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Protein Synthesis Inhibitors

4 Contact Hours including 4 Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Wednesday, February 15, 2023
Outcomes

92% of participants will know the use, monitoring, and adverse reactions of protein synthesis inhibitors.

Objectives

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

  1. Describe the mechanism of action for each group of protein synthesis inhibitors.
  2. Discuss indications and usage for each group of protein synthesis inhibitors.
  3. Discuss the specific warnings and precautions for each group of protein synthesis inhibitors.
  4. Describe the specific patient parameters that should be assessed before administering each group of protein synthesis inhibitors.
  5. Relate the contraindications for each protein synthesis inhibitors.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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Author:    Pamela Downey (MSN, ARNP)

Protein Synthesis Inhibitors

A protein synthesis inhibitor is an antibiotic that stops or slows the growth of new proteins. The following are the medications that are protein synthesis inhibitors.

  • Aminoglycosides
  • Tetracycline and glycylcycline
  • Oxazolidinones
  • Amphenicols and pleuromutilins
  • Macrolides and ketolides
  • Lincosamides
  • Streptogramins

Protein system inhibitors are toxic and require close monitoring. They 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. The previous alphabetical FDA categories of drug use during pregnancy and breastfeeding is discontinued (Drugs.com, 2020). Follow the directions on the packaging if considering use during pregnancy and breastfeeding.

Aminoglycoside

Aminoglycoside Antibiotics
Non-Parenteral Aminoglycosides (NIH, 2020h)
AgentsCommon Brand Name(s)Route(s)
Neomycin SulfateRibostamycin®, Mycifradin®, Neo-Fradin®Oral
Parenteral Aminoglycosides(NIH, 2020a, 2020b, 2020f, 2020i, 2020l)
AgentsCommon Brand Name(s)Route(s)
AmikacinAmikin®IM, IV
GentamicinGentamicin Injection®IM, IV
Kanamycin SulfateKantrex®No longer available in the United States
SpectinomycinTrebicin®Rarely used in the United States
StreptomycinStreptomycin® for InjectionIM
TobramycinAkteb®, Tobral®, Tobrex®, Nebcin®IM, IV

Aminoglycosides are also available in topical, inhaled, intrathecal, intraventricular, intraperitoneal, and impregnated cement formulations for specific indications. Only oral, IM, and IVs will be considered in this course.

Indications and Use(NIH, 2020h) (NIH, 2020a, 2020b, 2020f, 2020i, 2020l)

In general, aminoglycosides are active across a broad spectrum of aerobic gram-negative and gram-positive organisms and mycobacteria. Anaerobic bacteria are intrinsically resistant to aminoglycosides. Aminoglycosides have antibacterial activity against susceptible.

Microbiology

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

Clinical Indications

The widespread clinical use of parenteral aminoglycosides is generally limited because less toxic agents with comparable efficacy are available. Other agents do not require the serum drug concentration monitoring needed for aminoglycosides use.

Aminoglycosides remain important as a second agent in treating 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 in which monotherapy with aminoglycosides is an adequate treatment.

Monotherapy

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

Prophylactic use of aminoglycosides is used in surgical procedures involving the gastrointestinal, urinary tract, or female genital tract in patients with beta-lactam allergies. Routine measurement of serum aminoglycoside concentrations is not necessary with prophylactic therapy given for less than 24 hours. 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.

Combination Therapy

Aminoglycosides are not active alone against Streptococci and Enterococci. However, they may have additive or synergistic effects in combination with other antibiotics. 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. Lower concentrations of aminoglycosides are targeted when used in combination with other agents to treat a serious gram-positive infection.

Aminoglycosides may be combined with other antibiotics for the following organisms:

Mycobacteria

  • Mycobacterium abscessus
  • Mycobacterium chelonae
  • Mycobacterium fortuitum
  • Mycobacterium tuberculosis

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

  • Chronic hepatic insufficiency
  • Hepatic encephalopathy

The most frequent clinical use of aminoglycosides in combination with other antibacterial agents is 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)
  • Septicemia
  • Serious staphylococcal, Pseudomonas aeruginosa, and Klebsiella infections
  • Skin, soft tissue, bone, and joint infections
  • Tuberculosis caused by Mycobacteria

Aminoglycosides are useful for treating drug-resistant tuberculosis and certain nontuberculous mycobacterial infections in combination with other antimycobacterial agents. 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 or intraperitoneal
  • Prosthetic joint infections, impregnated cement formulations

Pharmacodynamics and Pharmacokinetics

Non-Parenteral Aminoglycoside

Neomycin Sulfate (NIH, 2020h)
AbsorptionOral
Time to serum Peak1 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%
ExcretionFeces (97% of oral dose as unchanged drug) Urine (30% to 50% of absorbed drug as unchanged drug)

Parenteral Aminoglycosides

Aminoglycosides (NIH, 2020a, 2020b, 2020f, 2020i, 2020l)
AbsorptionIV, IM: Rapid and complete
Time to Peak, SerumPeak serum aminoglycoside concentrations are measured approximately 30 to 60 minutes after completion of an intravenous infusion or 30 to 90 minutes after an intramuscular injection.
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 renal 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.
  • Aminoglycosides have 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 the meninges are inflamed.
  • Aminoglycoside distribution is increased in patients with edema, ascites, burns, pregnancy, cystic fibrosis, fluid overload, and decreased patient dehydration.
  • Local installation into the pleural space or peritoneal cavity can result in significant serum concentrations.
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 administered dose is eliminated unchanged in the urine primarily by glomerular filtration. A small amount (1%) may be excreted in bile, saliva, sweat, and tears.

Monitoring(NIH, 2020h) (NIH, 2020a, 2020b, 2020f, 2020i, 2020l)

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 two 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)

Monitor initial and appropriately timed periodic serum concentrations of aminoglycosides, particularly in critically ill patients with serious infections or in disease states known to alter aminoglycoside pharmacokinetics significantly like 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 renal and eighth cranial nerve toxicity risk. Discontinue use if any allergic reaction occurs. Cross-sensitivity to other aminoglycosides may occur.

Prolonged use of aminoglycosides may result in fungal or bacterial superinfection, including Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis. CDAD has been observed for two months or longer after post-antibiotic treatment. Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, or alternative therapy selection.

Dosing Considerations(NIH, 2020a, 2020b, 2020f, 2020i, 2020l)

Improved patient outcomes are correlated with the rapid therapeutic concentrations of aminoglycosides. Dosing should be optimized to achieve this effect. Dosing also should be tailored to minimize aminoglycoside toxicity. The traditional approach to parenteral dosing of aminoglycoside in adults involves administering a weight-based dose divided two to three times daily in patients with normal renal function. The dose is reduced or the dosing interval extended in patients with decreased renal function. Once-daily aminoglycoside is extended-interval, aminoglycoside therapy utilizes a higher weight-based dose administered at an extended interval, every 24 hours. This administration method should not be confused with traditional intermittent dosing with lower individual doses administered at 24-hour intervals because of renal impairment.

The following general principles apply to all patients, regardless of whether traditional intermittent versus extended-interval daily dosing strategies are used. Intravenous administration of aminoglycosides should occur over 30 minutes for traditional intermittent and 60 minutes for extended-interval dosing. The initial dose and frequency of aminoglycosides are based on administration, indication, dosing weight, and renal function. Dosing adjustments should be based upon the results of serum drug concentration monitoring.

  • Peak serum concentrations are intended to take advantage of the pharmacodynamic properties to optimize the potential for efficacy.
  • Trough concentrations are targeted to avoid concentration-related toxicity.

In underweight and non-obese patients, use the total body weight (TBW) for determining the initial mg/kg/dose. Ideal body weight (IBW) may also be used to determine doses. For obesity, the initial dosage requirement may be estimated using a dosing weight of IBW + 0.4. Definitions of obesity are:

  • Moderate obesity is TBW or IBW ≥1.25
  • Morbid obesity is TBW or IBW >2.

Creatinine Clearance

Since aminoglycosides are eliminated primarily by glomerular filtration, renal function affects the rate of drug clearance and affects the optimal dosing interval. The creatinine clearance can be estimated from the serum creatinine concentration using the Cockcroft-Gault formula, which considers 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 supposes 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 diseases or other factors may alter the relationship between serum creatinine concentration and creatinine clearance. In particular, creatinine production is reduced in severe liver disease, malnutrition, and significant muscle mass loss. Loss of muscle mass may occur from quadriplegia, paraplegia, or amputation. Reduced creatinine concentration may cause 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:

  • A 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 refers to the ability to escalate concentrations of aminoglycosides to induce more rapid killing of the pathogen

Selection of Dosing Strategy

Extended-interval 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, aminoglycosides pharmacodynamic profiles and greater ease of administration 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 than those used for other indications. Systemic therapy is not intended for long-term therapy due to toxic hazards associated with extended administration. Dosage modification may be required during systemic therapy. 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 dosing method) that render extended-interval dosing less useful or may be more likely to have aminoglycoside toxicity when administered at high doses. This group includes patients with:

  • Burns greater than 20% total body surface area
  • Ascites
  • Pregnancy
  • Creatinine clearance less than 40 mL/min or greater than 120 mL/min

IV administer is done by intermittent infusion over 30 to 60 minutes

  • Higher doses are generally administered over 60 minutes
  • Flush line with an appropriate solution both before and after administration of the aminoglycoside

IM Injection is done by deep IM injection into a large muscle mass. Rotate injection sites.

Special Circumstances

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 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.

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.

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

Patients with significant burns may exhibit larger volumes of distribution. 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 undergoing aggressive fluid resuscitation in 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 pharmacokinetics determination, such as distribution volume.

Since many elderly patients have reduced renal function or are receiving concomitant nephrotoxic agents, caution should be used in prescribing aminoglycosides. Reduced muscle mass and the resulting reductions in serum creatinine concentration in the elderly may result in overestimating renal function when formulas such as the Cockcroft-Gault equation are utilized. Therefore, relatively normal serum creatinine may be associated with a substantial renal function loss 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.

Gentamicin and Tobramycin Dosing in Adults(NIH, 2020e, 2020l)

Traditional Intermittent Dosing and Monitoring

Administration of an initial loading dose is determined by the type or site of infection, for which different peak serum gentamicin or tobramycin concentrations are desired. For maintenance dosing, a percentage of the loading dose is given at a dosing interval. Both depend on creatinine clearance. In those patients where a loading dose was not given, the maintenance dose is still determined by the estimated loading dose for the indication.

Serum concentrations of gentamicin or tobramycin are used to guide dose adjustments. To meet the desired target concentrations, both the maintenance dose and the dosing interval may need to be adjusted. Target concentrations are dependent upon the indication and site of infection. Monitoring of serum aminoglycoside concentrations is essential to ensure efficacy and to avoid toxicity. 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 adjusting the dose.

The peak levels of gentamicin vary based on the indications for usage. For example, when the drug is being given for synergy, in treating serious, invasive infections, and the organism's susceptibility in targeted patient populations such as cystic fibrosis. Trough concentrations for gentamicin and tobramycin should be below two mcg/mL. Peak concentrations are drawn 30 to 45 minutes after 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 samples are essential to interpret the results. 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 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, but those changes are not proportional. Therefore, the calculation of patient-specific pharmacokinetics is the optimal method to determine the 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 any renal function changes. Serum aminoglycoside monitoring should be repeated 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 are important for dose and dosing interval determination. A loading dose is not needed in the setting of extended-interval aminoglycoside administration.

Subsequent monitoring of serum concentrations of gentamicin or tobramycin is needed to guide dose adjustments. When an extended interval daily dosing strategy is employed, serum drug concentration monitoring's timing and frequency differ from those used in traditional intermittent dosing. Concentrations can be targeted either by using a published nomogram that extrapolates the desired dosing interval based on a single drug concentration or by analyzing two or more serum concentrations checked during the dosing cycle.

Target concentrations for extended-interval aminoglycoside dosing is a peak serum concentration of approximately 15 to 20 mcg/mL for gentamicin and tobramycin to target approximately ten times the minimum inhibitory concentration (MIC) of the pathogen. Trough serum concentrations should be less than one mcg/mL because of the long dosing interval. The estimated drug-free interval is less than 8 hours. Nomogram-based monitoring requires 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.

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 using the nomogram 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 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 dosing and monitoring indications to repeat drug concentrations, drug concentrations change renal function and duration of therapy beyond 7 to 10 days.

Regardless of the method used to determine patient dosing needs, the phlebotomist must document sampling times to interpret results accurately. Also, requests for laboratory determinations of serum levels should include a provision to indicate that extended-interval dosing is being used. Since serum levels obtained 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(NIH, 2020b)

Traditional Intermittent Dosing and Monitoring

  • Administer a loading dose
  • Subsequent maintenance dose 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. These dose adjustments consider:
    • 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 eight mcg/mL is often targeted at 1 to 4 mcg/mL
  • Higher peaks of 40 to 50 mcg/mL are generally achieved with extended-interval dosing

Extended-Interval Dosing and Monitoring

  • Administration of a loading dose
    • The initial dosing interval is based upon the creatinine clearance
  • Subsequent monitoring of serum concentrations 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(NIH, 2020i)

The dosing of streptomycin varies based on the indications for its use, like

  • 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.

Warnings and Precautions(NIH, 2020a, 2020b, 2020f, 2020i, 2020l)

Contraindications

Myasthenia gravis is an absolute contraindication to aminoglycoside use, regardless of the dosing method used. Hypersensitivity to aminoglycosides or any component of the formulations is a contraindication. Avoid concurrent or sequential use of other neurotoxic or nephrotoxic drugs, particularly other aminoglycosides, 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 not give aminoglycosides concurrently with potent diuretics, such as ethacrynic acid and furosemide. Some diuretics cause ototoxicity, and IV administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Avoid using aminoglycosides as surgical irrigation due to risks of irreversible deafness, renal failure, and death.

Clinical Concerns

Aminoglycoside preparations may contain sulfites that may cause allergic-type reactions and life-threatening or less severe asthmatic episodes in certain individuals. Use caution in patients with:

  • Pre-existing vertigo, tinnitus, or hearing loss
  • Hypocalcemia
  • Neuromuscular disorders, including myasthenia gravis and Parkinson disease
  • Pre-existing renal insufficiency

Some penicillin derivatives may accelerate the degradation of aminoglycosides. This may be clinically significant for ticarcillin, piperacillin, carbenicillin, gentamicin, and 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 the intact intestinal mucosa, resulting in increased fecal bile acid excretion, and reduced intestinal lactase activity. Oral doses of greater than 12g/day produce malabsorption of fats, nitrogen, cholesterol, carotene, glucose, xylose, lactose, sodium, calcium, cyanocobalamin, and iron.

Toxicity

Aminoglycoside toxicity may cause neurotoxicity. Neurotoxicity may be manifested as both auditory and vestibular ototoxicity. The auditory changes:

  • Are usually irreversible
  • Are 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 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. Risk factors include:

  • Pre-existing renal impairment
  • Aminoglycosides administered for longer periods or in higher doses than those recommended
  • Taking concomitant neuro or nephrotoxic medications
  • Advanced age
  • Dehydration

Nephrotoxicity may not become apparent until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity is usually 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, respiratory failure, and prolonged respiratory paralysis. Risk factors include administration of aminoglycosides by any route, especially in patients who:

  • Have disease states or concomitant drug therapy that interfere with neuromuscular transmission
  • Receive anesthetics
  • Receive neuromuscular blocking agents such as tubocurarine, succinylcholine, and decamethonium
  • Receive massive transfusions of citrate-anticoagulated blood
    • If a blockage occurs, calcium salts may reverse these phenomena, but mechanical respiratory assistance may be necessary

Adverse Reactions

Generalized
  • Fever
Central Nervous System
  • Abnormal gait
  • Ataxia
  • Confusion
  • Depression
  • Disequilibrium
  • Disorientation
  • Dizziness
  • Drowsiness
  • Drug fever
  • Headache
  • Lethargy
  • Lightheadedness
  • Seizure activity
  • Vertigo
  • Myasthenia
  • Paresthesia of face
  • Pseudomotor cerebri
Ophthalmic
  • Amblyopia
  • Visual disturbance
Otic
  • Auditory ototoxicity
  • Hearing loss
  • Tinnitus
  • Vestibular ototoxicity
Cardiovascular
  • Edema
  • Hypertension
  • Hypotension
Respiratory
  • Dyspnea
  • Laryngeal edema
  • Pulmonary fibrosis
  • Respiratory depression
Neuromuscular and Skeletal
  • Arthralgia
  • Muscle cramps
  • Muscle fatigue (myasthenia gravis-like syndrome)
  • Muscle twitching
  • Numbness
  • Paresthesia
  • Peripheral neuropathy
  • Tremor
  • Weakness
Endocrine and Metabolic
  • Decreased serum calcium
  • Decreased serum magnesium
  • Decreased serum potassium
  • Decreased serum sodium
  • Increased lactate dehydrogenase
  • Increased nonprotein nitrogen
  • Weight loss
Dermatologic
  • Alopecia
  • Angioedema
  • Erythema
  • Exfoliative dermatitis
  • Pruritis
  • Skin rash
  • Skin tingling
  • Urticaria
Gastrointestinal
  • Anorexia
  • Clostridium difficile-associated diarrhea (CDAD)
  • Decreased appetite
  • Diarrhea
  • Enterocolitis
  • Irritation or soreness of the mouth or rectal area
  • Nausea
  • Vomiting
  • Stomatitis
Genitourinary
  • Azotemia
  • Casts in urine
  • Changes in distal tubules (dysfunction)
  • Decreased creatinine clearance
  • Decreased urine specific gravity
  • Fanconi-like syndrome
  • Increased blood urea nitrogen
  • Increased serum creatinine
  • Nephrotoxicity
  • Oliguria
  • Proteinuria
  • Polyuria
  • Renal failure
  • Renal tubular necrosis
Hematologic and Oncologic
  • Agranulocytosis
  • Anemia
  • Eosinophilia
  • Granulocytopenia
  • Hemolytic anemia
  • Leukocytosis
  • Leukopenia
  • Pancytopenia
  • Purpura
  • Reticulocytopenia
  • Reticulocytosis
  • Thrombocytopenia
Hepatic
  • Increased serum ALT
  • Increased serum AST
  • Increased serum bilirubin
  • Hepatomegaly
  • Splenomegaly
Hypersensitivity
  • Anaphylactoid reaction
  • Drug reaction with eosinophilia and systemic symptoms (DRESS)
  • Erythema mutiforme
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
Local
  • Pain at the local injection site
  • Phlebitis
  • Thrombophlebitis

Tetracycline and Glycylcycline

Tetracycline Antibiotics (NIH, 2020j, 2020c, 2020d, 2020g)
AgentsCommon Brand Name(s)Route(s)
Chlortetracycline Used in veterinary medicine
TetracyclineTetracycline® HClOral
DemeclocyclineDemeclocycline® HClOral
DoxycyclineActiclate®
Adoxa®
Adoxa® Pak 1/100
Adoxa® Pak 1/150
Adoxa® Pak 2/100
Avidoxy®
Doryx®
Doryx® MPC
Doxy® 100
Mondoxyne® NL
Monodox®
Morgidox®
Oracea®
TargaDOX®
Vibramycin®
Oral, IV
MinocyclineDynacin®
Minocin®
Minocycline® HCL
Solodyn®

Oral, IV

Glycylcycline Antibiotic (NIH, 2020k)
AgentsCommon Brand Name(s)Route(s)
TigecyclineTygacil®IV

Indications and Use(NIH, 2020j, 2020c, 2020d, 2020g)

The tetracyclines and tigecycline are considered broad-spectrum bacteriostatic antibiotics used to treat infection caused by gram-positive and gram-negative bacteria and 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.

Microbiology

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 Use

  • 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 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-label Uses

  • 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

Tetracyclines and Glycylcycline (NIH, 2020j, 2020c, 2020d, 2020g)(NIH, 2020k)
Absorption
  • Oral: 66% to 88% depending on the therapeutic agent
  • Absorption of oral tetracyclines occurs primarily in the proximal small intestine and the stomach
  • The extent of absorption is reduced by food and certain antacids and dairy products containing aluminum, calcium, magnesium, or iron
Time to Peak, Serum
  • Oral: 1 to 4 hours, depending on the therapeutic agent
  • IV: 30 minutes to 1 hour, depending on the therapeutic agent
Distribution
  • In general, tetracyclines penetrate tissues and body fluids fairly well. Among the following therapeutic agents, the degree of tissue penetration correlates to lipid solubility: minocycline > doxycycline > tetracycline
  • Tetracycline: distributes well into most body fluids and tissues, including ascetic, synovial, and pleural fluids, and bronchial secretions, with poor penetration into CSF
  • Doxycycline: therapeutic concentrations have been widely distributed in 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 for 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 bone and teeth of the fetus. They are also excreted in breast milk
Protein Binding
  • 40% to 90%, depending on the therapeutic agent
Metabolism
  • Demeclocycline: None
  • Doxycycline: Not hepatic, partially inactivated in the GI tract by chelate formation
  • Minocycline:  Hepatic to inactive metabolites
  • Tigecycline: Hepatic, glucuronidation, N-acetylation, and epimerization to several metabolites, each less than10% of the dose
Half-life Elimination
  • Tetracycline oral: 6 to 11 hours
  • Demeclocycline oral: 10 to 16 hours
  • Doxycycline: Single dose: 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)
  • Minocycline IV: 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%)
  • Demeclocycline: 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)

Dosing Considerations(NIH, 2020j, 2020c, 2020d, 2020g)(NIH, 2020k)

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

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 end-stage renal disease patients.

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

Administration

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 an adequate amount of fluid to reduce the risk of esophageal irritation and ulceration
  • Administer at least 1 to 2 hours before 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 to 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 Administration

  • Infuse over 30 to 60 minutes up to 4 hours (depending on the therapeutic agent) through a dedicated line or Y-site
  • If the same IV line is used for several drugs' sequential, 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

Warnings and Precautions(NIH, 2020j, 2020c, 2020d, 2020g)(NIH, 2020k)

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

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
  • 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 to treat 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 penicillin

Laboratory and Diagnostics

  • Perform culture and sensitivity testing before initiating therapy and where appropriate during treatment
  • Monitor the patient’s temperature
  • Monitor liver function tests, renal function tests, CBC, WBC as needed, and periodically with prolonged therapy
  • If symptomatic for an autoimmune disorder, monitor ANA and CBC
  • Ophthalmologic evaluation if visual disturbances occur
  • If therapeutic agents are 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 diagnosing 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

Discontinue use if allergic reactions occur. Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, or alternative therapy selection.

Disease-related Concerns

  • Hepatic impairment
    • Hepatotoxicity and hepatic failure have rarely been reported with use
    • Dose adjustment or adjustment in interval frequency is recommended
    • The risk may be increased in patients with preexisting hepatic or renal impairment
    • Use with caution in patients with hepatic impairment or 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 or adjustment in interval frequency is recommended

Concerns Related to Special Populations

  • Pregnancy
    • Do not use during pregnancy
    • In addition to affecting the fetus's tooth development, 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 consider 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 adult patients' trials
    • Use is only restricted if no alternative antibiotics are available

Because of effects on tooth development (yellow-gray-brown discoloration), use in patients eight years of age or younger is not recommended.

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

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 used therapeutically to treat inappropriate antidiuretic hormone secretion (SIADH)
      • Diabetes insipidus syndrome: Dose-dependent nephrogenic diabetes insipidus is common with the use of demeclocycline but is reversible on the therapeutic agent's discontinuation. 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 resolve 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, or papilledema) has been associated with use
      • Usually, it resolves after discontinuation of treatment, but the 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 and Ulceration
    • Esophagitis and ulcerations may occur
    • Patients with dysphagia 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), has been reported using 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 of post-antibiotic treatment
    • A patient with continued diarrhea, fever, and a rising white blood count should be evaluated for Clostridium difficile-associated diarrhea (CDAD)

Adverse Reactions

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 of mucous membrane and 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 anemia
  • Hypoproteinemia
  • 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 the 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

Oxazolidinones

Oxazolidinones (NIH, 2020u, 2020y)
AgentsCommon Brand Name(s)Route(s)
LinezolidLinox®, Zyvox®Oral, IV
Tedizolid PhosphateSivextro®Oral, IV

Indications and Use(NIH, 2020u, 2020y)

Microbiology

Linezolid is a synthetic oxazolidinone with activity against various gram-positive organisms that 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 various gram-positive organisms, 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, pneumococcus)
    • Streptococcus pyogenes (aka, group A streptococcus or GAS)
    • Viridans streptococci
  • Gram-negative organisms:
    • Pasteurella
      • Pasteurella multocida

Clinical Indications

  • Enterococcal infections, vancomycin-resistant
  • Treatment of vancomycin-resistant Enterococcus faecium infections with or without bacterial invasion of the bloodstream
  • Treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only)
  • Linezolid is also acceptable second-line treatment for community-acquired pneumococcal pneumonia when penicillin resistance is present
  • 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 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 MRSA cases confirmed as the causative organism or when MRSA infection is suspected based on the clinical presentation.

Linezolid is prescribed to treat complicated skin and skin structure infection (cSSSI’), including diabetic foot infections, unless complicated by osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae.

Linezolid is prescribed for the treatment of uncomplicated skin and skin structure infections (SSSI) 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 to treat adult patients with acute bacterial skin and skin structure infection (ABSSSI) caused by susceptible isolates of Gram-positive microorganisms.

Other Uses

  • Bone and joint infections, including chronic osteomyelitis
  • Tuberculosis in combination with other drugs
  • Alternative to vancomycin in the treatment of febrile neutropenia in cancer patients when a gram-positive infection is suspected
  • Linezolid appears superior to vancomycin in treating community-acquired MRSA infections of the central nervous system

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.

Off-label Uses

  • 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 the cavernous or dural venous sinus (Staphylococcus aureus [methicillin-resistant])

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

Pharmacodynamics and Pharmacokinetics

Oxazolidinones (NIH, 2020u, 2020y)
Absorption
  • Oral: The systemic absorption of linezolid approaches 100% following oral administration
  • Tedizolid phosphate is an inactive prodrug converted 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: 1 to 1.5 hours, depending on the therapeutic agent
Distribution
  • Linezolid binds poorly to serum proteins (31%), and thus it penetrates well into most body compartments, including bone, alveoli, and the cerebrospinal 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 with the cytochrome P450 oxidative system but rather undergoes hepatic oxidative metabolism into two inactive metabolites. Its metabolites are eliminated predominantly in the urine
  • Phosphatases convert Tedizolid phosphate to tedizolid (active, parent drug). There are no other significant circulating metabolites
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 the 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

Dosing Considerations(NIH, 2020u, 2020y)

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

Dosing: Renal Impairment

  • Linezolid
    • Mild to severe renal impairment:
      • No dosage adjustment is 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 is needed
    • Continuous renal replacement therapy (CVVH, CVVHD, CVVHDF):
      • Some have suggested no supplemental dose or dosage adjustment is 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 are suggested
  • Tedizolid
    • No dosage adjustment is necessary

Dosing: Hepatic Impairment

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

Administration

  • Administer intravenous 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 of other drugs, flush the line with an appropriate compatible solution both before and after administration

Warnings and Precautions(NIH, 2020u, 2020y)

Discontinue use if allergic reactions occur. Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, or selection of alternative therapy.

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

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/mm
      • Alternative therapies should be considered when treating neutropenia and acute bacterial skin and skin structure infections (ABSSI’s)

Laboratory and Diagnostics

  • Perform culture and sensitivity testing before 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

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 using 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.

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.

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 the 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 that may cause bone marrow suppression or 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 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 using linezolid with concomitant pro serotonergic drugs that reduce linezolid 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 using 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 of 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

Adverse Reactions

Oxazolidinones
Generalized
  • Fever
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
Neuromuscular and Skeletal
  • Generalized weakness
Endocrine and Metabolic
  • Hypoglycemia in diabetes mellitus patients receiving oral hypoglycemic agents or insulin
  • Increased amylase
  • Increased lactate dehydrogenase
Dermatologic
  • Bullous skin disease
  • Dermatitis
  • Pruritus
  • Skin rash
  • Urticaria
Gastrointestinal
  • Abdominal pain
  • Constipation
  • Diarrhea
  • Clostridium difficile associated diarrhea
  • Dysgeusia
  • Increased serum lipase
  • Nausea
  • Oral candidiasis
  • Pancreatitis
  • Pseudomembranous colitis
  • Tongue discoloration
  • Vomiting
Genitourinary
  • Increased blood urea nitrogen (BUN)/Creatinine (Cr)
  • Vaginal candidiasis
  • Vulvovaginal candidiasis
Hematologic and Oncologic
  • Anemia
  • Decrease in absolute neutrophil count
  • Eosinophilia
  • Leukopenia
  • Pancytopenia
  • Neutropenia
  • Thrombocytopenia
Hepatic
  • Increased bilirubin
  • Increased serum alkaline phosphatase
  • Increased serum transaminases (AST or SGOT and ALT or SGPT)
Hypersensitivity
  • Anaphylaxis
  • Angioedema
  • Hypersensitivity reactions
  • Stevens-Johnson syndrome
Local
  • Localized phlebitis
Others
  • Fungal infection
  • IV related reaction
  • Lactic acidosis
  • Rhabdomyolysis
  • Serotonin syndrome (with concurrent use of other serotonergic agents)

Amphenicols and Pleuromutilins

Amphenicols (NIH, 2020o, 2020m)
AgentsCommon Brand Name(s)Route(s)
ChloramphenicolChloromycetin®; Chloromycetin® SuccinateOphthalmic, IV infusion
AzidamfenicolAzidoamphenicol®Ophthalmic
Pleuromutilins (NIH, 2020x)
AgentsCommon Brand Name(s)Route(s)
RetapamulinAltabax®Topical

Indications and Usage(NIH, 2020o, 2020m)(NIH, 2020x)

Microbiology

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- hemolytic Streptococci (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)

Clinical Indications

Chloramphenicol is used to treat serious infections due to organisms resistant to other less toxic antibiotics or when its penetrability into the infection site 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 treating brain abscesses due to mixed organisms or when the causative organism is unknown.

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

  • Neisseria meningitidis
  • Streptococcus pneumoniae
  • Haemophilus influenzae

Chloramphenicol remains the drug of choice in treating 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 several bacteria, including:

  • Escherichia coli
  • Staphylococcus aureus
  • Streptococcus pneumoniae

Retapamulin is often indicated for the treatment of impetigo, a skin infection for which patients seek care from dermatologists. The most common bacteria found in skin and soft tissue infections (SSTI) 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-negative Staphylococci
  • Fusobacterium spp
  • Porphyromonas spp
  • Prevotella spp
  • Propionibacterium spp (including P acnes)
  • Staphylococcus aureus (methicillin-susceptible isolates only) (MSSA)
  • Streptococcus agalactiae
  • Streptococci viridans
  • Streptococcus pyogenes (aka, Group A β- hemolytic Streptococci (GABHS) and Group A Streptococcus (GAS)

Pharmacodynamics and Pharmacokinetics

Amphenicols and Pleuromutilins (NIH, 2020o, 2020m, 2020x)
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, Serum
  • Chloramphenicol succinate: IV: ~70%; highly variable, dependent upon rate and extent of metabolism to chloramphenicol
Distribution
  • Chloramphenicol 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 body tissues, including the brain.
  • Distribution is not uniform, with the highest liver and kidney concentrations and the lowest in the brain and cerebrospinal fluid. The concentration achieved in the 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 decreasedwith 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 system
Half-life Elimination
  • Half-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
Excretion
  • Chloramphenicol succinate is excreted 30% unchanged in the urine

Dosing Considerations(NIH, 2020o, 2020m, 2020x)

Serious infections:

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

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

  • The kidneys excrete most of the chloramphenicol dose 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 chloramphenicol levels must be monitored in the elderly and patients with abnormal liver or kidney function
    • Because chloramphenicol's efficacy and toxicity are associated with a maximum serum concentration, peak levels (one hour after the intravenous dose is given) should be 10 - 20 µg/ml with toxicity greater than 40 µg/ml. Trough levels (taken immediately before a dose) should be 5 - 10 µg/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

  • The liver metabolizes chloramphenicol 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

Administration

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 Administration

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

Warnings and Precautions(NIH, 2020o, 2020m, 2020x)

Discontinue use if allergic reactions occur.

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

Drug Interactions to 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

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 for retapamulin

Laboratory and Diagnostics

  • Perform culture and sensitivity testing if possible before 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 at both peak and trough
  • Monitor for superinfections

If using retapamulin, monitor for creatine phosphokinase (CPK) elevation where appropriate

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

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

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

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

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 two months of post-antibiotic treatment
  • A patient with continued diarrhea, fever, and a rising white blood count should be evaluated for Clostridium difficile-associated diarrhea (CDAD)

Adverse Reactions

Amphenicols and Pleuromutilins Adverse Reactions
Generalized
  • Fever
Central Nervous System
  • Confusion
  • Delirium
  • Depression
  • Headache
Ophthalmic
  • Macular rashes
  • Optic neuritis
Respiratory
  • Epistaxis
  • Nasopharyngitis
Dermatologic
  • Contact dermatitis
  • Eczema
  • Skin rash
  • Urticaria
Gastrointestinal
  • C. difficile-associated diarrhea (CDAD)
  • Diarrhea
  • Enterocolitis
  • Glossitis
  • Nausea
  • Pseudomembranous colitis
  • Stomatitis
  • Vomiting
Hematologic and Oncologic
  • Aplastic anemia
  • Bone marrow depression
  • Granulocytopenia
  • Hypoplastic anemia
  • Pancytopenia
  • Thrombocytopenia
Hypersensitivity
  • Anaphylaxis
  • Angioedema
  • Hypersensitivity reactions
Local
  • Application site irritation:
    • blisters
    • burning
    • redness
    • swelling
    • oozing at the site where the ointment is applied
Others
  • Gray Baby Syndrome
  • Increased creatine phosphokinase (CPK)

Macrolides and Ketolides

Macrolide Antibiotics (NIH, 2020n, 2020p, 2020r, 2020s)
AgentsCommon Brand Name(s)Route(s)
Azithromycin
  • Ophthalmic: AzaSite®
  • Oral: Zithromax®; Zithromax® Tri-Pak; Zithromax® Z-Pak; Zmax®
  • IV: Zithromax®
Ophthalmic solution, Oral, IV
Clarithromycin
  • Biaxin®; Biaxin® XL; Biaxin® XL Pac
Oral
Erythromycin
  • Ophthalmic: Ilotycin®
  • Oral: E.E.S. 400; E.E.S. Granules; Ery-Tab®; EryPed 200; EryPed® 400; Erythrocin® Stearate; PCE; Ery-tab
  • IV: Erythrocin® Lactobionate
  • Topical: Erygel®
Ophthalmic ointment, Oral, IV, Topical
Fidaxomicin
  • Dificid®
Oral
Ketolide Antibiotics (NIH, 2020z)
AgentsCommon Brand Name(s)Route(s)
Telithromycin
  • Ketek®
Oral

Indications and Use(NIH, 2020n, 2020p, 2020r, 2020s) (NIH, 2020z)

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 Streptococcus dysgalactiae
      • Group G streptococcal (GGS) infection caused by Streptococcus dysgalactiae
      • Streptococcus pneumoniae
  • 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

Clinical Indications

Azithromycin, clarithromycin, and telithromycin have a broader spectrum of activity than erythromycin. The greatest use of 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, 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

Off-label Uses

  • 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 non-cystic 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

Macrolides and Ketolides (NIH, 2020n, 2020p, 2020r, 2020s)(NIH, 2020z)
Absorption
  • Azithromycin: oral
    • Rapid from the GI tract
  • Clarithromycin: oral
    • Immediate release: Rapid absorption. Food delays rate, but not the 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, undergoes extensive first-pass metabolism
  • Erythromycin: Demethylation primarily hepatic
  • Fidaxomicin: Intestinal hydrolysis
  • Telithromycin: Hepatic
Bioavailability
  • Azithromycin: oral
    • Tablet, immediate-release oral suspension: 34% to 52%
    • Extended-release oral suspension: 28% to 43
  • Clarithromycin: oral ~50%
  • Telithromycin: 57%
Half-life Elimination
  • Azithromycin: oral
    • Immediate-release: 68 to 72 hours
    • Extended-release: 59 hours
  • Clarithromycin: oral
    • Immediate release: 3-7 hours
    • 14-OH-clarithromycin: 5-9 hours
  • Erythromycin: Peak: 1.5-2 hours. End-stage renal disease: 5-6 hours
  • Telithromycin: 10 hours
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)

Dosing Considerations(NIH, 2020n, 2020p, 2020r, 2020s) (NIH, 2020z)

Erythromycin and, to some extent, clarithromycin interact with numerous drugs because they inhibit hepatic metabolism. 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: 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 the 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

Administration

Ophthalmic

  • 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 the tip of the 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 a drop
    • Wash hands before and after installation
  • Erythromycin Ophthalmic Ointment (Ilotycin Ophthalmic)
    • For ophthalmic use only
    • Do not touch the tip of the applicator
    • Avoid contact of the tip of the ophthalmic ointment tube with the affected eye
    • Avoid contamination

Oral

  • 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 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 regard to meals but may consider administering after food to decrease GI discomfort
    • Swallow a delayed-release capsule or enteric-coated tablets whole
      • Do not chew or break
  • Fidaxomicin
    • May be administered with or without food

IV

  • 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 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

Before treatment, thoroughly wash the 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 the 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 a single-use
      • Additional pads may be used if needed

Warnings and Precautions(NIH, 2020n, 2020p, 2020r, 2020s)

Discontinue use if allergic reactions occur.

Drug-Drug Interactions

  • Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, or alternative therapy selection
  • Avoid concurrent use with strong CYP3A4 inhibitors, thus avoiding the risk of sudden cardiac death

Contraindications

  • Patients who have had an allergic reaction or hypersensitivity reaction to macrolides 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

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 treatment failure incidence
    • Current guidelines recommend 10 to 14 days of therapy (triple or quadruple) to eradicate 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

Laboratory and Diagnostics

  • Perform culture and sensitivity testing before 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

Disease-Related Concerns

  • Gonorrhea/Syphilis
    • May mask or delay incubating gonorrhea or syphilis symptoms, so appropriate culture, and susceptibility tests should be performed before initiating a treatment regimen
  • Hepatic Impairment
    • Use with caution in patients with preexisting liver disease, hepatic impairment, including hepatocellular 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

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 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

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 an 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 are 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 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 is 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 two months of 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 the ability to operate machinery or drive and to use caution until effects are known

Adverse Reactions

Macrolides and Ketolides
Generalized
  • Fatigue
  • Malaise
  • Weakness
Central Nervous System
  • Aggressive 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
Ophthalmic
  • Accommodation disturbance
  • Blurred vision
  • Corneal erosion
  • Decreased visual acuity
  • Diplopia
  • Eye irritation/pain
  • Hypersensitivity
  • Minor ocular irritation
  • Punctate keratitis
  • Redness
  • Swelling of eye
  • Xerophthalmia
Otic
  • Deafness
  • Hearing loss
  • Otitis media
  • Tinnitus
Cardiovascular
  • Atrial arrhythmias, including atrial fibrillation
  • Bradycardia
  • Cardiac arrest
  • Chest pain
  • Diaphoresis
  • Hypotension
  • Ischemic heart disease
  • Palpitations
  • Prolonged Q-T 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 Skeletal
  • Arthralgia
  • Myalgia
  • Increased creatine phosphokinase
  • Dyskinesia
  • Hyperkinesia
  • Neck stiffness
Endocrine and Metabolic
  • Decreased 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
  • Xerostomia
Genitourinary
  • 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 Oncologic
  • Basophilia
  • 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)
  • Increased liver enzymes (PT/INR, aPTT, Albumin, Bilirubin-both direct and indirect)
  • Increased serum bilirubin
  • Increased liver transaminases (AST or SGOT and ALT or SGPT)
  • Increased serum alkaline phosphatase
  • Jaundice
Hypersensitivity
  • Anaphylactoid reaction
  • Anaphylaxis
  • Angioedema
  • DRESS syndrome
  • Fixed drug reaction
  • Lambert-Eaton syndrome
  • Local ocular hypersensitivity reaction including a burning sensation of eyes, eye discharge, eye irritation, eye pruritus, stinging of eyes
  • Henoch-Schonlein purpura (IgA vasculitis)
  • Hypersensitivity reaction
  • Stevens-Johnson syndrome (SJS)
  • Toxic epidermal necrolysis (TEN)
Local
  • Adults with IV administration:
    • Pain at the injection site
    • Local inflammation
  • Localized thrombophlebitis
Others
  • Anosmia
  • Dysgeusia
  • Epistaxis
  • Exacerbation of myasthenia gravis
  • Facial edema
  • Hemorrhage
  • Increased serum phosphate
  • Metabolic acidosis
  • Rhabdomyolysis

Lincosamides

Lincosamides (NIH, 2020q, 2020t)
AgentsCommon Brand Name(s)Route(s)
Clindamycin
  • Oral:
    • Cleocin; Clindamycin HCL; Clindamycin Palmitate HCL
  • IM:
    • CLIN single use; Cleocin Phosphate; Clindamycin Phosphate
  • IV:
    • 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, Topical, Vaginal
Lincomycin
  • Lincocin Injection
  • Lincomycin HCL Injection
IM, IV

Lincomycin ophthalmic route is not discussed in this course.

Indications and Use(NIH, 2020q, 2020t)

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

Clinical indications and Uses

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 acne 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

Off-label Uses

  • 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 before cesarean delivery and may be used in certain situations before 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

Lincosamides (NIH, 2020q, 2020t)
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: 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

Dosing Considerations(NIH, 2020q, 2020t)

The appropriate use of Lincosamides is reserved when treatment with other antibiotics is inappropriate. Lincosamides are not appropriate for treating meningitis due to inadequate penetration into the cerebrospinal fluid. In serious bacterial infections, administration frequency may be increased if needed due to its severity.

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, the 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

Administration

Oral

  • 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 level
    • Coadministration with food does not adversely affect the absorption of clindamycin-flavored granules

Intravaginal and Topical

  • 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 the product comes into contact with mucous membranes, abraded skin, or eyes
    • Use caution when applying near the mouth (unpleasant taste)
  • Foam
    • Clindamycin foam may irritate, especially when used with abrasive, desquamating, or peeling agents
    • Dispense directly into the 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 the 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 a single-use
      • May use more than one pledget for each application to cover the area

IM Administration

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

IV Administration

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

Warnings and Precautions(NIH, 2020q, 2020t)

Discontinue use if allergic reactions occur. Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, or alternative therapy selection.

Contraindications

  • Hypersensitivity to clindamycin, lincomycin, or any component of the formulation
  • Patients with a 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

Laboratory and Diagnostics

  • Perform culture and sensitivity testing if possible before 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

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

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

Concerns Related to Adverse Reactions

  • Colitis
    • Clostridium difficile–associated diarrhea (CDAD) has been reported using 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 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 two months of 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 the overgrowth of nonsusceptible organisms, particularly yeast
    • Should superinfection occur, appropriate measures should be taken as indicated by the clinical situation

Adverse Reactions

Lincosamides
Generalized
  • None
Central Nervous System
  • Metallic taste (IV)
  • Vertigo
Ophthalmic
  • Eye irritation/pain
Otic
  • Tinnitus
Cardiovascular
  • Cardiopulmonary arrest
  • Hypotension
Respiratory
  • Upper respiratory infection
Neuromuscular and Skeletal
  • Polyarthritis
Endocrine and Metabolic
  • Hyperthyroidism
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
  • Pruritus 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 Oncologic
  • Agranulocytosis
  • Aplastic anemia
  • Eosinophilia (transient)
  • Immune thrombocytopenia
  • Leukopenia
  • Neutropenia (transient)
  • Pancytopenia
  • Thrombocytopenia
Hepatic
  • Abnormal hepatic function tests
  • Increased liver transaminases (AST or SGOT and ALT or SGPT)
  • Jaundice
Hypersensitivity
  • Anaphylactoid reaction
  • Anaphylactic shock
  • Anaphylaxis
  • Angioedema
  • DRESS syndrome
  • Hypersensitivity reaction
  • Serum sickness
  • Stevens-Johnson Syndrome (SJS)
  • Toxic epidermal necrolysis (TEN)
Local
  • Abscess at the injection site (IM)
  • Induration at the injection site (IM)
  • Irritation at the injection site (IM)
  • Pain at the injection site (IM)
  • Thrombophlebitis (IV)
Others
  • Bacterial infection
  • Dysgeusia
  • Edema
  • Epistaxis
  • Flank pain
  • Fungal infection

Streptogramins

Streptogramins (NIH, 2020w, 2020v)
AgentsCommon Brand Name(s)Route(s)
PristinamycinPristinamycineOral
Quinupristin/DalfopristinSynercidIV

Pristinamycin is marketed primarily in Europe, so it will not be considered in this course. All information about Quinupristin/Dalfopristin applies except for the route of administration.

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

Indications and Use(NIH, 2020w, 2020v)

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

Clinical indications and Uses

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

Off-label Uses

  • 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

Streptogramins (NIH, 2020w, 2020v)
Distribution
  • Quinupristin: 0.45 L/kg
  • Dalfopristin: 0.24 L/kg
Metabolism
  • Quinupristin 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 hours
  • Dalfopristin: 0.7 hours (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%)

Dosing Considerations(NIH, 2020w, 2020v)

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: 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

Administration

IV

  • The IV line should be flushed with 5% dextrose in water before and after administering an infusion of Quinupristin/Dalfopristin to minimize venous irritation
  • IV 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, Quinupristin/Dalfopristin's infusion 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 compatible with D5W but incompatible with saline

Warnings and Precaution(NIH, 2020w, 2020v)

Discontinue use if allergic reactions occur. Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, or alternative therapy selection.

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.

Laboratory and Diagnostics

  • Perform culture and sensitivity testing if possible before 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

Concerns Related to Adverse Reactions

  • Arthralgias/Myalgias
    • May cause arthralgias or myalgias, sometimes severe
    • Reversible with treatment discontinuation
    • Improvement in some patients occurs with a 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 taking the last dose of the antibiotic
    • CDAD has been observed longer than two months of post-antibiotic treatment

Adverse Reactions

Streptogramins
Generalized
  • Fever
  • Worsening of an underlying illness
Central Nervous System
  • Brain disease
  • Dysautonomia
  • Headache
  • Pain
  • Paraplegia
  • Seizure activity
Cardiovascular
  • Cardiac arrhythmias
  • Hypotension
  • Pericarditis
  • Shock
  • Syncope
Respiratory
  • Apnea
  • Dyspnea
  • Pleural effusion
  • Respiratory distress
Neuromuscular and Skeletal
  • Arthralgias
  • Gout
  • Increased creatine phosphokinase
  • Myalgias
  • Myasthenia
  • Neuropathy
  • Paresthesia
Endocrine and Metabolic
  • Hyperglycemia
  • Hyperkalemia
  • Increased lactate dehydrogenase
  • Increased gamma-glutamyl transferase
Dermatologic
  • Maculopapular rash
  • Pruritus
  • Skin rash
  • Urticaria
Gastrointestinal
  • Diarrhea
  • Diarrhea caused by Clostridium difficile (CDAD)
  • Mesenteric artery occlusion
  • Nausea
  • Pancreatitis
  • Pseudomembranous colitis
  • Stomatitis
  • Vomiting
Genitourinary
  • Hematuria
  • Vaginitis
Hematologic and Oncologic
  • Anemia
  • Hemolytic anemia
  • Pancytopenia
  • Thrombocytopenia
Hepatic
  • Hepatitis
  • Hyperbilirubinemia
  • Jaundice
Hypersensitivity
  • Anaphylactoid reaction
  • Hypersensitivity reaction
Local
  • Inflammation at IV site
  • Localized edema
  • Pain at IV site
  • Thrombophlebitis (IV)

Select one of the following methods to complete this course.

Take TestPass an exam testing your knowledge of the course material.
OR
Reflect on Practice ImpactDescribe how this course will impact your practice.   (No Test)

References

  • Drugs.com. (2020, December 4). Pregnant? Breastfeeding? Better Drug Information Is Coming. Drugs.Com. Visit Source.
  • NIH. (2020a, June 12). Spectinomycin (hydrochloride hydrate) | C14H26Cl2N2O7—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020b, December 5). Amikacin | C22H43N5O13—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020c, December 5). Demeclocycline | C21H21ClN2O8—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020d, December 5). Doxycycline | C22H24N2O8—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020e, December 5). Gentamicin | C21H43N5O7—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020f, December 5). Kanamycin sulfate monohydrate | C18H38N4O12—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020g, December 5). Minocycline | C23H27N3O7—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020h, December 5). Neomycin sulfate | C23H52N6O25S3—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020i, December 5). Streptomycin | C21H39N7O12—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020j, December 5). Tetracycline | C22H24N2O8—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020k, December 5). Tigecycline | C29H39N5O8—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020l, December 5). Tobramycin | C18H37N5O9—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020m, December 12). Azidamfenicol | C11H13N5O5—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020n, December 12). Azithromycin | C38H72N2O12—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020o, December 12). Chloramphenicol | C11H12Cl2N2O5—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020p, December 12). Clarithromycin | C38H69NO13—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020q, December 12). Clindamycin | C18H33ClN2O5S - PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020r, December 12). Erythromycin | C37H67NO13—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020s, December 12). Fidaxomicin | C52H74Cl2O18—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020t, December 12). Lincomycin | C18H34N2O6S - PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020u, December 12). Linezolid | C16H20FN3O4—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020v, December 12). Pristinamycin | C71H84N10O17—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020w, December 12). Quinupristin-dalfopristin | C87H117N13O19S2—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020x, December 12). Retapamulin | C30H47NO4S - PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020y, December 12). Tedizolid | C17H15FN6O3—PubChem. National Institute of Health National Library of Medicine. Visit Source.
  • NIH. (2020z, December 12). Telithromycin | C43H65N5O10—PubChem. National Institute of Health National Library of Medicine. Visit Source.