Antibiotics Review _ __________________________________________________________________________
SIDE EFFECTS/TOXICITY Apart from the (avoidable) red man syndrome, vancomycin administration is well tolerated and side effects are uncom- mon. As with beta-lactams and sulfonamides, vancomycin is a good sensitizing agent; allergic manifestations such as fixed drug eruptions and drug fever are relatively common. Vancomycin nephrotoxicity does occur. The incidence is low, the exact mechanism is poorly understood, and the impact is usually reversible upon discontinuation of the drug. Risk factors for nephrotoxicity include total daily dose in excess of 3–4 grams, trough serum vancomycin levels >20 mcg/mL, pre- existing renal disease, concomitant use of other nephrotoxic drugs (e.g. aminoglycosides), and duration of therapy longer than one week [159]. In 2017, the FDA published a safety review that indicated that use of intraocular vancomycin prophylactically during cataract surgery, alone or in a compound formula, should be avoided because of the risk of hemorrhagic occlusive retinal vasculitis [6; 160]. Reversible neutropenia, presumably from bone marrow toxicity, is sometimes seen in patients receiving prolonged vancomycin therapy (e.g., for endocarditis and osteomyelitis). Oral vancomycin is not absorbed and thus imposes no risk of nephrotoxicity or ototoxicity. ANTIMICROBIAL PEPTIDES The increasing prevalence of antimicrobial resistance among clinical isolates of staphylococci and streptococci severely limits therapeutics for serious infections caused by these common pathogens. Thus, there is ongoing research on alternative antimicrobial mechanisms and development of novel therapies needed for treatment of multidrug-resistant bacterial infection. Antimicrobial peptides are naturally occurring molecules and semisynthetic derivatives that have bactericidal activity against micro-organisms. Naturally occurring peptides with antimi- crobial activity are produced by a variety of organisms (e.g., plants, insects, marine life) and serve to protect the host from pathogenic micro-organisms. Antimicrobial peptides exert their effects via multiple mechanisms: cell-membrane attach- ment, disruption, and leakage of cell contents; inhibition of intracellular protein and nucleic acid synthesis; attenuation of protein folding; and prevention of cell wall biosynthesis [175]. DAPTOMYCIN Daptomycin is a cyclic lipopeptide produced by Streptomyces roseosporus having bactericidal activity against a wide range of gram-positive cocci. The spectrum of activity includes human pathogens such as methicillin-sensitive Staphylococcus aureus, MRSA, and Enterococcus. The exact mechanism of action is unclear; it targets the bacterial cell membrane where interac- tions lead to rapid depolarization due to potassium efflux,
VANCOMYCIN Vancomycin is the oldest member of the glycopeptide antibiot- ics class, a group of large molecules that inhibit bacterial cell wall synthesis. Glycopeptides have a high binding affinity for peptides found only in bacterial cell walls. This interaction disrupts peptidoglycan polymerization, the late-stage reaction that imparts rigidity to the cell wall [6; 156]. Gram-positive organisms, both cocci and bacilli, are highly susceptible to glycopeptides. Vancomycin was developed more than 50 years ago as an alternative intravenous therapy for serious staphylococcal and streptococcal infections in patients allergic to beta-lactams. In this early period, vancomycin usage was associated with a high incidence of vestibular and renal toxicity. The cause was attributed in large part to impurities in the formulation, a problem solved in subsequent years. At present, the major role for vancomycin is in the treatment of serious infections caused by MRSA, methicillin-resistant S. epidermidis (MRSE), and ampicillin-resistant enterococci [157]. An oral formulation is available for the treatment of C. difficile -associated diarrhea/ colitis.
MECHANISMS OF ACTION AND PHARMACOKINETICS
Vancomycin is not absorbed by the intestinal tract and must be administered by intravenous infusion, except for the formula- tion for the treatment of C. difficile -associated diarrhea/colitis [6]. The determination of a safe, effective dosage regimen, and decisions regarding monitoring of therapy, are complex matters that require consideration of multiple factors, including the site and severity of infection, the patient’s weight and renal function, the susceptibility of the infecting organism, and the anticipated duration of therapy [158]. The usual adult dose is 15–20 mg/kg/dose every 12 hours. The rate of infusion should be no more than 500 mg/hour, as rapid infusion causes an uncomfortable generalized erythroderma (“red man” syndrome) [6]. The red man syndrome is a histamine-mediated flushing that occurs during or immediately following infusion and does not mandate discontinuation unless slowing the infusion rate fails to mitigate the reaction. ABSORPTION/ELIMINATION Vancomycin is cleared almost entirely by the kidneys. Pro- longed usage at excessively high therapeutic serum levels has been associated with nephrotoxicity and ototoxicity [6]. In treating patients with invasive staphylococcal infection and MRSA, it is considered important to use the maximum dosage (target trough serum vancomycin level of 15–20 mcg/mL) in order to assure optimal therapeutic effect [158]. The serum creatinine and trough vancomycin level (target <20 mcg/mL) should be monitored once or twice weekly in such cases, as well as in all patients who are elderly or have impaired renal function.
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