Protein Synthesis Inhibitors

Tetracyclines are used to treat the following:

• Rickettsial infections
• Ehrlichiosis
• Anaplasmosis
• Leptospirosis
• Amebiasis
• Actinomycosis
• Nocardiosis
• Brucellosis
• Melioidosis
• Tularemia
• Chlamydial infections
• Pelvic inflammatory disease
• Syphilis
• Traveler's diarrhea
• Early Lyme disease
• Acne
• Legionnaire's disease
• Whipple disease
• Borrelia recurrentis
• Mycobacterium marinum
• Mycoplasma pneumoniae
• Staphylococcus aureus (including MRSA)
• Vibrio vulnificus
• Vancomycin-resistant enterococci (susceptible strains)
• Rosacea
• Bullous dermatoses
• Sarcoidosis
• Kaposi sarcoma
• Pyoderma gangrenosum
• Hidradenitis suppurativa
• Sweet syndrome
• Alpha-1 antitrypsin deficiency
• Panniculitis
• Pityriasis lichenoides chronica
• Rheumatoid arthritis
• Scleroderma
• Cancer
• Cardiovascular diseases such as abdominal aortic aneurysm and acute myocardial infarction

Tetracyclines can also be used to achieve meningococcal prophylaxis. Moreover, they are used off-label to treat Helicobacter pylori eradication, malaria, and periodontitis (Shutter & Akhondi, 2023).

Tetracyclines are broad-spectrum antibiotics with bacteriostatic activity, which means they stop bacterial growth but do not kill the microbes. Most of its subclasses share a similar spectrum of activity. However, tigecycline shows a different activity compared to earlier tetracyclines (Shutter & Akhondi, 2023).

Tetracyclines are active against:

• Gram-positive bacteria
• Gram-negative bacteria
• Chlamydiae
• Mycoplasmas
• Rickettsiae
• Coxiella
• Spirochetes
• Some mycobacteria

Most streptococci are sensitive, except:

• Streptococcus agalactiae
• Enterococci

Susceptible gram-positive bacilli include:

• Actinomyces israelii
• Arachnia propionica
• Listeria monocytogenes
• Most clostridia
• Bacillus anthracis

Nocardia species are much less susceptible. However, minocycline shows the greatest activity against them.

Among gram-negative bacteria:

• Most strains of Moraxella catarrhalis
• Neisseria meningitidis
• Haemophilus influenzae
• Legionellae
• Brucellae
• Francisella tularensis
• Vibrio cholerae
• Campylobacter spp.
• Helicobacter pylori
• Plesiomonas shigelloides
• Aeromonas hydrophila

Many anaerobic bacteria are susceptible, especially to:

• Doxycycline
• Minocycline

Rickettsiae are generally sensitive to:

• Doxycycline
• Minocycline
• Tetracycline

Tetracycline is not effective against:

• Pseudomonas aeruginosa
• Proteus spp.
• Providencia spp. (Shutter & Akhondi, 2023)

Most tetracyclines are given by mouth. However, doxycycline and tigecycline can be given parenterally through an IV route.

Tetracyclines are absorbed largely in the proximal small bowel but can be hindered by the simultaneous presence of food, milk, or cations, with which tetracyclines form nonabsorbable chelates. Moreover, cimetidine and other histamine type 2 (H2) receptor antagonists also impair tetracycline absorption by interfering with their dissolution, which is pH-dependent. The absorption was a real problem for the earlier tetracyclines. However, newly developed compounds such as lymecycline, demeclocycline, and methacycline have better absorption. However, doxycycline and minocycline have the best absorption, and they can even be administered with food; the proportion of administered dose absorbed is more than 90% (Shutter & Akhondi, 2023).

When orally administered, tetracyclines achieve peak serum concentrations within 1-4 hours of ingestion, with an available serum level of 1.5 to 4.0 mg/liter (L). Most tetracyclines are given four times daily to maintain the therapeutic concentrations, except demeclocycline and minocycline, which can be administered twice daily, and doxycycline, which can be administered once daily.

Tetracyclines penetrate the body fluids and tissues well, leading to a large volume of distribution. The concentration of most tetracyclines in the cerebrospinal fluid (CSF) is usually about 10 to 25% of those in the blood. However, penetration of tigecycline into the CSF is poor. Tetracyclines deposit and persist in areas where bone is being laid down. Older tetracyclines penetrate into sebum and are excreted in perspiration, which is why they are mostly used in the management of acne. The older tetracyclines also concentrate in the eye.

Tetracyclines are excreted through the kidneys and feces. They are excreted in feces after parenteral administration by passing into bile. The concentration in bile is 5 to 25 times higher than in blood, especially doxycycline. However, these concentrations are lowered in biliary obstruction. In urine, the concentration of tetracycline is found in the range of 20-60% (Tao et al., 2023).

The most common adverse effect of tetracyclines is gastrointestinal intolerance. Moreover, tetracyclines also cause photosensitivity, mostly by demeclocycline. Older tetracyclines deposit in developing bones and teeth. Therefore, their use should be excluded in young children and during late pregnancy.

Tetracyclines cause nausea and vomiting because of the direct irritant effect of the drug on the gastric mucosa. Still, diarrhea likely results from the disturbance of normal flora in the gastrointestinal tract (Shutter & Akhondi, 2023).

The frequency and nature of superinfection by tetracyclines depend much on local ecology. Older tetracyclines have been shown to cause pseudomembranous colitis. Organisms that become dominant in the fecal flora after oral administration of tetracyclines are Candida, Proteus, Pseudomonas spp., and Staphylococcus aureus(Ahn et al., 2021).

Other well-recognized side effects of tetracyclines are glossitis, pruritus, vaginitis, and vulvitis. However, less common side effects of tetracyclines include esophageal ulceration and acute pancreatitis.

Hypersensitivity to tetracyclines is rare. However, when it occurs, it can cause rashes, exfoliation, skin reactions, and manifestations of photosensitivity. The reaction can occur after administration of any tetracycline but is more common with demeclocycline and less common with doxycycline and minocycline.

Tetracycline can also cause fixed drug eruptions and onycholysis, along with nail and thyroid pigmentation. Angioedema and anaphylaxis reactions with tetracyclines are rare. However, if the patient is hypersensitive to one tetracycline, the risk of being hypersensitive to another tetracycline exists (Orylska-Ratynska et al., 2022).

Tetracyclines interact with iron-containing preparations by forming complexes with divalent and trivalent cations. Moreover, anticonvulsant drugs such as phenytoin, carbamazepine, and barbiturates can decrease the half-life of doxycycline through enzyme induction. The anesthetic drug methoxyflurane, when co-administered with older tetracyclines, can cause nephrotoxicity.

Tigecycline can affect the pharmacokinetic profile of warfarin, affecting its anticoagulant activity. Tetracyclines also affect the efficiency of oral contraceptives.

The drug interactions of tetracyclines with other drugs and their management recommendations can be summarized below:

• Tetracyclines, when given with antacids, can result in decreased tetracycline concentration. Therefore, avoid their concomitant administration and space them two hours apart.
• When given with atovaquone, tetracyclines result in around 40% decreased atovaquone concentration. Therefore, use alternative therapy if possible.
• Doxycycline, when given with barbiturates, can result in decreased doxycycline concentration. Therefore, use other tetracyclines.
• Tetracyclines, when given with bismuth, result in decreased tetracycline concentration. Therefore, a space of two hours should be allocated to their administration.
• Doxycycline, when given with carbamazepine, results in decreased doxycycline concentration. Therefore, other tetracyclines should be used.
• Tetracyclines, when given with colestipol, result in decreased tetracycline concentration. Their administration should be spaced by at least two hours.
• Tetracyclines, when administered with digoxin, can result in increased digoxin concentration. Therefore, the digoxin dose should be adjusted appropriately.
• Ergotamine tartrate, when given with tetracyclines, can result in ergotism. Therefore, dose adjustment is required.
• Doxycycline, when given to patients who ingest alcohol chronically, can result in decreased doxycycline concentration that would not cure the infection and can lead to drug resistance. Therefore, use other tetracyclines.
• Tetracyclines, when given with iron, can cause decreased tetracycline concentration. A two-hour space should be given between their administration.
• Isotretinoin, when given with tetracyclines, can result in pseudotumor cerebri. Therefore, their concomitant use should be avoided.
• Tetracyclines, when given with kaolin-pectin, can result in decreased tetracycline concentration. Their administration should be spaced by at least two hours.
• Tetracyclines, when given with lithium salts, can result in increased lithium concentration, leading to lithium toxicity. Therefore, monitor lithium concentration closely and adjust the dose appropriately with concomitant tetracycline therapy.
• Tetracyclines, when given with methotrexate, can lead to increased methotrexate concentration and toxicity. Therefore, methotrexate concentration should be monitored, and leucovorin should be used as a rescue.
• Tetracyclines, when given with methoxyflurane, can increase the risk of nephrotoxicity. Therefore, their concomitant use should be avoided.
• Tetracyclines can reduce the effectiveness of oral contraceptives. With their concomitant use, counsel the patient to use additional forms of contraception to prevent the occurrence of unplanned pregnancy.
• Doxycycline, when given with phenytoin or fosphenytoin, can lead to decreased doxycycline concentration. Therefore, other tetracyclines should be used.
• Tetracyclines, when given with quinine, can result in quinine toxicity. Therefore, dose adjustments should be made, and patients should be monitored for quinine toxicity.
• When given with rifampin or rifabutin, doxycycline can result in decreased doxycycline concentration. Therefore, other tetracycline drugs should be used if double antibiotic therapy is required.
• Tetracyclines, when given with sodium bicarbonate, can cause decreased tetracycline concentration. A space of at least two hours should be provided for their administration.
• Tetracyclines, when given with theophylline, can result in increased tetracycline concentration. Therefore, serum theophylline concentration should be monitored closely, and the dose should be adjusted appropriately.
• Tetracyclines, when given with warfarin, can result in enhanced coagulation. Therefore, the patient's prothrombin time and international normalized ratio (INR) should be monitored, and the warfarin dose should be adjusted accordingly.
• Tetracyclines, when given with zinc, can result in decreased tetracycline concentration. Therefore, a space of at least two hours should be given in between their administration (DRUGBANK Online, 2024; Drugs.com, 2023a; Medscape, n.d.-b).

• Oral tetracyclines should be administered on an empty stomach, such as one hour before or two hours after food, milk, or dairy products, for maximum absorption with a full glass of water to reduce the risk of esophageal irritation.
• If antacids containing aluminum or magnesium are given, tetracyclines should be administered at least 1-2 hours before or four hours after to prevent absorption interference.
• Minocycline can be given with or without food without having a significant effect on serum levels.
• Pellet-filled capsules or extended-release tablets/capsules should be consumed whole; do not chew, crush, or split before administration.
• Do not administer oral tetracyclines within one hour of bedtime to prevent esophageal reflux.
• Keep the reconstituted tetracyclines in the refrigerator and away from sunlight. Moreover, check the drug's expiration date before administration, as expired tetracyclines can cause nephrotoxicity.
• Infuse tetracyclines over 30 to 60 minutes (duration varies by agent); use dedicated lines or Y-site. Flush the line before and after administration if used sequentially with other drugs. Avoid rapid administration and extravasation. Reserve for cases where oral administration is not feasible. However, prolonged IV therapy may lead to thrombophlebitis.
• Adjust dosage in hepatic impairment; monitor closely for hepatotoxicity.
• Adjust dosage in renal impairment (creatinine clearance [CrCl] <80 milliliters [mL]/minute); monitor for nephrotoxicity.
• Use with caution in patients with renal or hepatic impairment or concurrent use of hepatotoxic drugs.
• Use with caution in pediatric patients; avoid use in children under eight years due to tooth discoloration.
• Monitor for anaphylactic/hypersensitivity syndromes, including severe skin reactions (e.g., drug reaction with eosinophilia and systemic symptoms [DRESS] syndrome).
• Central nervous system (CNS) effects such as dizziness, blurred vision, and intracranial hypertension (pseudotumor cerebri) may occur.
• Gastrointestinal inflammation and ulceration, hepatotoxicity, and photosensitivity are potential adverse effects.
• Superinfection, including Clostridium difficile (C. difficile)-associated diarrhea (CDAD), may occur with prolonged use.
• Educate patients on potential drug interactions (e.g., with oral isotretinoin, beta-lactams) and adherence to dosing and administration instructions.
• Encourage patients to report any new or worsening symptoms promptly.
• Do not use during pregnancy; it is associated with fetal tooth and skeletal development issues.
• Limited safety and efficacy data in children and adolescents under 18 years.

• Hypersensitivity to any tetracycline or formulation component.
• Avoid use in pregnant or lactating women.
• Specific limitations apply to different conditions.

• Perform culture and sensitivity testing before initiating therapy.
• Monitor the patient's temperature.
• Monitor liver function tests, renal function tests, CBC, and white blood count (WBC) as needed and periodically with prolonged therapy.
• Consider additional tests for autoimmune disorders if symptomatic.
• Obtain ophthalmologic evaluation if visual disturbances occur.
• Test for a cure for gonococcal infections seven days after treatment and conduct serologic tests for syphilis three months after treatment (Drugs.com, 2023b).

The doses, route of administration, and common side effects of the most commonly used tetracycline drugs can be summarized as follows:

Aminoglycosides have the following indications:

• Empirical treatment: Effective against multi-drug-resistant gram-negative pathogens.
  • Severe illness: Indicated for empirical therapy in severe illness cases such as:
    • Infective endocarditis
    • Sepsis
    • Complicated intraabdominal infections
    • Complicated genitourinary infections
  • Duration: Typically used for no more than two days in empirical settings due to potential toxicity

Directed Treatment

• Acceptable use for longer than 48 hours: In specific directed treatments, aminoglycosides can be used for more than 48 hours. These include:
  • Combination Therapy:
    • Brucellosis
    • Listeriosis
    • CNS nocardiosis
    • Pseudomonas aeruginosa infection
  • Monotherapy:
    • Tularemia
    • Resistant mycobacteria
    • Bacteremia caused by Campylobacter spp.
    • Bacteremia caused by Yersinia spp.
    • Drug-resistant gram-negative pathogens (Block & Blanchard, 2023)

Aminoglycosides show activity against several pathogens, particularly gram-negative and certain gram-positive bacteria.

Aminoglycosides are active against the following gram-positive bacteria:

• Staphylococcus aureus
• Coagulase-negative staphylococci
• Corynebacterium spp.
• Limited activity against streptococci. Aminoglycosides interact synergistically with penicillin and other antibiotics against streptococci and enterococci. This combination is essential in treating enterococcal endocarditis.

Aminoglycosides are active against the following gram-negative bacteria:

• Enterobacteriaceae
• Aerobic gram-negative bacilli, including Pseudomonas aeruginosa, for some aminoglycosides
• Mycobacteria: Several aminoglycosides, including streptomycin, are effective against Mycobacterium tuberculosis and other mycobacteria.

Aminoglycosides are effective against anaerobic bacteria because of the diminished membrane potential required for aminoglycosides to cross the bacterial cell membrane under anaerobic conditions (Drew, 2024).

Aminoglycosides are highly polar molecules carrying a positive charge on them. When given through the oral route, less than 1% of the oral dose is absorbed from the gut. However, this may be clinically significant in patients with renal failure or gut inflammation, leading to increased uptake. From serous cavities and intramuscular (IM) sites, the absorption of aminoglycosides is rapid, and the plasma protein binding is low, less than 10%. Aminoglycosides are distributed into the extracellular water and some serous fluids, such as ascites and pleural fluid, with a volume of distribution of 0.25 L/kg. Moreover, intracellular penetration of aminoglycosides is low. Therefore, the penetration to cerebrospinal fluid and aqueous humor is also low. However, this concentration may be higher if inflammation is present.

Aminoglycosides bind extensively to tissues, principally renal tissues, which causes initial incomplete excretion of aminoglycosides and prolonged excretion even after dosing is terminated.

The plasma half-lives of different aminoglycoside drugs are about two hours, but this varies in patients with renal impairment. Moreover, aminoglycosides are excreted unchanged by glomerular filtration, which gives a high concentration of active antibiotics in urine. Therefore, when renal function is impaired, the aminoglycoside excretion reduces and accumulates in the body.

Aminoglycosides are readily removed by hemodialysis because of their low protein binding, relatively small volume of distribution, and small molecular size. In hemodialysis, the half-life of aminoglycosides is reduced to about four hours from the 50 hours typically seen in patients with end-stage renal failure. In a 3-4 hour hemodialysis session, around 50% of the drug is removed. However, the removal of aminoglycosides by peritoneal dialysis is quite less efficient, with the half-life of aminoglycosides around 36 hours.

Aminoglycosides get inactivated by many beta-lactam antibiotics if they are combined chemically, such as in the infusion or possibly in patients with renal failure where the half-life of both antibiotics is prolonged and interaction can occur (Block & Blanchard, 2023).

Aminoglycosides can cause side effects, including some serious ones, such as ototoxicity, nephrotoxicity, and neuromuscular blockade. There are differences in the absolute and relative frequencies of these adverse effects between the various aminoglycosides.

Ototoxicity: Aminoglycosides have the potential to cause ototoxicity to both vestibular and cochlear function of the eighth cranial nerve, with the damage usually being permanent. When aminoglycosides accumulate in the endolymph and possibly perilymph, the hair cells are also damaged. Accumulation of aminoglycosides occurs because of persisting and high plasma concentration, which prevents aminoglycosides from diffusing back into the plasma. Once aminoglycosides damage the hair cells, it may continue to increase in severity for up to four weeks, even if the aminoglycoside therapy has been stopped. Vestibulotoxicity causes vertigo, especially on rising from bed, oscillopsia, and ataxia. However, cochlear toxicity shows up as deafness, particularly to high tones.

Ototoxicity by aminoglycosides is potentiated if the patient has previously received aminoglycoside therapy and concomitant exposure to loop diuretics and other ototoxic drugs and noise. Aminoglycosides can cause toxicity in all patients, but there is an enhanced susceptibility to cochlear toxicity in patients with A>G substitution in location 1555 of the mitochondrial ribosomal ribonucleic acid (rRNA); a second mutation involving a thymidine deletion in the 12S ribosomal RNA gene. These patients may experience ototoxicity in relatively normal drug exposure to aminoglycosides. To overcome this, genetic testing may be useful in identifying them before initiating therapy.

Nephrotoxicity: With ototoxicity, aminoglycosides have a tendency to cause nephrotoxicity by accumulating in the renal cortex. The frequency of nephrotoxicity caused by aminoglycosides depends on various factors, such as the clinical state of the patient, the way of administration, and the agent administered (Chou et al., 2022).

Ototoxicity is highly specific to aminoglycosides, but the diagnosis of nephrotoxicity by aminoglycosides is not that certain, depending on various other factors that cause diminished renal function. Nephrotoxicity can lead to poor outcomes. Therefore, it is important to detect its onset as soon as possible and gauge the risk versus benefit ratio of continuing aminoglycoside therapy. For that, serial measurements of serum plasma creatinine levels should be made daily for no less than three days. Since serum creatinine levels may vary from day to day, measuring the clearance of aminoglycosides may help gauge the onset of nephrotoxicity. Other indicators that help in knowing about renal damage are urinary phospholipids, renal enzymes, or Beta-2 (β2)-microglobulin. However, they are not widely used in routine activities (Mudd, 2024).

The amount of nephrotoxicity caused by aminoglycosides may differ. When there is a longer dosage interval in the administration of aminoglycosides, the body gets more time to clear the drug from renal tissues between doses. The risk of nephrotoxicity is more commonly associated with therapy for more than seven days. Moreover, simultaneous exposure to other potentially nephrotoxic drugs such as amphotericin B, vancomycin, and non-steroidal anti-inflammatory drugs increases the risk of nephrotoxicity. Patients with hypotension, diabetes, and hypovolemia are also at increased risk of nephrotoxicity with aminoglycoside therapy. The degree of renal damage varies by different aminoglycosides and is related to the accumulation of high concentrations of the drug in the renal cortex.

The frequency of nephrotoxicity after systemic administration of aminoglycosides varies from around 2% to 60%, depending on the dose of the drug, patient population, and criteria of renal damage. Gentamicin is considered more nephrotoxic compared to netilmicin because of its lower excretion rate and higher degree of net reabsorption. The earliest and most sensitive indication of the onset of renal impairment can be gauged by the abnormal persistence of aminoglycosides in the plasma between doses.

Neuromuscular blockade: Aminoglycosides may produce neuromuscular blockade, probably by acting as membrane stabilizers in the same way as curare. The effect is relatively feeble and rarely occurs in patients with normal neuromuscular function. However, antibiotics are customarily given in much larger amounts than curare, and patients who are also receiving muscle relaxants or anesthetics or who are suffering from myasthenia gravis are at special risk of neuromuscular blockade.

• The risk of nephrotoxicity with aminoglycosides may be increased with co-administration of other drugs that are nephrotoxic or in patients receiving loop diuretics (e.g., furosemide).
• Respiratory depression may occur if aminoglycosides are given with nondepolarizing muscle relaxants.
• Neomycin may affect digoxin levels by altering the bowel flora responsible for the metabolism of digoxin in the gastrointestinal tract.
• Gentamicin may also cause increased serum digoxin levels.
• In vitro deactivation of penicillins due to acylation has been observed, so the drugs should not be mixed in vitro.
• Tobramycin inhalation solution cannot be mixed in the nebulizer with dornase alfa (Hughes, 2021).

• Rapid therapeutic concentrations improve patient outcomes.
• Dosing optimization:
  • Weight-based dose divided 2-3 times daily for patients with normal renal function.
  • Adjust dose or interval for patients with decreased renal function.
• Once-daily extended-interval dosing:
  • Higher weight-based dose every 24 hours.
  • Do not confuse it with traditional intermittent dosing at 24-hour intervals for renal impairment.
• Administration:
  • IV over 30 minutes for traditional intermittent dosing.
  • IV over 60 minutes for extended interval dosing.
• Initial dose and frequency depend on administration, indication, dosing weight, and renal function.
• Dosing adjustments based on serum drug concentration monitoring.
• Peak serum concentrations aim to optimize efficacy.
• Trough concentrations aim to avoid toxicity.
• Weight considerations:
  • Use total body weight (TBW) or ideal body weight (IBW).
  • For obesity: Dosing weight = IBW + 0.4 × (TBW - IBW).
• CrCl impacts drug clearance and dosing interval.
  • Use the Cockcroft-Gault formula for estimation.
• Acute renal failure: Adjust creatinine clearance estimation based on stable serum creatinine levels.
• Diseases affecting creatinine production:
  • Severe liver disease, malnutrition, muscle mass loss (e.g., quadriplegia, paraplegia, amputation).

• Traditional intermittent dosing:
  • Smaller doses multiple times per day.
• Extended-interval dosing:
  • High doses at extended intervals.
  • Advantages: Decreased nephrotoxicity, ease of administration, reduced monitoring costs, facilitate inpatient to outpatient care.
  • Relies on post-antibiotic effect and concentration-dependent killing.

• Continuous ambulatory peritoneal dialysis (CAPD):
  • Gentamicin and tobramycin for peritonitis.
  • Target intraperitoneal concentrations: 4-8 mg/L.
  • Systemic illness: IV loading dose.
• Intermittent hemodialysis:
  • Reduces pre-dialysis concentrations by 50%.
  • Supplemental doses post-dialysis are needed.
• Continuous arteriovenous (AV) hemofiltration:
  • Initial daily gentamicin or tobramycin: 2.5 mg/kg once daily.
  • Follow with serum concentration monitoring.
• Cystic fibrosis:
  • Higher starting doses are needed for target serum concentrations.
• Burn patients:
  • Larger maintenance doses of gentamicin and tobramycin.
  • Serum concentration monitoring is required.
• Septic patients:
  • Close monitoring is required due to fluid resuscitation and renal function changes.
• Elderly patients:
  • Caution due to reduced renal function and potential nephrotoxic agents.
  • Reduced muscle mass may overestimate renal function.

The dosage, route of administration, and notes for the most commonly used aminoglycosides are (Drew, 2024):

Macrolide antibiotics are used to treat the following conditions:

• Azithromycin, clarithromycin, and erythromycin are commonly used to treat infections like pneumonia, sinusitis, pharyngitis, and tonsillitis.
• The Food and Drug Administration (FDA) has approved the use of macrolide antibiotics to treat uncomplicated skin infections and otitis media in pediatric patients.
• Clarithromycin is used to treat Helicobacter pylori infections in standard triple therapy protocols regardless of clarithromycin resistance status.
• Macrolides are used to treat sexually transmitted infections such as gonococcal and chlamydial infections. They are also used as primary drugs to treat atypical pneumonia, usually caused by organisms like Mycoplasma pneumoniae, Legionella, and Chlamydia pneumoniae.
• Recent studies show that macrolide maintenance therapy improves the quality of life, and spirometry findings in adults and children with non-cystic fibrosis bronchiectasis show it reduces the number of bronchiectasis exacerbations (although it does not reduce hospital admissions for exacerbations).
• Macrolides are integral to treatment regimens for chronic obstructive pulmonary disease (COPD) exacerbations due to their anti-inflammatory and immunomodulatory characteristics (Patel & Hashmi, 2023).

Macrolides are active against: 

• Gram-positive bacteria: Some Streptococcus pyogenes, some viridans streptococci, some Streptococcus pneumoniae, and some Staphylococcus aureus.
• Gram-negative bacteria: Neisseria spp., some Haemophilus influenzae, and Bordetella pertussis.
• Atypical bacteria: Chlamydia spp., Mycoplasma spp., Legionella pneumophila, and some Rickettsia spp.
• Mycobacteria: Mycobacterium avium complex, Mycobacterium leprae.
• Spirochetes: Treponema pallidum, Borrelia burgdorferi(Patel & Hashmi, 2023)

Erythromycin has poor water solubility and is rapidly inactivated by gastric acid, resulting in widely varying bioavailability after oral administration. However, derivatives of erythromycin A have improved pharmacological properties, including gastrointestinal tolerance, bioavailability, higher peak plasma levels, improved tissue concentrations, longer apparent elimination plasma half-lives, and improved tissue concentrations. Moreover, macrolides are absorbed readily, with plasma peaks varying between 0.4 mg/L (azithromycin) and 11 mg/L (roxithromycin). Maximum concentrations are reached between 0.5 hours (rokitamycin) and three hours (clarithromycin) and are dose-dependent. The apparent elimination half-life varies from one hour (mikamycin) to 44 hours (dirithromycin); the absolute bioavailability varies between 10% (dirithromycin) and 55–60% (roxithromycin, clarithromycin).

The main elimination route is via the bile and feces; a proportion of clarithromycin is excreted via the intestinal mucosa. A substantial part of the administered dose of clarithromycin is eliminated in urine. The long apparent elimination half-lives of roxithromycin, azithromycin, and dirithromycin allow them to be administered as single daily oral doses.

Generally, macrolides are safe and rarely cause serious adverse events. However, an exception exists with erythromycin estolate, which is hepatotoxic and can cause hepatitis, probably as a result of the mixture of lauryl sulfate and the 2′-propenyl ester.

Gastrointestinal complaints such as nausea, vomiting, abdominal pain, or, less frequently, diarrhea are most common with erythromycin. They present a problem mainly with erythromycin doses higher than those recommended and are partly due to a hemiketal degradation product that acts on motilin, an intestinal endopeptidase. However, semisynthetic 14- and 15-membered-ring macrolides are more acid-stable than erythromycin A and are better tolerated.

It is worth remembering that macrolides cause many drug interactions because they tend to inhibit the enzyme cytochrome P450 3A4 (CYP3A4) and lead to QT interval prolongation. Therefore, it is essential to check any drug interactions with macrolides before administering them.

Macrolides such as azithromycin, clarithromycin, erythromycin, and others may interact with other medications, such as:

Statins

Macrolides, when given with statins, lead to an increased risk of myopathy and rarely rhabdomyolysis. Warn patients against signs of myopathy, such as weakness and muscle pain. The use of simvastatin is contraindicated with erythromycin and clarithromycin. However, if the macrolide therapy cannot be avoided, suspend simvastatin for the same duration and at least seven days after intake of the last antibiotic dose. Moreover, the use of a statin that is not dependent on CYP3A metabolism, such as fluvastatin, can be considered.

Macrolides should not be given with atorvastatin therapy. Instead, the statin should be withheld until macrolide antibiotics are being administered. However, if that's not possible, give the lowest possible statin dose with clarithromycin. If the patient receives doses greater than 20 mg, reduce it to 20 mg for the duration of macrolide treatment.

If combined with clarithromycin, Pravastatin should be limited to 40 mg daily.

Warfarin

Macrolides, when given with warfarin, can increase the bleeding risk. Monitor INR within the first three days of initiating the therapy, during therapy, and after discontinuation, with dosage adjusted accordingly.

Direct Oral Anticoagulants

Direct oral anticoagulant use should be avoided with macrolide antibiotics. Dabigatran, when combined with macrolides, can lead to increased levels of dabigatran and, hence, increased bleeding. Therefore, discontinue dabigatran, especially if bleeding occurs. Monitor the patient closely for any adverse effects.

Rivaroxaban, when combined with macrolides, can lead to increased levels of rivaroxaban. Monitor the patient for signs of bleeding.

Patients receiving apixaban and edoxaban should be closely monitored for bleeding symptoms when combined with macrolides.

Drugs That Prolong QT Interval

Macrolides are strongly contraindicated with drug therapy that causes QT interval prolongation. For example, erythromycin and clarithromycin are contraindicated with the antipsychotic medication quetiapine. Macrolides should not be prescribed with drugs that tend to prolong the QT interval, such as amiodarone, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, alfuzosin, galantamine, indapamide, domperidone, lithium, methadone, tamoxifen, tizanidine, quinine sulfate, hydroxyzine, ranolazine, and ivabradine.

Colchicine

Macrolides such as azithromycin, erythromycin, and clarithromycin tend to increase colchicine exposure. Concomitant use of clarithromycin and colchicine is contraindicated.

Antiepileptic Drugs

Carbamazepine, when given with macrolides such as clarithromycin and erythromycin, results in increased plasma concentrations of carbamazepine. Moreover, phenytoin or valproate, when given with clarithromycin, results in increased phenytoin or valproate concentration. Therefore, dose adjustments are necessary if the patient has to take macrolides with ongoing antiepileptic therapy. Advise the patient to report any signs of antiepileptic drug toxicity, such as mental confusion, ataxia, diplopia, and dizziness.

Oral Hypoglycemic Agents or Insulin

Concomitant use of insulin or oral hypoglycemics with macrolides can result in hypoglycemia. Monitor the serum glucose levels.

Benzodiazepines & Z-Drugs

Concomitant administration of clarithromycin with oral midazolam is contraindicated. If benzodiazepines and macrolides are given together, dose adjustment is necessary, and monitor the patient for signs of toxicity, such as sedation. Similarly, caution should be exercised with Z-drugs such as zopiclone.

Digoxin

Macrolides, when given with digoxin, can increase serum concentration. Therefore, dose adjustments are necessary with the concomitant administration of macrolides and digoxin. Monitor the patient for signs of digoxin toxicity, such as bradycardia (Health Service Executive (HSE), n.d.).

• Patients who have had an allergic reaction or hypersensitivity reaction to macrolides or any component of the formulation should not be given macrolides.
• Patients with a previous history of cholestatic jaundice/hepatic dysfunction should not be given macrolide antibiotics.
• Concomitant administration of macrolides is contraindicated 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 should be avoided because of the potential for fatal cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes) (Patel & Hashmi, 2023):
  • Astemizole
  • Cisapride
  • Pimozide
  • Terfenadine
  • Ergotamine
  • Ticagrelor
  • Ranolazine
  • Dihydroergotamine
  • Lovastatin, simvastatin, or atorvastatin (cholesterol medications)
  • Theophylline
  • Methadone

Systemic indications of clindamycin include the following:

• Respiratory tract infections
• Skin/soft tissue infections
• Sepsis
• Intra-abdominal infections
• Infections of the female pelvis and genital tract
• Bacterial endocarditis prophylaxis for dental and upper respiratory procedures in penicillin-allergic patients
• Perioperative prophylaxis

Topical

• Treatment of acne vulgaris.

Intravaginal

• Treatment of bacterial vaginosis.

Off-Label Uses

• Actinomycosis
• Babesiosis
• Erysipelas
• Malaria
• Otitis media
• Pneumocystis jiroveci pneumonia (PCP)
• Sinusitis
• Toxoplasmosis

Oral

Treatment of bacterial vaginosis (Murphy et al., 2024)

Clindamycin shows activity against the following: 

• Gram-positive anaerobes:
  • Actinomyces israelii
  • Clostridium clostridioforme
  • Clostridium perfringens
  • Eubacterium centum
  • Finegoldia ("Peptostreptococcus") magus
  • 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 such as:
  • Bacteroides fragilis
  • Prevotella melaninogenica
  • Fusobacterium necrophorum
  • Fusobacterium nucleatum
  • Prevotella intermedia
  • Prevotella bivia(Murphy et al., 2024)

When given orally, the absorption of clindamycin hydrochloride is rapid, and about 90% of the drug is absorbed. However, when given as clindamycin palmitate, it must get hydrolyzed in the gastrointestinal tract before becoming active. Topical preparations of clindamycin phosphate in the form of solution or foam have minimal absorption. Moreover, as a vaginal cream, 5% of the drug is absorbed, whereas, in the form of a suppository, approximately 30% of the clindamycin phosphate is absorbed. Clindamycin has a protein binding of 92-94%.

The time to achieve serum peak varies from the route of administration. When given orally, clindamycin achieves a peak in 60 minutes; through an IM route, it takes 1-3 hours to achieve serum peak. Moreover, vaginal cream and the suppository of clindamycin take approximately 10-14 hours to achieve a serum peak.

Clindamycin is distributed in body fluids and tissues with high concentrations in bone and urine. It is not found in the cerebrospinal fluid, not even with inflamed meninges.

Clindamycin is metabolized through the hepatic route and has an elimination half-life of approximately three hours in adults when given orally. Moreover, when given orally, clindamycin is excreted in urine, 10% as active drug and metabolites and approximately 4% as active drug and metabolites in feces (Murphy et al., 2024).

Side effects and toxicity of clindamycin depend on the route of administration.

When applied topically, clindamycin may cause erythema, burning, pruritis, exfoliation, or oily skin. Moreover, when administered intravaginally, its common side effects are pruritis, vaginal candidiasis, vulvovaginitis, and vulvovaginal disease.

Through the systemic route, the most common side effect of clindamycin is diarrhea, especially when given orally because of C. difficile toxins. It happens because clindamycin kills many components of the normal existing flora in the gastrointestinal tract. In some cases, clindamycin can also lead to pseudomembranous colitis- a serious condition causing necrotizing plaques in the intestine. To rule out C. difficile-induced diarrhea, a stool culture should be done.

Parenteral administration of clindamycin can lead to elevation of transaminases and serum alkaline phosphatase, but that's generally reversible (Murphy et al., 2024).

Clindamycin has the potential to cause neuromuscular blockade. Therefore, its use should be avoided with other drugs having neuromuscular blocking actions, such as atracurium, cisatracurium, and rocuronium.

Clindamycin is metabolized primarily by the enzymes CYP3A4 and CYP3A5. Therefore, it should be given cautiously with drugs that inhibit CYP3A4 and CYP3A5, as the levels of clindamycin can increase in the bloodstream. Drugs such as rifampicin, known to induce CYP3A4, may result in increased metabolism and reduced efficacy of clindamycin (Murphy et al., 2024).

Clindamycin use is contraindicated in the following conditions: 

• Hypersensitivity to clindamycin or any component of the formulation.
• Patients with a history of CDAD, regional enteritis, or ulcerative colitis.
• Not appropriate for use in the treatment of meningitis due to inadequate penetration into CSF (Murphy et al., 2024).

• Do not refrigerate a reconstituted oral solution, as it will thicken. The solution remains stable for up to two weeks at room temperature.
• Administer the capsule form with a full glass of water to prevent dysphagia.
• Check the IV site daily for signs of phlebitis and irritation. Follow the drug's dilution protocol and administer as directed.
• Inject the drug deeply into the muscle and rotate injection sites. Inform the patient that IM injections may be painful. Avoid doses over 600 mg per injection.
• Be aware that IM injections may cause an increase in creatine kinase levels due to muscle irritation.
• Do not administer opioid antidiarrheals for drug-induced diarrhea, as they may prolong and worsen the condition.

Oral Administration:

• Serious infection: 150 to 300 mg orally every six hours
• More severe infection: 300 to 450 mg orally every six hours

Parenteral Administration:

• Serious infection: 600 to 1,200 mg per day via IV infusion or IM injection, divided into 2-4 equal doses.
• Severe infection: 1,200 to 2,700 mg per day via IV infusion or IM injection, divided into 2-4 equal doses.
• More severe infection: Up to 4,800 mg per day via IV infusion (Drugs.com, 2024a).

Oxazolidinones are indicated in the treatment of:

1. Treatment of Infections:
   • Vancomycin-resistant Enterococcus faecium infections:
     • Used for infections with or without bacterial invasion of the bloodstream.
   • Community-acquired pneumonia:
     • Effective against Streptococcus pneumoniae (including cases with concurrent bacteremia) and Staphylococcus aureus (methicillin-susceptible isolates only).
     • Second-line treatment for community-acquired pneumococcal pneumonia when penicillin resistance is present.
   • Hospital-acquired, healthcare-associated, and ventilator-associated pneumonia:
     • Treats pneumonia caused by Staphylococcus aureus (both methicillin-susceptible and resistant isolates) and Streptococcus pneumoniae.
     • U.S. guidelines recommend linezolid or vancomycin as first-line treatment for hospital-acquired MRSA pneumonia. Linezolid may have advantages over vancomycin, particularly in patients with renal insufficiency or in cases of ventilator-associated pneumonia due to better bronchial fluid penetration.
2. Skin and Skin Structure Infections:
   • Complicated skin and skin structure infections (cSSSI):
     • Treats infections, including diabetic foot infections (unless complicated by osteomyelitis) caused by Staphylococcus aureus (both methicillin-susceptible and resistant isolates), Streptococcus pyogenes, and Streptococcus agalactiae.
   • Uncomplicated skin and skin structure infections (SSSI):
     • Effective against infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) and Streptococcus pyogenes.
     • Not recommended for uncomplicated skin and soft tissue infections caused by MRSA. Tedizolid is preferred for acute bacterial skin and skin structure infections caused by susceptible gram-positive microorganisms.
3. Other Uses:
   • Bone and joint infections:
     • Includes treatment of chronic osteomyelitis.
   • Tuberculosis:
     • Used in combination with other drugs.
   • Alternative to vancomycin:
     • Alternative in treating febrile neutropenia in cancer patients when a gram-positive infection is suspected.
   • Community-acquired MRSA infections of the CNS:
     • Appears superior to vancomycin for treating these infections.
   • Endophthalmitis:
     • Effective due to its ability to diffuse into the vitreous humor, treating inflammation of the inner linings and cavities of the eye caused by susceptible bacteria.

Off-label Uses

The off-label uses of oxazolidinones include:

• Brain abscess, subdural empyema, and spinal epidural abscess (Staphylococcus aureus [methicillin-resistant])
• Infective endocarditis
• Meningitis caused by:
  • Staphylococcus aureus (methicillin-resistant)
  • Vancomycin-resistant enterococci: 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.

Linezolid and tedizolid are active against the following microorganisms:

Against Susceptible Gram-Positive Organisms:

• Enterococcus:
  • Enterococcus faecalis (Group D Streptococcus, 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 (Group B Streptococcus, GBS)
  • Streptococcus anginosus group, including:
    • Streptococcus anginosus
    • Streptococcus intermedius
    • Streptococcus constellatus
  • Streptococcus pneumoniae (Pneumococcus)
  • Streptococcus pyogenes (Group A Streptococcus, GAS)
  • Viridans streptococci

Against Susceptible Gram-Negative Organisms:

• Pasteurella:
  • Pasteurella multocida

When given orally, the systemic absorption of linezolid approaches 100%. Moreover, tedizolid phosphate is an inactive prodrug converted by serum phosphatases to the active form, tedizolid. It exhibits excellent bioavailability (91%) after oral administration. The time to achieve a peak in the serum varies depending on the route of administration. Upon oral administration, it takes 1-3 hours for oxazolidinones to achieve serum peak; with IV administration, it takes 1-1.5 hours.

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. Furthermore, protein binding for linezolid is 31% and 70-90% for tedizolid.

To get metabolized, 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, and tedizolid phosphate is converted into the active drug tedizolid by phosphatases. The elimination half-life for linezolid in adults is 4.9-7 hours and 12 hours for tedizolid.

Linezolid is primarily excreted in urine, and tedizolid in feces as inactive sulfate conjugates (Azzouz & Preuss, 2024).

The most common and serious adverse effects of linezolid are decreased hemoglobin, platelets, and WBCs. It also causes nausea, headache, diarrhea, elevated pancreatic enzymes and liver functions, and neuropathy.

Linezolid can interact with various drugs, such as:

• Adrenergic drugs such as pseudoephedrine, epinephrine, norepinephrine, dopamine, and dobutamine; co-administration with linezolid can lead to a hypertensive crisis, increasing cardiovascular risk.
• Serotonergic drugs such as selective serotonin reuptake inhibitors, tricyclic antidepressants, bupropion, buspirone, triptans, and meperidine; linezolid can cause serotonin syndrome when used with serotonergic agents, leading to potentially life-threatening symptoms such as agitation, hallucinations, tachycardia, and hyperthermia.
• Myelosuppressive agents such as clozapine and cladribine; combining linezolid with myelosuppressive drugs can exacerbate bone marrow suppression, leading to increased risks of anemia, leukopenia, or thrombocytopenia(Azzouz & Preuss, 2024).

Linezolid use should be avoided in patients with a high risk of myelosuppression, hypoglycemia, serotonin syndrome, those receiving insulin or oral hypoglycemics, lactic acidosis, seizures, and hypertension that is being treated with adrenergic drugs as it can worsen the pre-existing condition. Moreover, linezolid has a warning for irreversible peripheral and optic neuropathy when used for 28 days or more. Some patients have also reported blurred vision, even when given linezolid for a short time.

Prolonged use of linezolid can lead to fungal or bacterial infection, including C. difficile infection and pseudomembranous colitis. Linezolid can also lead to lactic acidosis. Therefore, evaluate patients complaining about nausea, vomiting, unexplained acidosis, and low bicarbonate concentrations with linezolid use (Azzouz & Preuss, 2024).

Dosing considerations for linezolid are:

The usual dose of linezolid in adults for the treatment of bacteremia is 600 mg IV or orally every 12 hours. For pneumonia, the duration of therapy should be 10 to 14 consecutive days, and treatment for vancomycin-resistant Enterococcus faecium infections should be 14 to 28 consecutive days (Drugs.com, 2024d).

The usual adult dose of tedizolid for skin and structural infection is 200 mg IV or orally once a day for six days(Drugs.com, 2024f).

Chloramphenicol and retapamulin are indicated to treat conditions such as:

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

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 has a broad spectrum of activity and has 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 that have become resistant to the leading topical antimicrobials used in clinical practice include gram-positive and some gram-negative organisms.

Chloramphenicol and retapamulin are active against:

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)
  • Streptococcus viridans

Gram-Negative Organisms:

• Bacteroides spp.
• Clostridium spp.
• Escherichia
  • Escherichia coli
• Fusobacterium spp.
• Haemophilus
  • ​​​​​​​Haemophilus influenzae
• Neisseria
  • ​​​​​​​Neisseria meningitidis
• Porphyromonas spp.
  • Porphyromonas gingivalis
• Prevotella spp.
• Rickettsia
• Salmonella
• Vibrio
  • ​​​​​​​Vibrio cholerae (tetracycline-resistant)

When given through the IV route, chloramphenicol succinate is absorbed by around 70%. Since chloramphenicol is highly lipid-soluble, with low protein binding, it penetrates effectively into all body tissues, including the brain, though distribution is not uniform. The highest concentrations of chloramphenicol are found in the liver and kidneys, and the lowest in the brain and CSF. Concentrations in the brain and CSF reach about 30-50% of the overall body concentration, increasing to 89% when the meninges are inflamed. Moreover, chloramphenicol has approximately 60% protein binding. However, it decreases in patients with hepatic or renal dysfunction. To get metabolized, chloramphenicol is metabolized in the liver to inactive metabolites. Chloramphenicol succinate is hydrolyzed in the liver, kidneys, and lungs to chloramphenicol. In adults, the half-life elimination of chloramphenicol is 3-4 hours. However, in patients with end-stage renal disease, it is 3-7 hours and also prolonged in patients with hepatic disease. Chloramphenicol succinate is excreted 30% unchanged in the urine (Werth, 2024).

Retapamulin has minimal absorption on topical application. It has 94% protein binding and is metabolized through the hepatic system (Oong & Tadi, 2023).

Chloramphenicol can cause glossitis because of the overgrowth of Candida albicans, which is fairly common if the course of treatment exceeds one week. Other side effects include nausea, vomiting, diarrhea, and stomatitis. Jarisch–Herxheimer–like reactions have been described in patients treated for brucellosis, enteric fever, and syphilis.

Chloramphenicol exerts a dose-related but reversible depressant effect on the marrow of all those treated, resulting in vacuolization of erythroid and myeloid cells and reticulocytopenia and ferrokinetic changes indicative of decreased erythropoiesis.

Infants given large doses may develop exceedingly high plasma levels of the drug because of their immature conjugation and excretion mechanisms. A life-threatening disorder called the 'gray baby' syndrome, characterized by vomiting, refusal to suck, and abdominal distention followed by circulatory collapse, may appear when the plasma concentration exceeds 20 mg/L. If concentrations reach 200 mg/L, the disorder can develop in older children or even adults.

Optic neuritis has been described in children with cystic fibrosis receiving prolonged treatment for pulmonary infection. Most improve when the drug is discontinued, but central visual acuity can be permanently impaired (Oong & Tadi, 2023).

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 (Oong & Tadi, 2023):

• Antidepressants
• Anticoagulants
• Antiepileptics
• Proton pump inhibitors

Inhibition of CYP3A4 causes increased levels of (Oong & Tadi, 2023):

• Anticoagulants
• Antivirals
• Azole antifungals
• Benzodiazepines
• Calcium channel blockers
• Cardiac antiarrhythmics
• Chemotherapeutic drugs
• Immunosuppressants
• Macrolide antibiotics
• Phosphodiesterase-5 (PDE5) inhibitors
• Selective serotonin reuptake inhibitors
• Statins
• Tricyclic antidepressants 

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. Drug interactions may occur with the following (DRUGBANK Online, 2024; Drugs.com, 2024e):

• Atazanavir
• Clarithromycin
• Darunavir
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Nefazodone
• Nelfinavir
• Ritonavir
• Telithromycin
• Tipranavir
• Saquinavir

• 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.
• Generally, there are no contraindications for retapamulin (DRUGBANK Online, 2024; Drugs.com, 2024e; Oong & Tadi, 2023).

In patients with hepatic impairment (DRUGBANK Online, 2024; Drugs.com, 2024e; Oong & Tadi, 2023):

• Use amphenicols with caution in patients with hepatic impairment.
• Reduced dosage and serum concentration monitoring, both peak and trough are recommended.

In patients with renal impairment (DRUGBANK Online, 2024; Drugs.com, 2024e; Oong & Tadi, 2023):

• 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)

Use chloramphenicol with caution in patients with glucose 6-phosphate dehydrogenase deficiency.

The use of chloramphenicol 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, and prompt termination of therapy is required. Reaction may result from drug accumulation caused by impaired neonatal hepatic or renal function (Oong & Tadi, 2023).

The usual adult dose of chloramphenicol for the treatment of bacteremia is 12.5 to 25 mg/kg IV every six hours (Drugs.com, n.d.-a).

The usual amount of retapamulin for adults for the treatment of impetigo is to be applied on the affected area (up to 100 centimeters [cm]² in total area) twice a day for five days (Drugs.com, 2024e).

Clinical indications of quinupristin/dalfopristin include:

• cSSSI caused by MSSA or Streptococcus pyogenes

Off-label uses of quinupristin/dalfopristin include:

• Bacteremia caused by MRSA
• Infective endocarditis caused by MRSA
• Infective endocarditis caused by multidrug-resistant Enterococcus faecium
• Intravascular catheter-associated bloodstream infections caused by methicillin-resistant coagulase-negative staphylococci or ampicillin- and vancomycin-resistant Enterococcus faecium(Werth, 2024).

Streptogramins have antibacterial activity against the following susceptible organisms:

Gram-positive bacteria:

• Enterococcus faecium, including:
  • Ampicillin-resistant Enterococcus faecium
  • Multi-drug-resistant Enterococcus faecium
  • Vancomycin-resistant Enterococcus faecium 
• Staphylococcus aureus, including:
  • MRSA
  • MSSA
  • Multi-resistant coagulase-negative Staphylococcus aureus
• Staphylococcus epidermidis, including:
  • Methicillin-resistant Staphylococcus epidermidis
• Streptococcus species:
  • Streptococcus agalactiae
  • Streptococcus pyogenes(Werth, 2024).

Quinupristin has a distribution volume of 0.45 L/kg. It undergoes metabolism in the liver, where it is conjugated with glutathione and cysteine to form active metabolites. The elimination half-life of quinupristin is approximately 0.85 hours, though when considering its metabolites, the mean elimination half-life extends to about three hours. Quinupristin is primarily excreted through feces, accounting for 75-77% of its excretion, with a smaller portion (15% to 19%) excreted in urine.

Dalfopristin has a distribution volume of 0.24 L/kg. In the liver, it is hydrolyzed to an active metabolite. The elimination half-life of dalfopristin is around 0.7 hours, and including its metabolites, the mean elimination half-life is approximately one hour. Similar to quinupristin, dalfopristin is mainly excreted in feces (75-77%) and to a lesser extent in urine (15% to 19%) (Werth, 2024).

When quinupristin/dalfopristin is given through a peripheral IV catheter, adverse effects related to the site of infusion are very common, such as pain, inflammation, and thrombophlebitis. Therefore, it is recommended that this drug be given through a central venous catheter. However, arthralgias, myalgias, and hyperbilirubinemia are also common.

Prolonged use of quinupristin and dalfopristin may result in superinfections, including fungal or bacterial overgrowth, such as CDAD and pseudomembranous colitis. Symptoms, including watery and bloody stools, with or without stomach cramps and fever, can develop even as late as two or more months after taking the last dose of these antibiotics. CDAD has been observed to occur longer than two months following post-antibiotic treatment (Werth, 2024).

The metabolism of quinupristin/dalfopristin is not affected by the CYP3A4 system but may alter the metabolism of other drugs metabolized by this pathway, such as ciclosporin (cyclosporine). Quinupristin/dalfopristin can also interfere with the metabolism of drugs associated with QTc prolongation, and co-administration of these compounds should be avoided (Werth, 2024).

Quinupristin/dalfopristin is contraindicated in patients with known hypersensitivity to either drug or prior hypersensitivity to other streptogramins or any component of the formulation (Werth, 2024).

• 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 infusion should be completed over 60 minutes (toxicity may be increased with shorter infusion).
• If severe venous irritation occurs following peripheral administration, quinupristin/dalfopristin may be further diluted (500-750 ml) from 250 ml.
• In general, quinupristin/dalfopristin infusion by a peripherally inserted central catheter (PICC) or a central venous catheter is recommended to avoid phlebitis.
• The line should not be flushed with saline or heparin after quinupristin/dalfopristin administration because of concerns about incompatibility.
• Quinupristin/dalfopristin is compatible with 5% dextrose in water but incompatible with saline (Werth, 2024).

The usual adult dose of quinupristin/dalfopristin for the treatment of skin or soft tissue infection is 7.5 mg/kg IV every 12 hours, infused over one hour, and for vancomycin-resistant Enterococcus faecium infection, the dose of quinupristin/dalfopristin is 7.5 mg/kg IV every eight hours, infused over one hour (Drugs.com, n.d.-b).