenzae
      • Haemophilus ducreyi
    • Helicobacter
      • Helicobacter pylori
    • Legionella
      • Legionella pneumophila
    • Moraxella
      • Moraxella catarrhalis
    • Neisseria
      • Neisseria gonorrhoeae
    • Salmonella spp
    • Shigella spp
    • Vibrio
      • Vibrio cholera
    • Yersinia
      • Yersinia enterocolitica
  • Atypical pathogens such as:
    • Babesia
      • Babesia microti
    • Chlamydia
      • Chlamydia trachomatis
    • Mycobacterium
      • Mycobacterium avium complex
    • Mycoplasma
      • Mycoplasma pneumoniae
      • Mycoplasma hominis
    • Rickettsiae
    • Toxoplasma
      • Toxoplasma gondii
    • Treponema
      • Treponema pallidum
    • Ureaplasma
      • Ureaplasma urealyticum
  • Zoonotic infections such as:
    • Borrelia
      • Borrelia burgdorferi
    • Chlamydophila
      • Chlamydophila pneumoniae

Indications and Usage

Azithromycin, clarithromycin and telithromycin have a broader spectrum of activity than erythromycin. The greatest use of the macrolides is in the treatment of upper respiratory tract infections.

The newer macrolides have enhanced gram-negative activity compared to erythromycin. As a result, an erythromycin-resistant gram-negative organism may be sensitive to azithromycin, clarithromycin and/or telithromycin.

Clinical indications and uses of macrolides and ketolides include:

  • Acute bacterial sinusitis, acute exacerbation of chronic bronchitis, acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) and acute otitis media caused by:
    • Haemophilus influenza
    • Haemophilus parainfluenzae (chronic bronchitis only)
    • Moraxella catarrhalis
    • Streptococcus pneumoniae
  • Bacterial conjunctivitis
  • Chlamydia trachomatis infection
  • Clostridium difficile-associated diarrhea (CDAD)
  • Community-acquired pneumonia (CAP) caused by:
    • Chlamydophila (also known as Chlamydia) pneumoniae
    • Haemophilus influenza
    • Haemophilus parainfluenzae
    • Moraxella catarrhalis
    • Mycoplasma pneumoniae
    • Streptococcus pneumoniae (including multidrug-resistant isolates)
  • Corynebacterium diphtheria in carriers
  • Genital ulcer disease (in men) caused by Haemophilus ducreyi (chancroid)
  • Impetigo
  • Legionnaire disease
  • Mild to moderate respiratory tract, skin and soft tissue infections
  • Mycobacterium avium complex (MAC), disseminated (prevention and treatment) in patients with advanced HIV infection caused by:
    • Mycobacterium avium
    • Mycobacterium intracellulare
  • Ocular infections (superficial): Treatment of superficial ocular infections involving the conjunctiva or cornea caused by organisms susceptible to erythromycin ophthalmic ointment.
  • Pelvic inflammatory disease (PID) caused by:
    • Chlamydia trachomatis
    • Mycoplasma hominis
    • Neisseria gonorrhoeae
  • Peptic ulcer disease: Eradication of Helicobacter pylori
  • Pertussis
  • Pharyngitis/Tonsillitis caused by:
    • Susceptible group A streptococci (Penicillin allergic patients)
    • Streptococcus pyogenes
  • Skin and skin structure infections (uncomplicated) caused by:
    • Staphylococcus aureus
    • Streptococcus agalactiae
    • Streptococcus pyogenes
  • Toxoplasmosis caused by:
    • Toxoplasma gondii
  • Urethritis and cervicitis caused by:
    • Chlamydia trachomatis
    • Neisseria gonorrhoeae

Some off-label uses of macrolides and ketolides include:

  • Acne vulgaris
  • Babesiosis
  • Bartonellosis in HIV-infected patients (excluding CNS infections and endocarditis)
  • Bartonella spp infections (bacillary angiomatosis [BA], peliosis hepatis [PH])
  • Bartonella spp infections in HIV-infected patients caused by:
    • Bacillary angiomatosis
    • Peliosis hepatis
    • Bacteremia
    • Osteomyelitis
  • Bronchiolitis obliterans syndrome
  • Cat scratch disease
  • Cesarean section (nonelective), prophylaxis (preoperative)
  • Chancroid
  • Gastroparesis
  • Gonococcal infection, conjunctivitis
  • Gonococcal infection, disseminated (arthritis, arthritis-dermatitis syndrome, meningitis, endocarditis)
  • Gonococcal infection, expedited partner therapy
  • Gonococcal infection, uncomplicated (cervix, rectum, urethra)
  • Gonococcal infection, uncomplicated (pharynx)
  • Granuloma inguinale (donovanosis)
  • Helicobacter pylori infection
  • Infection prophylaxis in neutropenia
  • Infective endocarditis (prophylaxis)
  • Lymphogranuloma venereum
  • Lyme disease
  • Mycoplasma genitalium
  • Pertussis
  • Prevention of pulmonary exacerbations in patients with noncystic fibrosis bronchiectasis
  • Prophylaxis against infective endocarditis
  • Prophylaxis against sexually transmitted diseases following sexual assault
  • Shigella dysentery type 1
  • Surgical (preoperative) prophylaxis (colorectal)
  • Traveler’s diarrhea

Macrolides are not used to treat meningitis.

Pharmacodynamics and Pharmacokinetics of Macrolides and Ketolides

Macrolides and Ketolides
Absorption

Azithromycin: oral
Rapid from the GI tract.
Clarithromycin: oral
Immediate release: Rapid absorption. Food delays rate, but not extent of absorption.
Extended-release: Fasting is associated with ~30% lower AUC relative to administration with food.
Erythromycin: oral
Variable but better with salt forms than with base form (18% to 45%). Ethylsuccinate may be better absorbed with food.
Fidaxomicin: oral
Minimal systemic absorption.
Telithromycin: oral
Rapid from the GI tract.

Time to Peak, Serum

Azithromycin: oral
Immediate release: ~2 to 3 hours.
Extended release: 3 to 5 hours.
Clarithromycin: oral
Immediate release: 2-3 hours.
Extended-release: 5-8 hours.
Erythromycin: oral
Base: 4 hours; Ethylsuccinate: 0.5-2.5 hours; Stearate: 3 hours. Delayed with food due to differences in absorption.
Telithromycin: 1 hour

Distribution

Azithromycin:
Extensive tissue distribution. Distributes well into skin, lungs, sputum, tonsils and cervix. Penetration into CSF is poor.
Clarithromycin:
Widely distributed into most body tissues. Unknown data regarding CNS penetration.
Erythromycin:
Relative diffusion from blood into CSF: Minimal even with inflammation. CSF: blood level ratio: Normal meninges: 2% to 13%; Inflamed meninges: 7% to 25%.
Fidaxomicin:
Largely confined to the gastrointestinal tract.
Telithromycin: 2.9 L/kg

Protein Binding

Azithromycin: Concentration dependent and dependent on alpha1-acid glycoprotein concentrations. Oral, IV: 7% to 51%.
Clarithromycin: 42% to 70%.
Erythromycin: Base: 73% to 81%.
Telithromycin: 60% to 70%. Primarily bound to albumin.

Metabolism

Azithromycin: Hepatic to inactive metabolites.
Clarithromycin: Partially hepatic via CYP3A4. Converted to 14-OH clarithromycin (active metabolite). Undergoes extensive first-pass metabolism.
Erythromycin: Demethylation primarily via hepatic CYP3A4.
Fidaxomicin: Intestinal hydrolysis to less active metabolite (OP-1118).
Telithromycin: Hepatic, via CYP3A4 (50%) and non-CYP-mediated pathways.

Bioavailability

Azithromycin: oral
Tablet, immediate release oral suspension: 34% to 52%.
Extended release oral suspension: 28% to 43%.
Clarithromycin: oral ~50%.
Telithromycin: 57%.

Excretion

Azithromycin:
Oral, IV: Biliary (major route 50%, unchanged). Urine (6% to 14% unchanged).
Clarithromycin:
Urine (20% to 40% as unchanged drug; additional 10% to 15% as metabolite). Feces (29% to 40% mostly as metabolites). Clearance: Approximates normal GFR.
Erythromycin:
Primarily feces. Urine (2% to 15% as unchanged drug).
Fidaxomicin: Feces (>92% as unchanged drug and metabolites). Urine (<1% as metabolite).
Telithromycin: Urine (13% unchanged drug, remainder as metabolites). Feces (7% unchanged drug).

Significant Adverse Reactions

Microlides and Ketolides
GeneralizedFatigue
Malaise
Weakness
Central Nervous SystemAggressive behavior
Agitation
Anxiety
Confusion
Depression
Disorientation
Dizziness
Drowsiness
Emotional lability
Hallucinations
Headache
Hyperactivity
Hostility
Insomnia
Irritability
Loss of consciousness
Manic behavior
Nervousness
Parasomnias
Paresthesia
Seizures
Vertigo
OphthalmicAccommodation disturbance
Blurred vision
Corneal erosion
Decreased visual acuity
Diplopia
Eye irritation
Hypersensitivity
Minor ocular irritation
Punctate Keratitis
Redness
Swelling of eye
Xerophthalmia
OticDeafness
Hearing loss
Otitis media
Tinnitus
CardiovascularAtrial arrhythmias including atrial fibrillation
Bradycardia
Cardiac arrest
Chest pain
Diaphoresis
Hypotension
Ischemic heart disease
Palpitations
Prolonged QT interval on ECG*
Syncope
Ventricular arrhythmias including ventricular tachycardia and torsade de pointes*
Respiratory

Asthma
Bronchospasm
Bronchitis
Cough
Dyspnea*
Pleural effusion
Pharyngitis
Pulmonary embolism
Rhinitis
Sinusitis

Neuromuscular and SkeletalArthralgia/Myalgia
Increased creatine phosphokinase
Dyskinesia/Hyperkinesia
Neck Stiffness
Endocrine and MetobolicDecreased serum bicarbonate
Increased gamma-glutamyl transferase
Increased serum bicarbonate
Hypoglycemia/Hyperglycemia
Hyponatremia
Hypokalemia/Hyperkalemia
Increased lactate dehydrogenase
Dermatologic

Acne vulgaris
Cellulitis
Contact dermatitis
Dermatitis
Erythema multiforme
Eczema
Maculopapular rash
Pruritus*
Skin photosensitivity
Skin rash*
Urticaria
Vesiculobullous dermatitis

Gastrointestinal

Abdominal distention/pain/tenderness
abnormal stools/constipation/diarrhea/melena
Ageusia/Dysgeusia
Anorexia
Diarrhea caused by Clostridium difficile (CDAD) {Clostridium difficile (colitis)}*
Dyspepsia
Dysphagia
Enteritis
Esophagitis
Flatulence
Gastric distress
Gastritis
Gastroenteritis
Gastrointestinal disease
Gastrointestinal hemorrhage
Gastroesophageal reflux disease
Glossitis
Intestinal obstruction
Megacolon
Mucositis
Nausea
Oral candidiasis
Pancreatitis
Pyloric stenosis
Pseudomembranous colitis
Stomatitis
Tongue discoloration
Vomiting
Xerostoma

Genitouriary

Acute renal failure
Dysuria
Increased blood urea nitrogen (BUN)/Creatinine (Cr)
Fungal vaginosis
Genital candidiasis
Interstitial nephritis
Nephritis
Urine discoloration
Vaginal infections
Vaginitis
Vulvovaginal candidiasis

Hematologic and OncologicBasophilia
Decrease/increase in absolute neutrophil count
Lymphocytopenia
Anemia
Eosinophilia
Increased monocytes
Leukopenia
Prolonged prothrombin time
Thrombocytopenia
Hepatic

Cholestatic hepatitis/Cholestatic jaundice
Hepatic insufficiency/failure
Hepatic necrosis
Hepatitis
Hepatotoxicity (idiosyncratic)
Increaed liver enzymes (PT/INR, aPTT, Albumin, Bilirubin-both direct and indirect)
Increased liver transaminases (AST or SGOT and ALT or SGPT)?
Increased serum bilirubin
Increased serum alkaline phosphatase
Jaundice

HypersensitivityAnaphylactoid reaction
Anaphylaxis*
Angioedema*
DRESS syndrome
Fixed drug reaction
Lambert-Eaton syndrome
Local ocular hypersensitivity reaction including burning sensation of eyes, eye discharge, eye irritation, eye pruritus, stinging of eyes
Henoch-Schonlein purpura (IgA vasculitis)*
Hypersensitivity reaction*
Steven-Johnson syndrome (SJS)*
Toxic epidermal necrolysis (TEN)*
LocalAdults with IV administation:
Pain at injections site
Local inflammation
Localized thrombophletitis
OthersAnosmia
Dysgeusia
Epistaxis
Exacerbation of myasthenia gravis*
Facial edema
hemorrhage
Increased serum phosphate
Metabolic acidosis
Rhabdomyolysis
* US Box Warning

Warnings/Precautions Related to Macrolides and Ketolides

Patients should be monitored for:

  1. Concerns Related to Adverse Reactions
  • Hypersensitivity Reactions
    • Allergic reactions (e.g., angioedema [mouth, face, throat], dyspnea, pruritis and rash, anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) and Henoch-Schönlein purpura (IgA vasculitis) have been reported (rare), including fatalities.
    • Discontinue therapy and initiate treatment immediately for severe acute hypersensitivity reactions.
    • Reappearance of allergic reaction may occur shortly after discontinuation of symptomatic treatment without further azithromycin exposure.
  • Altered Cardiac Conduction
    • Macrolides (especially Erythromycin) have been associated with rare QT interval prolongation and ventricular arrhythmias, including torsade de pointes.
    • Consider avoiding use in patients with:
      • Prolonged QT interval
      • Congenital long QT syndrome
      • History of ventricular cardiac arrhythmias including torsade de pointes
      • Bradyarrhythmias
      • Uncorrected hypokalemia or hypomagnesemia
      • Clinically significant bradycardia
      • Uncompensated heart failure
      • Concurrent use of Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents or other drugs known to prolong the QT interval.
  • Cardiac Risk (Azithromycin only)
    • There appears to be an increased cardiac mortality risk with azithromycin. In a retrospective population study of U.S. veterans, azithromycin was shown to significantly increase the risk of mortality and arrhythmia on days 1 to 5, but not on days 6 to 10 after dispensing the prescription.
  • Hepatic Effects (Clarithromycin and Telithromycin)
    • May lead to acute hepatic failure or death, especially in the presence of preexisting diseases and/or concomitant use of medications.
    • Less severe hepatic dysfunction associated with increased liver enzymes and hepatitis with or without jaundice has also been reported but are usually reversible.
    • Discontinue immediately if signs and symptoms of hepatitis (e.g., anorexia, jaundice, abdominal tenderness, pruritus, dark urine) or liver damage occur.
  • Superinfection
    • Prolonged use may result in fungal or bacterial superinfection, including Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis.
    • CDAD has been observed greater than 2 months post antibiotic treatment.
    • A patient with continued diarrhea, fever and a rising white blood count should be evaluated for CDAD
  • Visual Disturbances (Telithromycin only)
    • May cause visual disturbances (e.g., changes in accommodation ability, diplopia, blurred vision).
    • Most cases are mild to moderate, but severe cases have been reported.
    • Caution patients that these events may interfere with ability to operate machinery or drive and to use caution until effects are known.
  1. Laboratory/Diagnostic Results
  • Perform culture and sensitivity testing prior to initiating therapy and where appropriate during treatment.
  • Coagulation studies
  • Complete CBC with differential
  • Electrolytes including BUN/Creatinine, Magnesium
  • Liver function tests
  • Ophthalmologic evaluation if visual disturbances occur.
  1. Hypersensitivity Reactions
  • Discontinue use if allergic reactions occur.
  1. Drug-Drug Interactions
  • Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring and/or selection of alternative therapy.
  • Erythromycin is a major inhibitor of CYP3A4 so should be used with caution with any agents with substantial metabolism through the CYP3A4 pathway. Avoid concurrent use with strong CYP3A4 inhibitors thus avoiding the risk of sudden cardiac death.
  1. Disease-Related Concerns
  • Gonorrhea/Syphilis
    • May mask or delay symptoms of incubating gonorrhea or syphilis, so appropriate culture and susceptibility tests should be performed prior to initiating a treatment regimen.
  • Hepatic Impairment
    • Use with caution in patients with preexisting liver disease, hepatic impairment, including hepatocellular and/or cholestatic hepatitis, with or without jaundice.
    • Hepatic necrosis, failure and death have occurred.
    • Discontinue immediately if symptoms of hepatitis occur (malaise, nausea, vomiting, abdominal colic, fever).
  • Myasthenia Gravis
    • Life-threatening (including fatal) respiratory failure has occurred in patients with myasthenia gravis.
    • Use in these patients is contraindicated.
    • Exacerbations of myasthenia gravis may occur within hours of the first dose.
    • Respiratory failure with a rapid onset and progression has been reported.
  • Renal Impairment
    • Use with caution in patients with severe renal impairment (GFR less than 10 mL/minute).
    • Increased gastrointestinal adverse effects may occur.
    • Dosage adjustment may be required.
  1. Concerns Related to Special Populations
  • Contact Lens Wearers (Azithromycin ophthalmic)
    • Solution contains benzalkonium chloride which may be absorbed by contact lenses.
    • Contact lens should not be worn during treatment.
  • Elderly (Clarithromycin and Erythromycin)
    • Use with caution.
    • Systemic exposure is increased.
    • Elderly patients may be at increased risk of adverse reactions including hearing loss and/or torsade de pointes, particularly if concurrent severe renal/hepatic impairment.
  • HIV patients (Clarithromycin)
    • Decreased survival has been observed in HIV patients with Mycobacterium avium complex (MAC) receiving clarithromycin doses above the maximum recommended dose.
    • Maximum recommended dosing should not be exceeded in this population.
    • Development of resistance to clarithromycin has been observed when used as prophylaxis and treatment of MAC infection.

Contraindications

  • Patients who have had an allergic reaction or hypersensitivity reaction to macrolides and/or ketolides or any component of the formulation.
  • Patients with a previous history of cholestatic jaundice/hepatic dysfunction.
  • Concomitant administration with colchicine as it may lead to colchicine toxicity. Symptoms of colchicine toxicity include gastrointestinal upset, fever, myalgia, pancytopenia and organ failure.
  • Concomitant administration with any of the following medications because of the potential for fatal cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes):
    • Astemizole
    • Cisapride
    • Pimozide
    • Terfenadine
    • Ergotamine
    • Ticagrelor
    • Ranolazine
    • Dihydroergotamine
    • Lovastatin or Simvastatin or Atorvastatin (Cholesterol medications)
    • Theophylline
    • Methadone
  • Telithromycin is contraindicated in patients with myasthenia gravis due to reports of fatal and life-threatening respiratory failure.

Other Warnings/Precautions

  • Limitations of use:
    • Azithromycin
      • Azithromycin (tablets, oral suspension, Zmax only)
      • Not recommended for use in patients with moderate to severe pneumonia with any of the following concomitant conditions: cystic fibrosis, nosocomial infections, known or suspected bacteremia, hospitalized, elderly or debilitated or significant health problems that affect the ability to respond to illness (e.g., immunodeficiency, functional asplenia).
    • Clarithromycin for Helicobacter pylori eradication
      • Short-term combination therapy (7 days or less) has been associated with a higher incidence of treatment failure.
      • Current guidelines recommend 10 to 14 days of therapy (triple or quadruple) for eradication of Helicobacter pylori in adult patients.
    • Fidaxomicin
      • Do not use for systemic infections since systemic absorption is negligible.
      • Use only in patients with proven or strongly suspected Clostridium difficile infections.

Use During Pregnancy and Breastfeeding

Macrolide Antibiotics
AgentsPregnancy Risk Factor*Breastfeeding Considerations
AzithromycinBExcreted in low amounts into breast milk
ClarithromycinCExcreted into breast milk
ErythomycinBErythomycin is excreted in breast milk. Erythromycin is considered compatible with breastfeeding
FidaxomicinBIt is not known if fidaxomicin is excreted in breast milk
* See Appendix A
Ketolide Antibiotics
AgentPregnancy Risk Factor*Breastfeeding Considerations
TelithromycinCIt is not known if tigecycline is excreted in breast milk
* See Appendix A

Resistance

There are three kinds of acquired bacterial resistance to macrolides/ketolides:

  • Post-transcriptional methylation of the 23S bacterial ribosomal RNA either plasmid-mediated or chromosomal, i.e., through mutation, so cross-resistance to macrolides occurs.
  • Production of drug-inactivating enzymes (esterases or kinases).
  • Production of active ATP-dependent efflux proteins that transport the drug outside of the cell.

Dosing Considerations

Dosing: Adult

Erythromycin and, to some extent, clarithromycin interact with numerous drugs because they inhibit hepatic metabolism via the cytochrome P-450 (CYP450) system. Azithromycin is the least likely to interact with other drugs. Interactions may occur when erythromycin or clarithromycin are taken with the following:

  • Warfarin: Further elevation of the PT/INR
  • Lovastatin and Simvastatin: Rhabdomyolysis
  • Midazolam and Triazolam: Somnolence
  • Theophylline: Nausea, vomiting and seizures
  • Tacrolimus, Cyclosporine, and Ergot Alkaloids: Elevated serum levels of these drugs

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

  • Azithromycin
    • Use with caution in patients with GFR less than 10 mL/minute. However, no dosage adjustment is provided in the manufacturer’s labeling.
    • No supplemental dose or dosage adjustment necessary, including patients on intermittent hemodialysis, peritoneal dialysis or continuous renal replacement therapy (e.g., CVVHD).
  • Clarithromycin
    • CrCl ≥30 mL/minute: No dosage adjustment necessary.
    • CrCl <30 mL/minute: Decrease clarithromycin dose by 50%.
    • Hemodialysis: Administer after hemodialysis session is completed.
    • In combination with atazanavir or ritonavir:
      • CrCl 30 to 60 mL/minute: Decrease clarithromycin dose by 50%.
      • CrCl less than 30 mL/minute: Decrease clarithromycin dose by 75%.
  • Erythromycin
    • There are no dosage adjustments provided in the manufacturer's labeling.
    • Dialysis: Slightly dialyzable (5% to 20%). A supplemental dose is not necessary for hemo- or peritoneal dialysis or continuous arteriovenous or venovenous hemofiltration.
  • Fidaxomicin
    • No dosage adjustment necessary (minimal systemic absorption).
  • Telithromycin
    • CrCl ≥ 30 mL/minute: No dosage adjustment necessary
    • CrCl <30 mL/minute: Decrease daily dosage.
    • CrCl <30 mL/minute and concomitant hepatic impairment: Decrease daily dosage.
    • Hemodialysis: Administer after dialysis on dialysis days.

Dosing: Hepatic Impairment

  • Azithromycin is predominantly hepatically eliminated.
    • Use with caution due to the potential for hepatotoxicity (rare).
    • Discontinue immediately for signs or symptoms of hepatitis.
  • Clarithromycin
    • In patients with hepatic impairment and concomitant severe renal impairment, a dosage reduction or prolonged dosing intervals may be appropriate.
  • Erythromycin
    • There are no dosage adjustments provided in the manufacturer's labeling.
    • Use with caution.
  • Fidaxomicin
    • No dosage adjustment provided in manufacturer’s label.
    • Due to minimal systemic absorption, no dosage adjustment predicted.
  • Telithromycin
    • No dosage adjustment necessary, unless concurrent renal impairment (e.g., CrCl <30 mL/minute) is present.

Ophthalmic Administration

  • Azithromycin Ophthalmic Drops (AzaSite):
    • For topical ophthalmic use only.
    • Do not inject subconjunctivally or introduce directly into the anterior chamber of the eye.
    • Avoid touching tip of applicator to the eye or other surfaces.
    • Invert closed bottle and shake once before each use.
    • With bottle inverted, remove cap, tilt head back and gently squeeze bottle to instill drop.
    • Wash hands before and after instillation.
  • Erythromycin Ophthalmic Ointment (Ilotycin Ophthalmic)
    • For ophthalmic use only.
    • Do not touch the tip of applicator.
    • Avoid contact of the tip of ophthalmic ointment tube with affected eye.
    • Avoid contamination.

Oral Administration/Dietary Considerations

  • Azithromycin
    • Immediate release suspension and tablet may be taken without regard to food.
    • Extended release suspension should be taken on an empty stomach (at least 1 hour before or 2 hours following a meal), within 12 hours of reconstitution.
    • Oral suspensions: Immediate release and extended release suspensions are not interchangeable.
    • Tablet may be administered with food to decrease GI effects.
    • Some products may contain sodium and/or sucrose.
  • Clarithromycin
    • Immediate release tablets and granules for suspension:
      • Administer with or without meals.
      • Administer every 12 hours rather than twice daily to avoid peak and trough variation.
      • Shake suspension well before each use.
  • Extended release tablets:
    • Administer with food.
    • Do not break, crush or chew.
  • Erythromycin
    • Administer base, PCE or stearate dosage forms on an empty stomach (2 hours before or after a meal).
    • Administer ethylsuccinate (EES) or delayed-release (ERY-TAB) without regards to meals but may consider administering after food to decrease GI discomfort.
    • Swallow delayed release capsule or enteric coated tablets whole.
      • Do not chew or break.
  • Fidaxomicin
    • May be administered with or without food.


IV Infusion Administration

  • Azithromycin
    • IV: Infuse over 1 hour (2 mg/ml infusion) or over 3 hours (1 mg/ml infusion).
    • Not for IM or IV bolus administration.
  • Erythromycin
    • IV: Infuse 1 g over 20 to 60 minutes.
    • IV infusion may be very irritating to the vein.
    • Infusion should be sufficiently slow to minimize pain along the vein.
    • Do not administer IV push or bolus.


Topical Administration

Prior to treatment, thoroughly wash affected area with mild soap and warm water, rinse and pat dry. Wash hands after use. Avoid contact with the eyes, nose, mouth, other mucous membranes and broken skin.

  • Erythromycin
    • Gel: (Erygel 2%)
      • Apply sparingly as a thin film over the affected area once or twice daily.
      • Therapeutic response may take up to 6 to 8 weeks.
      • Discontinue use if no improvement after 6 to 8 weeks or if condition worsens.
    • Ointment (Akne-Mycin: 2%; solution (Generic: 2%)
      • Apply to affected area twice daily (morning and evening).
      • Drying and peeling may be controlled by reducing the frequency of application.
    • Pads (Ery 2%):
      • Rub pad over affected areas twice daily (morning and evening).
      • Discard pad after single use.
      • Additional pads may be used if needed. 

Summary

Azithromycin (Zithromax), clarithromycin (Biaxin) and fidaxomicin (Dificid) are macrolide antibiotics derived from the older macrolide antibiotic, erythromycin. Telithromycin (Ketek) is the first member of the ketolide class of antimicrobials, which is related to the macrolide class. The mechanism of action of the newer macrolides is similar to that of erythromycin. Structural changes have made the newer macrolides more acid stable than erythromycin, providing improved oral absorption, tolerance and pharmacokinetic properties. The newer macrolides also have a broader spectrum of antibacterial activity than erythromycin.

Because of its more frequent gastrointestinal side effects and the earlier appreciation of the risk of QT prolongation and sudden death, erythromycin is rarely recommended, but subsequent reports and studies have also described QT prolongation with clarithromycin and azithromycin, as well as, the ketolide, telithromycin.  Reports have also identified various hepatic abnormalities in patients receiving macrolides, including cases that have resulted in death. The macrolides have a variety of drug interactions, many of which are mediated by inhibition of hepatic cytochrome CYP (P450) 3A enzymes. In contrast with the other macrolides, azithromycin does not appear to affect hepatic enzymes significantly, leading to fewer documented drug interactions.

Lincosamides

Lincosamides
AgentsCommon Brand Name(S)Route(s)
Clindamycin

Oral: Cleocin; Clindamycin HCL; Clindamycin Palmitate HCL

IM: CLIN single use; Cleocin Phosphate; Clindamycin Phosphate

IV infusion: Cleocin in D5W; Cleocin Phosphate Intravenous; Clindamycin Phosphate Intravenous

Topical: Cleocin; Cleocin-T; Clindacin ETZ; Clindacin Pac; Clindacin-P; Clindagel; ClindaMax; Clindesse; Evoclin

Vaginal cream: Cleocin 2%; Clindesse 2%; Generic 2%

Vaginal Foam: Evoclin 1%; Generic 1%

Vaginal Gel: Cleocin-T 1%; Clindagel 1%; ClindaMax 1%; Generic 1%

Kit External: Clindacin ETZ 1%; Clindacin Pac 1%

Lotion External: Cleocin-T 1%; Generic 1%

Solution External: Cleocin-T 1%; Generic 1%

Swab External: Cleocin-T 1%; Clindacin ETZ 1%; Clindacin-P 1%; Generic 1%

Vaginal Suppository: Cleocin vaginal
Oral, IM, IV infusion, Topical, Vaginal
LincomycinLincocin Injection; Lincomycin HCL InjectionIM, IV infusion*
* Lincomycin ophthalmic route will not be discussed in the learning module

Mechanism of Action

Lincosamides reversibly bind to 50S ribosomal subunits preventing peptide bond formation thus inhibiting bacterial protein synthesis. These therapeutic agents are bacteriostatic or bactericidal depending on drug concentration, infection site and organism.

Microbiology

Lincosamides have antibacterial activity against susceptible organisms such as:

  • Gram-positive anaerobes:
    • Actinomyces israelii
    • Clostridium clostridioforme
    • Clostridium perfringens
    • Eubacterium lentum
    • Finegoldia ("Peptostreptococcus") magna
    • Micromonas ("Peptostreptococcus") micros
    • Peptostreptococcus anaerobius
    • Propionibacterium acnes
    • Staphylococcus aureus
    • Staphylococcus epidermidis
    • Streptococcus agalactiae
    • Streptococcus anginosus
    • Streptococcus mitis
    • Streptococcus oralis
    • Streptococcus pneumoniae
    • Streptococcus pyogenes
  • Gram-negative anaerobes:
    • Bacteroides fragilis
    • Prevotella melaninogenica
    • Fusobacterium necrophorum
    • Fusobacterium nucleatum
    • Prevotella intermedia
    • Prevotella bivia 

Indications and Usage

Clinical indications and uses of Lincosamides caused by susceptible anaerobes include:

  • Central nervous system infections including:
    • CNS Toxoplasmosis
  • Lower respiratory tract infections including:
    • Empyema
    • Lung abscess
    • Pneumonia
    • Pneumocystis (Carinii)
    • Staphylococcus aureus
    • Streptococcus pneumoniae
    • Other streptococci (except Enterococcus faecalis)
  • Skin, skin structure, mucous membrane and sinus infections including:
    • Impetigo
    • Orofacial/Parapharyngeal Space Infections
    • Pharyngitis, group A streptococci
    • Propionibacterium acnes treatment
    • Rosacea
    • Skin and soft tissue infections due to MSSA
    • Streptococcal skin infections
  • Gynecological infections including:
    • Amnionitis
    • Bacterial vaginosis
    • Endometritis
    • Gardnerella vaginalis
    • Nongonococcal tubo-ovarian abscess
    • Pelvic cellulitis
    • Pelvic Inflammatory Disease (PID)
    • Postsurgical vaginal cuff infection
  • Intra-abdominal infections including:
    • Intra-abdominal abscess
    • Peritonitis
  • Septicemia including:
    • Staphylococcus aureus
    • Streptococci (except Enterococcus faecalis)
    • Toxic Shock Syndrome
  • Bone and joint infections including:
    • Acute hematogenous osteomyelitis caused by Staphylococcus aureus
    • Adjunctive therapy in the surgical treatment of chronic bone and joint infections
    • Gangrenous pyomyositis
    • Prosthetic joint infections
  • Other clinical infections including:
    • Sarcoidosis
    • Toxoplasmosis

Some off-label uses of Lincosamides include:

  • Acute bacterial rhinosinusitis
  • Anthrax (inhalational and gastrointestinal)
  • Babesiosis
  • Bite wounds (animal)
  • Group B streptococcus (GBS) infection (maternal use for neonatal prophylaxis in penicillin-allergic women)
  • Infective endocarditis (prophylaxis)
  • Malaria (uncomplicated, severe)
  • Methicillin-resistant staphylococcus aureus (MRSA) infection
  • Osteomyelitis due to MRSA
  • Pneumonia due to MRSA
  • Pneumocystis pneumonia (PCP) in HIV-infected patients (adolescents and adults)
  • Prophylactic use prior to cesarean delivery and may be used in certain situations prior to vaginal delivery in women at high risk for endocarditis
  • Prophylaxis in patients with prosthetic joint implants undergoing dental procedures which produce bacteremia
  • Prosthetic joint infection Chronic antimicrobial suppression, Staphylococci (oxacillin-susceptible)
  • Septic arthritis due to MRSA
  • Skin and soft tissue infections due to MRSA
  • Skin and soft tissue necrotizing infections (empiric therapy of polymicrobial infections or in combination with penicillin IV for the treatment of group A streptococcal or Clostridium species necrotizing infections)
  • Surgical (perioperative) prophylaxis
  • Toxoplasma gondii encephalitis (treatment/chronic maintenance) in HIV-infected patients (adolescents and adults)

Pharmacodynamics and Pharmacokinetics of Lincosamides

Lincosamide
Absorption

Clindamycin:

Oral, hydrochloride: Rapid (90%). Clindamycin palmitate must be hydrolyzed in the GI tract before it is active

Topical solution or foam, phosphate: Minimal

Vaginal cream, phosphate: ~5%

Vaginal suppository, phosphate: ~30%

Lincomycin: No oral form
Time to Peak, Serum

Clindamycin:

Oral: Within 60 minutes

IM: 1 to 3 hours

Vaginal cream: ~10-14 hours (range: 4-24 hours).

Vaginal suppository: ~5 hours (range: 1-10 hours).

Lincomycin:

IM: 30-60 minutes
Distribution

Clindamycin:

Distributed in body fluids and tissues. High concentrations in bone and urine. No significant levels in CSF, even with inflamed meninges

Lincomycin:

Distributed in body fluids and tissues including peritoneal fluid, pleural fluid, synovial fluid, bone, bile, aqueous humor eye. No significant levels in the CSF
Protein Binding

Clindamycin: 94%.

Lincomycin: 57-72%
Metabolism

Clindamycin:

IM or IV infusion:Clindamycin phosphate is converted to clindamycin HCl (active)

Hepatic: forms metabolites (variable activity).

Lincomycin: Hepatic

Half-life Elimination

Clindamycin:

Adults: 3 hours

Elderly (oral) 4 hours (range: 3.4 to 5.1 hours)

Vaginal cream: 1.5-2.6 hours following repeated dosing

Vaginal suppository: 11 hours (range: 4-35 hours, limited by absorption rate)

Lincomycin:

~5 hours. Prolonged with renal or hepatic impairment
Excretion

Clindamycin:

Urine (10%) and feces (~4%) as active drug and metabolites

Urine (<0.2% with topical foam and solution)

Lincomycin:

Urine (2% to 30%); bile

Significant Adverse Reactions to Lincosamides

Lincosamides
GeneralizedNone
Central Nervous System

Metallic taste (IV)
Vertigo

OphthalmicEye Irritation/pain
OticTinnitus
CardiovascularCardiopulmonary arrest
Hypotension
RespiratoryUpper respiratory infection
Neuromuscular and SkeletalPolyarthritis
Endocrine and MetabolicHyperthyroidism
Dermatologic

Acute generalized exanthematous pustulosis
Bullous dermatitis
Burning sensation of skin (gel, lotion, solution)
Contact dermatitis
Erythema (gel, lotion, solution)
Erythema multiforme*
Exfoliative dermatitis (lotion, solution)
Folliculitis
Folliculitis (gram-negative infection)
Maculopapular rash
Oily skin (gel, lotion, solution)
Pruritus (gel, lotion, solution)
Skin rash
Urticaria
Vesiculobullous dermatitis
Xeroderma (gel, lotion, solution)

Gastrointestinal

Abdominal distress/pain
Constipation
Diarrhea
Diarrhea caused by Clostridium difficile (CDAD)* {Clostridium difficile (colitis)}*
Diarrhea (hemorrhagic or severe)
Dyspepsia
Esophagitis
Esophageal ulcer
Gastrointestinal disease
Glossitis
Nausea
Pruritis ani
Pseudomembranous colitis
Stomatitis
Vomiting

Genitourinary

Azotemia
Dysuria
Endometriosis
Menstrual disease
Oliguria
Proteinuria
Pyelonephritis
Renal insufficiency
Trichomonal vaginitis
Urinary tract infection
Uterine hemorrhage
Vaginal infection
Vaginal Pain
Vaginitis
Vaginal moniliasis
Vulvovaginitis
Vulvovaginal pruritis

Hematologic and OncologicAgranulocytosis
Aplastic anemia
Eosinophilia (transient)
Immune thrombocytopenia
Leukopenia
Neutropenia (transient)
Pancytopenia
Thrombocytopenia
HepaticAbnormal hepatic function tests
Increased liver transaminases (AST or SGOT and ALT or SGPT)
Jaundice
HypersensitivityAnaphylactoid reaction*
Anaphylactic shock*
Anaphylaxis*
Angioedema
DRESS syndrome*
Hypersensitivity reaction
Serum sickness
Steven-Johnson Syndrome (SJS)*
Toxic epidermal necrolysis (TEN)*
LocalAbscess at injection site (IM)
Induration at injection site (IM)
Irritation at injection site (IM)
Pain at injection site (IM)
Thrombophlebitis (IV)
OthersBacterial infection
Dysgeusia
Edema
Epistaxis
Flank pain
Fungal infection
* Alert: US Boxed Warning

Warnings/Precautions Related to Lincosamides

Patients should be monitored for:

  1. Concerns Related to Adverse Reactions
  • Colitis
    • Clostridium difficile–associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin and lincomycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of Clostridium difficile.
    • Because clindamycin and lincomycin therapy have been associated with severe colitis, which may end fatally, they should be reserved for serious infections for which less toxic antimicrobial agents are inappropriate.
    • Clindamycin and Lincomycin should not be used in patients with nonbacterial infections such as most upper respiratory tract infections.
    • Hypertoxin-producing strains of Clostridium difficile (toxins A and B) cause increased morbidity and mortality since these infections can be refractory to antimicrobial therapy and may require colectomy.
    • Clostridium difficile-associated diarrhea (CDAD) must be considered in all patients who present with diarrhea following antibiotic use.
      • CDAD has been reported to occur more than 2 months post antibiotic treatment.
      • If CDAD is suspected or confirmed, ongoing antibiotic use not directed against Clostridium difficile may need to be discontinued.
      • Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of Clostridium difficile and surgical evaluation should be instituted as clinically indicated.
  • Hypersensitivity
    • Severe hypersensitivity reactions, including severe skin reactions (e.g., drug reaction with eosinophilia and systemic symptoms [DRESS], Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN]), some fatal, have been reported.
    • Permanently discontinue treatment if these reactions occur.
    • Serious anaphylactoid or anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen and IV corticosteroids should also be administered as indicated.
  • Superinfection
    • Use may result in overgrowth of nonsusceptible organisms, particularly yeast.
    • Should superinfection occur, appropriate measures should be taken as indicated by the clinical situation.
  1. Laboratory/Diagnostic Results
  • Perform culture and sensitivity testing where possible prior to initiating therapy and where appropriate during treatment.
  • Observe for changes in bowel frequency or consistency (e.g., diarrhea).
    • If diarrhea occurs monitor:
      • Stool cultures and sensitivity
      • CBC with differential and electrolytes
      • Sigmoidoscopy and colonoscopy results
      • Computed tomography (CT) and abdominal x-ray results
  • Monitor for colitis and resolution of symptoms.
  • Monitor baseline renal function, liver function tests (LFTs) and electrolytes.
  • In severe liver disease monitor LFT’s periodically.
  • During prolonged therapy monitor complete blood count (CBC) with differential, liver and renal function tests periodically.
  1. Hypersensitivity Reactions
  • Discontinue use if allergic reactions occur.
  1. Drug-Drug Interactions
  • Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring and/or selection of alternative therapy.
  1. Disease-Related Concerns
  • Allergies
    • Use with caution in patients with significant allergies or a history of asthma.
  • Gastrointestinal Disease
    • Use with caution in patients with a history of GI disease, particularly colitis.
  • Hepatic Impairment
    • Use with caution in patients with moderate to severe liver disease since half-life may be prolonged.
    • However, when administered at every-8-hour intervals, drug accumulation is rare.
    • Monitor hepatic enzymes periodically as dosage adjustments may be necessary for patients with severe liver disease.
  • Renal Impairment (Lincomycin only)
    • Use with caution in patients with renal impairment since the half-life may be prolonged.
    • Dosage adjustment may be necessary with severe impairment.
  1. Concerns Related to Special Populations
  • Atopic patients
    • Use with caution in atopic patients.
  • Elderly
    • A subgroup of older patients with associated severe illness may tolerate diarrhea less well.
      • Monitor carefully for changes in bowel frequency and consistency.

Contraindications

  • Hypersensitivity to clindamycin, lincomycin or any component of the formulation.
  • Patients with a past history of CDAD (Clostridium difficile-associated diarrhea), regional enteritis, ulcerative colitis.
  • Not appropriate for use in the treatment of meningitis due to inadequate penetration into the cerebrospinal fluid.

Use During Pregnancy and Breastfeeding

Lincosamide Antibiotics
AgentsPregnancy Risk Factor*Breastfeeding Considerations
ClindamycinBClindamycin can be detected in breast milk. Not recommended by the manufacturer
LincomycinCLincomycincan be detected in breast milk. The manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.
* See Appendix A

Resistance

The resistance mechanism of lincosamides is methylation of the 23S binding site. If this occurs, then the bacteria are resistant to both the macrolides and the lincosamides. Also, enzymatic inactivation of clindamycin has been described.

Dosing Considerations

Dosing: Adult

The appropriate use of Lincosamides is reserved when treatment with other antibiotics is inappropriate. Lincosamides are not appropriate for use in the treatment of meningitis due to inadequate penetration into the cerebrospinal fluid.

In the case of serious bacterial infections, administration frequency may be increased if needed due to severity of infection.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

  • Clindamycin and Lincomycin
    • Mild to moderate impairment
      • There are no dosage adjustments provided in the manufacturer’s labeling.
    • Severe impairment
      • Use with caution.
      • May need to decrease the dosage of lincomycin by 70% to 75%.
    • End-stage renal disease (ESRD) on hemodialysis or peritoneal dialysis.
      • Not removed by hemodialysis or peritoneal dialysis. No supplemental dose or dosage adjustment necessary.
    • Continuous renal replacement therapy (CRRT) (e.g., CVVH, CVVHD, CVVHDF)
      • No supplemental dose or dosage adjustment necessary.

Dosing: Hepatic Impairment

  • Clindamycin and Lincomycin
    • Mild impairment
      • There are no dosage adjustments provided in the manufacturer's labeling.
      • Use with caution.
  • Clindamycin
    • Moderate to severe impairment
      • There are no dosage adjustments provided in the manufacturer's labeling.
      • In studies of patients with moderate or severe liver disease, half-life is prolonged, however, when administered on an every 8-hour schedule, accumulation should rarely occur.
      • In severe liver disease, use caution and monitor liver enzymes periodically during therapy.

Oral Administration/Dietary Considerations

  • Lincomycin
    • Administer with a full glass of water to minimize esophageal ulceration.
    • Give around-the-clock to promote less variation in peak and trough serum levels.
    • Coadministration with food does not adversely affect the absorption of clindamycin-flavored granules.

Intravaginal/Topical administration

  • Clindamycin
    • Intravaginal:
      • Points to Remember:
        • Vaginal products may weaken condoms or contraceptive diaphragms. Barrier contraceptives are not recommended to be used concurrently.
    • Cream
      • Insertion of the applicator should be as far as possible into the vagina without causing discomfort.
    • Ovule
      • The foil should be removed.
      • If the applicator is used for insertion, it should be washed for additional use.
    • Topical:
      • Points to Remember
        • Topical solution (including pledgets) contains an alcohol base and may cause eye irritation or burning.
        • Rinse with cool tap water if product comes into contact with mucous membranes, abraded skin or eyes.
        • Use caution when applying near mouth (unpleasant taste).
    • Foam
      • Clindamycin foam may cause irritation, especially when used with abrasive, desquamating or peeling agents.
      • Dispense directly into cap or onto a cool surface.
      • Do not dispense directly into hands or face (foam will melt on contact with warm skin).
      • Wash skin with mild soap and allow to dry fully.
      • Apply in small amounts to face using fingertips and gently massage into affected areas until foam disappears.
      • Avoid contact with eyes, mouth, lips, mucous membranes or broken skin.
    • Gel
      • Avoid contact with eyes.
    • Lotion
      • Shake well immediately before using.
    • Solution or Pledget
      • Avoid contact with eyes, mouth or other mucous membranes.
      • Solution/pledget contains an alcohol base and if inadvertent contact with mucous membranes occurs, rinse with liberal amounts of water.
      • Remove pledget from foil immediately before use.
        • Discard after single use.
        • May use more than one pledget for each application to cover area.

IM Administration

  • Inject deep into large muscle mass, rotate sites.
  • Clindamycin: Do not exceed 600 mg in a single injection.

IV Infusion Administration

  • Do not use undiluted as an IV bolus.
  • Administer by IV intermittent infusion over at least 10-60 minutes per physician order.
    • Cardiopulmonary arrest and hypotension have been reported following too rapid IV infusion.

Summary

Lincosamides reversibly bind to 50S ribosomal subunits preventing peptide bond formation thus inhibiting bacterial protein synthesis. These therapeutic agents are bacteriostatic or bactericidal depending on drug concentration, infection site and organism.

Lincosamides have antibacterial activity against various susceptible gram-positive and gram-negative anaerobes. Clinical indications for the use of Lincosamides primarily include central nervous system infections, lower respiratory tract infections, skin and skin structure, mucous membrane and sinus infections, gynecologic infections, intra-abdominal infections, septicemia and bone and joint infections. Lincosamides also have many off-label uses.

The pharmacodynamics and pharmacokinetics of the Lincosamides are important to an understanding of how the therapeutic agents work in the body and how significant adverse reactions can evolve. Thorough assessment and monitoring of the patient are imperative in the prevention of a worsening of the patient’s health status, as well as, enhancing the patients return to health by eradicating the serious pathogen.

Dosing considerations prior to the prescribing of the therapeutic agent by age considerations, as well as, renal and hepatic function are imperative. Administration of the Lincosamides varies as to route with thorough patient education being imperative in the out-patient setting.

Streptogramins

Streptogramins
AgentsCommon Brand Name(s)Route(s)
Pristinamycin*PristinamycineOral
Quinupristin/DalfopristinSynercidIV Infusion
* Pristinamycin is marketed primarily in Europe therefore, will not be considered in this learning module. All information about Quinupristin/Dalfopristin applies accept for route of administration

Pristinamycin is a streptogramin antibiotic. It is a mixture of two components that have a synergistic antibacterial action:

  • Pristinamycin IA (PI) is a macrolide and has a similar spectrum of activity to erythromycin.
  • Pristinamycin IIA (PII) (streptogramin A) is a depsipeptide.

Quinupristin and Dalfopristin are both Streptogramin antibiotics, derived from Pristinamycin.

  • Quinupristin is derived from Pristinamycin IA.
  • Dalfopristin from Pristinamycin IIA.
  • They are combined in a weight-to-weight ratio of 30% Quinupristin to 70% Dalfopristin.

The lack of an intravenous formulation of Pristinamycin led to the development of the Pristinamycin-derivative Quinupristin/Dalfopristin which may be administered intravenously for more severe MRSA infections.

Mechanism of Action

Quinupristin and Dalfopristin are protein synthesis inhibitors in a synergistic manner. While each of the two is only a bacteriostatic agent, the combination shows bactericidal activity.

  • Quinupristin binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide, as well as, causing incomplete chains to be released.
  • Dalfopristin binds to the 23S portion of the 50S ribosomal subunit thus changing the conformation of it, enhancing the binding of Quinupristin by a factor of about 100. In addition, it inhibits peptidyl transfer. 

Microbiology

Streptogramins have antibacterial activity against susceptible organisms such as:

  • Gram-positive bacteria:
    • Enterococcus faecium including:
      • Ampicillin-resistant Enterococcus faecium
      • Multi-drug resistant Enterococcus faecium
      • Vancomycin-resistant Enterococcus faecium (VRE)
    • Staphylococcus aureus including:
      • Methicillin-resistant Staphylococcus aureus (MRSA)
      • Methicillin-susceptible Staphylococcus aureus (MSSA)
      • Multi-resistant coagulase negative Staphylococcus aureus
    • Staphylococcus epidermidis including:
      • Methicillin-resistant Staphylococcus epidermidis
    • Streptococcus agalactiae
    • Streptococcus pyogenes

Indications and Usage

Clinical indications and uses of Streptogramins include:

  • Skin and skin structure infections (complicated) caused by:
    • Methicillin-susceptible Staphylococcus aureus (MSSA) or Streptococcus pyogenes

Some off-label uses of Streptogramins include:

  • Bacteremia caused by MRSA
  • Infective endocarditis caused by MRSA
  • Infective endocarditis caused by multidrug-resistant Enterococcus faecium
  • Intravascular catheter-associated bloodstream infections caused by methicillin-resistant coagulase negative staphylococci or ampicillin and vancomycin-resistant Enterococcus faecium  

Pharmacodynamics and Pharmacokinetics of Streptogramins

Streptogramins
DistributionQuinupristin: 0.45 L/kg.
Dalfopristin: 0.34 L/kg.
MetabolismQuinupristin is conjugated with glutathione and cysteine to active metabolites in the liver.
Dalfopristin is hydrolyzed to an active metabolite in the liver.
Half-life Elimination

Quinupristin: 0.85 hour.
Dalfopristin:0.7 hour (mean elimination half-lives, including metabolites: 3 and 1 hours, respectively).

Excretion

Feces (75% to 77% as unchanged drug and metabolites).
Urine (15% to 19%).

Significant Adverse Reactions to Streptogramins

Strptogramins
GeneralizedFever
Worsening of underlying illness
Central Nervous SystemBrain disease
Dysautonomia
Headache
Pain
Paraplegia
Seizure activity
CardiovascularCardiac arrhythmias
Hypotension
Pericarditis
Shock
Sncope
RespiratoryApnea
Dyspnea
Pleural effusion
Respiratory distress
Neuromuscular and SkeletalArthralgias*
Gout
Increased creatine phophokinase
Myalgias*
Myasthenia
Neuropathy
Paresthesia
Endocrine and MetabolicHyperglycemia
Hyperkalemia
Increased lactate dehydrogenase
Increased gamma-glutamyl transferase
DermatologicMaculopapular rash
Pruritus
Skin rash
Urticaria
GastrointestinalDiarrhea
Diarrhea caused by Clostridium difficile (CDAD)*
Mesenteric artery occulusion
Nausea
Pancreatitis
Pseudomembranous colitis*
Stomatitis
Vomiting
GenitourinaryHematuria
Vaginitis
Hematologic and OncologicAnemia
Hemolytic anemia
Pancytopenia
Thrombocytopenia
HepticHepatitis
Hyperbilirubinemia*
Jaundice
HypersensitivityAnaphylactoid reaction
Hypersensitivity reaction
LocalInflammation at IV site
Localized edema
Pain at IV site
Thrombophlebitis (IV)*
*Severe most common adverse reactions

Warnings/Precautions Related to Streptogramins

Patients should be monitored for:

  1. Concerns Related to Adverse Reactions
  • Arthralgias/Myalgias
    • May cause arthralgias and/or myalgias, sometimes severe.
    • Reversible with treatment discontinuation.
    • Improvement in some patients occurs with reduction of dosing frequency.
  • Hyperbilirubinemia
    • May cause hyperbilirubinemia (primarily conjugated bilirubin) possibly through competition for excretory pathways.
  • Phlebitis
    • May cause pain and phlebitis when infused through a peripheral line (not relieved by hydrocortisone or diphenhydramine).
  • Superinfection
    • Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis.
    • Development of watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.
    • CDAD has been observed longer than 2 months post antibiotic treatment.
  1. Laboratory/Diagnostic Results
  • Perform culture and sensitivity testing where possible prior to initiating therapy and where appropriate during treatment.
  • Observe for changes in bowel frequency or consistency (e.g., diarrhea).
    • If diarrhea occurs monitor:
      • Stool cultures and sensitivity
      • CBC with differential and electrolytes
      • Sigmoidoscopy and colonoscopy results
      • Computed tomography (CT) and abdominal x-ray results
  • Monitor for increased total and conjugated bilirubin if clinically indicated.
  • Monitor other appropriate laboratory values: AST, ALT, LDH, Alk Phosphatase, Gamma-GT, CPK, Creatinine, BUN, Blood glucose, CO2, Sodium, Potassium, Hemoglobin, Hematocrit, Platelets.
  1. Hypersensitivity Reactions
  • Discontinue use if allergic reactions occur.
  1. Drug-Drug Interactions
  • Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring and/or selection of alternative therapy.

Contraindications

Quinupristin/Dalfopristin is contraindicated in patients with known hypersensitivity to Quinupristin or Dalfopristin or with prior hypersensitivity to other streptogramins (e.g., Pristinamycin or Virginiamycin [only used in animals]) or any component of the formulation.

Use During Pregnancy and Breastfeeding

Streptogramin Antibiotics
AgentsPregnancy Risk Factor*Breastfeeding Considerations
PristinamycinBIt is not known if Pristinamycin is excreted in breast milk
Quinupritin/DalfopristinBIt is not known if Quinupristin/Dalfopristin is excreted in breast milk
* See Appendix A

Resistance

Resistance to Quinupristin/Dalfopristin is associated with resistance to both components (i.e., Quinupristin and Dalfopristin). In non-comparative studies, emerging resistance to Quinupristin/Dalfopristin has occurred.

Dosing Considerations

Dosing: Adult

Depending on the causative agent and the indication of usage Quinupristin/Dalfopristin dosage may range from 7.5 mg/kg every 8 to 12 hours with or without additional antibiotics.

Dosing: Geriatric

  • No dosage adjustment of Quinupristin/Dalfopristin is required for use in the elderly.

Dosing: Renal Impairment

  • No dosage adjustment of Quinupristin/Dalfopristin is required for use in patients with renal impairment or patients undergoing peritoneal dialysis.

Dosing: Hepatic Impairment

  • There are no dosage adjustments of Quinupristin/Dalfopristin required for use in patients with chronic liver insufficiency or cirrhosis.
  • Pharmacokinetic data suggest dosage adjustment may be necessary

IV Infusion Administration

  • The IV line should be flushed with 5% dextrose in water prior to and following administration of an infusion of Quinupristin/Dalfopristin to minimize venous irritation.
  • IV infusion should be completed over 60 minutes (toxicity may be increased with shorter infusion).
  • If severe venous irritation occurs following peripheral administration, Quinupristin/Dalfopristin may be further diluted (to 500 mL or 750 mL) from 250 mL.
  • In general, infusion of Quinupristin/Dalfopristin by a peripherally inserted central catheter (PICC) or a central venous catheter is advocated to avoid phlebitis.
  • The line should not be flushed with saline or heparin after Quinupristin/Dalfopristin administration because of incompatibility concerns.
  • Quinupristin/Dalfopristin is compatibility with D5W but incompatible with saline.

Summary

Pristinamycin is a streptogramin antibiotic. It is a mixture of two components Pristinamycin IA (PI) and Pristinamycin IIA (PII). Quinupristin and Dalfopristin are both Streptogramin antibiotics, derived from Pristinamycin in a combined in a weight-to-weight ratio of 30% Quinupristin to 70% Dalfopristin.

The most clinical indications and uses of Streptogramins are complicated skin and skin structure infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) or Streptococcus pyogenes. Quinupristin/Dalfopristin is metabolized into various metabolites primarily in the liver and excreted primarily in the feces and, to a lesser extent, the urine. Laboratory and diagnostic tests should include culture and sensitivity testing prior to initiating therapy, when possible, and when appropriate during treatment. Monitor the patient for changes in bowel frequency or consistency (e.g., diarrhea). Also,  monitor for increased total and conjugated bilirubin if clinically indicated, as well as, other appropriate laboratory values such as AST, ALT, LDH, Alk Phosphatase, Gamma-GT, CPK, Creatinine, BUN, Blood glucose, CO2, Sodium, Potassium, Hemoglobin, Hematocrit, and Platelets.

Quinupristin/Dalfopristin is contraindicated in patients with known hypersensitivity to Quinupristin or Dalfopristin or with prior hypersensitivity to other Streptogramins (e.g., Pristinamycin or Virginiamycin [only used in animals]) or any component of the formulation. Resistance to Quinupristin/Dalfopristin is associated with resistance to both components (i.e., Quinupristin and Dalfopristin). In non-comparative studies, emerging resistance to Quinupristin/Dalfopristin has occurred.

Care should be taken in the IV infusion of Quinupristin/Dalfopristin to ensure that the IV line is flushed with 5% dextrose in water prior to and following administration of Quinupristin/Dalfopristin to minimize venous irritation. In general, infusion of Quinupristin/Dalfopristin by a peripherally inserted central catheter (PICC) or a central venous catheter is advocated to avoid phlebitis. IV infusion should be completed over 60 minutes since toxicity may be increased with shorter infusion times. Quinupristin/Dalfopristin is compatible with D5W but incompatible with many other therapeutic agents.

Appendix A

FDA Pregnancy Categories

The FDA has established five categories to indicate the potential of a drug to cause birth defects if used during pregnancy. The categories are determined by the reliability of documentation and the risk to benefit ratio. They do not take into account any risks from pharmaceutical agents or their metabolites in breast milk. The pregnancy categories are:

Drug Rating in Pregnancy
(US Food and Drug Administration)
CategoryInterpretation
AControlled human studies show no risk
Controlled Studies in pregnant women fail to demonstrate a risk to the fetus on the first trimester with no evidence of risk in later trimesters.  The possibility of fetal harm appears remote.
BNo evidence of risk in studies
Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters.
CRisk cannot be ruled out
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects or other), and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefits justify the potential risk to the fetus.
DPositive evidence of risk
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
XContraindicated in pregnancy
Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

In 2015, the US Food and Drug Administration (FDA) began overseeing the phase-out of pregnancy risk categories (A, B, C, D, and X) from prescription drug labeling and began requiring information from available human and animal studies of (1) known or potential maternal or fetal adverse reactions and (2) dose adjustments needed during pregnancy and the postpartum period.

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This course is applicable for the following professions:

Advanced Registered Nurse Practitioner (ARNP), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Registered Nurse (RN)

Topics:

Advance Practice Nurse Pharmacology Credit, CPD: Practice Effectively, Pharmacology (All Nursing Professions)


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