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Vancomycin
Vancomycin MARK P. WILHELM, M.D., Division ofInfectious Diseases and Internal Medicine
Vancomycin is a glycopeptide antibiotic that is active against staphylococci, streptococci, and other gram-positive bacteria. It is the drug of choice for the treatment of infections due to methicillinresistant staphylococci, Corynebacterium jeikeium, and multiply resistant strains of Streptococcus pneumoniae. Vancomycin is an alternative treatment for serious staphylococcal and streptococcal infections, including endocarditis, when allergy precludes the use of penicillins and cephalosporins. Vancomycin is bactericidal against most strains of staphylococci and nonenterococcal streptococci. Although rare strains of stapbylococci and enterococci that .are resistant to vancomycin have been reported, bacterial resistance has thus far not emerged as a major clinical problem despite widespread use of vancomycin. When therapy is monitored by periodic determinations of serum concentrations of the drug and rapid infusion rates are avoided, vancomycin is rarely associated with serious toxicity.
Recent years have seen a considerable increase in the use of vancomycin, a glycopeptide antibiotic first isolated from a strain of Streptomyces (now Amycolatopsis) orientalis found in a Borneo jungle in 1956.1 After the introduction of this drug, it rapidly became an important agent for use against increasingly prevalent penicillin-resistant staphylococci. Its widespread clinical application was soon eclipsed by the arrival of the semisynthetic antistaphylococcal penicillins and the toxicity encountered with early impure preparations of vancomycin. The past decade has witnessed a resurgence of interest in vancomycin, primarily because of the increasing frequency of infections caused by ~-lactam-resistant gram-positive organisms.
MECHANISM OF ACTION Vancomycin is a complex tricyclic glycopeptide with a molecular weight of approximately 1,500. It exerts its main bactericidal effect by inhibiting the biosynthesis of the major structural polymer of the bacterial cell wall, peptidoglycan.' Vancomycin complexes with the o-alanyl-o-alanine portion Individual reprints of this article are not available. The entire Symposium on Antimicrobial Agents will be available for purchase as a bound booklet from the Proceedings Circulation Office at a later date. Mayo Clin Proc 66:1165-1170,1991
of peptide precursor units at the crucial site of attachment and thereby inhibits vital peptidoglycan polymerase and transpeptidation reactions. It inhibits the second stage of synthesis of peptidoglycan at a site earlier than the site of action of penicillin; thus, no cross-resistance occurs. In addition, vancomycin affects the permeability of cytoplasmic membranes' and may impair synthesis of RNA.4 Vancomycin is bactericidal against most gram-positive organisms except enterococci. The combination of gentamicin and vancomycin is synergistic against essentially all strains of Staphylococcus aureus and enterococci.>" The emergence of secondary resistance with prolonged use is exceedingly rare. The remarkable stability of susceptibility among organisms observed during the past 3 decades may be due to the multiple sites of antibacterial action.
PHARMACOLOGIC PROPERTIES Vancomycin is poorly absorbed from the gastrointestinal tract. Patients with normal renal function who receive 500 mg of vancomycin every 6 hours orally can be expected to have stool concentrations of vancomycin in the range of 900 to 9,000 ug/g.' Only small amounts of the drug have been detected in serum, even in patients with advanced renal failure. The presence of an inflammatory bowel disease may result in increased absorption of orally administered van-
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comycin. Because intramuscular injection of vancomycin causes considerable local. pain, only the intravenous route can be used for parenteral administration. Vancomycin is approximately 55% bound to plasma proteins. Its half-life in patients with normal renal function is approximately 6 hours. In the presence of anuria, however, the half-life is prolonged to approximately 7.5 days." In patients with normal renal function, the intravenous administration of 1 g of vancomycin usually yields peak levels of 20 to 50 ug/ml and trough levels of 5 to 10 ug/rnl.? After intravenous administration of vancomycin, 90% of the dose is excreted unchanged by glomerular filtration in a 24-hour period. Vancomycin diffuses well across serous membranes into pleural, pericardial, synovial, and ascitic fluids. Only small amounts appear in the bile after intravenous administration. Injection of vancomycin into serous cavities may produce an irritant effect. Although therapeutic levels can be obtained in the cerebrospinal fluid in patients with inflamed meninges, only low levels in the cerebrospinal fluid are achieved in those with noninflamed meninges.'? Vancomycin is not removed by conventional hemodialysis or peritoneal dialysis, but highflux methods of hemodialysis may remove substantial amounts of the drug. II Therapy should be monitored in individual patients by periodic determinations of serum concentrations of vancomycin.
SPECTRUM OF ACTIVITY The antibacterial spectrum of vancomycin is limited to aerobic and anaerobic gram-positive organisms. Vancomycin inhibits growth of almost all strains of S. aureus and coagulase-negative staphylococci (both methicillin-sensitive and methicillin-resistant organisms) at concentrations of 1 to 5 ug/ml or less (Table l). Although it is bactericidal at clinically achievable concentrations against S. aureus, coagulasenegative staphylococci, corynebacteria (including Corynebacterium jeikeium), Bacillus species, ~-hemolytic streptococci, viridans streptococci, anaerobic cocci, and clostridia, it is only bacteriostatic against most strains of enterococci. For Enterococcus faecium and Ei faecalis, concentrations of 100 ug/ml or greater are usually needed for a bactericidal effect.'? The addition of streptomycin provides a synergistic bactericidal effect against 40 to 70% of enterococcal isolates. Excluding rare isolates that exhibit high-level gentamicin resistance (500 ug/ml or more), the combination of vancomycin and gentamicin is bactericidal against essentially all enterococcal isolates. The susceptibility of lactobacilli and Actinomyces species to vancomycin is variable. Listeria monocytogenes is usually susceptible; thus, vancomycin may be considered a reasonable alternative to ampicillin or trimethoprim-sulfamethoxazole in patients who are intolerant of these agents.
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Table I.-Minimal Inhibitory Concentrations (MIC) of Vancomycin for Various Organisms Organism
MIC (ug/ml)
Staphylococcus aureus Methicillin-sensitive Methicillin-resistant S. epidermidis Streptococcus pyogenes S. pneumoniae Viridans streptococci Si faecalis Clostridium difficile Listeria monocytogenes Corynebacterium jeikeium
0.8-5.0 0.06-2.0 0.39-3.12 0.25-0.5 0.25-1.0 0.06-8.0 0.2-6.25 1.0-8.0 0.625-5.0 0.20-6.25
From Kucers A, Bennett NM: The Use of Antibiotics. Fourth edition. Philadelphia, JB Lippincott Company, 1987, pp 10451068. By permission.
Gram-negative bacteria are generally resistant except for occasional isolates of Neisseria gonorrhoeae," Although vancomycin has been used successfully to treat. infections attributable to Flavobacterium meningosepticum, these organisms are usually resistant in vitro. 14 Leuconostoc species are also usually resistant to vancomycin. They are rarely recovered in clinical specimens but should be suspected when the laboratory recovers "streptococci" that are resistant to vancomycin. IS Vancomycin-resistant strains of gram-positive microorganisms encountered in clinical practice remain exceedingly rare. Recent reports of resistant isolates of S. haemolyticus'? and enterococci," however, may portend a serious emerging clinical problem. High-level vancomycin resistance is plasmid mediated and therefore may be transferred between strains.
CLINICAL INDICATIONS Vancomycin is the drug of choice for treatment of serious infections due to methicillin-resistant strains of S. aureus and coagulase-negative staphylococci (Table 2). It is also used to treat serious infections caused by methicillin-susceptible staphylococci in patients who cannot tolerate penicillins or cephalosporins. Although vancomycin is effective for the treatment of staphylococcal endocarditis, it may be considerably less effective than nafcillin for the treatment of endocarditis due to methicillin-susceptible S. aureusP When clinical failures are encountered with vancomycin in treating infections due to rare staphylococcal isolates that show tolerance to its bactericidal effect, the addition of gentamicin, rifampin, or both should be considered. The combination of vancomycin and rifampin, with gentamicin added for the first 2 weeks, is used in the treatment of
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Table 2.-Therapeutic Indications for Vancomycin prosthetic valve endocarditis due to methicillin-resistant coagulase-negative staphylococci. Seriousinfections causedby methicillin-resistant strains of Infections that involve indwelling prosthetic material are Staphylococcus aureus and coagulase-negative staphylococci commonly due to coagulase-negative staphylococci. Slime Serious infections causedby S. aureus or streptococci in patients biofilms produced by these organisms may enhance bacterial intolerant of ~-lactam antibiotics persistence." Although S. epidermidis bacteremia associ- Endocarditis treatment-as alternative therapy in ~-lactamated with indwelling Hickman or Broviac catheters usually intolerant patients S. aureus can be eradicated with vancomycin alone, removal of the Coagulase-negative staphylococci indwelling foreign body may be necessary for cure. Usually, Streptococci cerebrospinal fluid shunt-related infections due to coagu~-Hemolytic streptococci lase-negative staphylococci can be successfully treated with Viridans streptococci a combination of intravenously and intraventricularly adNonenterococcal group D streptococci Enterococci (in combination withgentamicin) ministered vancomycin and removal of the shunt. 20 Staphylococcal peritonitis associated with an indwelling catheter Infections causedby multiply resistant gram-positive organisms (for example, Corynebacteriumjeikeium and resistant strains of for peritoneal dialysis can usually be cured without removal Streptococcus pneumoniae) of the catheter. Vancomycin can be used alone for treatment of strepto- Clostridium difficile colitis (oraladministration) coccal infections, including endocarditis, in patients who are Endocarditis prophylaxis (in combination withgentamicin) for selected genitourinary and gastrointestinal procedures in allergic to penicillin. When endocarditis due to enterococci penicillin-intolerant patients is treated, however, vancomycin must be used in conjunction with an aminoglycoside. Vancomycin is the drug of choice for infections due to resistant corynebacteria, including C. jeikeium, and rarely encountered multiply resistant strains of Streptococcus pneumoniae. 21 of the drug. Desirable ranges for therapeutic peak and Vancomycin is recommended for prevention of endocar- trough concentrations are 20 to 40 ug/ml and 5 to 10 ug/ml, ditis in patients at risk who are allergic to penicillin and must respectively. The dose of vancomycin must be modified in patients with undergo selected invasive genitourinary or gastrointestinal procedures likely to be associated with transient bacter- impaired renal function. On the basis of the linear relationernia." It may be effective prophylaxis during selected car- ship between the clearance of vancomycin and creatinine diac and neurosurgical procedures at medical centers where clearance, nomograms have been formulated to guide the methicillin-resistant staphylococcal infections are common, alteration of doses in the presence of renal failure.P:" These guidelines are not valid in the functionally anephric patient, particularly when foreign bodies are implanted. Orally administered vancomycin is generally considered however. Vancomycin dosing should be individualized on the drug of choice for treating seriously ill patients with the basis of pharmacokinetic data derived from measured antibiotic-associated Clostridium dijficile colitis. This or- concentrations in the serum." Regardless of renal function, ganism is uniformly susceptible to vancomycin. Less expen- an initial dose of 15 mg/kg should be given to achieve sive alternatives, such as metronidazole or bacitracin, should prompt therapeutic concentrations. Vancomycin has been used effectively in many patients on hemodialysis by the be considered in patients who are less seriously ill. administration of 1 g every 7 to 10 days. A similar dosage schedule can be used in patients on continuous ambulatory peritoneal dialysis. DOSAGE AND ADMINISTRATION Several drugs, including chloramphenicol, methicillin, The usual daily intravenous dosage of vancomycin in adults with normal renal function is 1 g every 12 hours (30 mg/kg and ticarcillin, may be incompatible with vancomycin in for a 70-kg adult). In seriously ill patients, 1 g of vancomy- intravenous solutions.P-" High concentrations of heparin cin can be administered every 8 hours for the first few days have been shown to cause inactivation of vancomycin and of therapy. Each dose should be administered during at least resultant persistent bacteremia when the two agents were a 60-minute interval to minimize infusion-related toxicity. administered through the same intravenous line." Although the optimal oral dose of vancomycin has not Vancomycin pharmacokinetics may be altered in elderly or been established for the treatment of antibiotic-associated C. obese patients. Individual patient factors may necessitate difficile colitis, a dosage of 125 mg every 6 hours has been modification of the dose, which is difficult to predict accurately. Therefore, therapy should be monitored by periodic shown to be as effective as higher doses." The usual duradeterminations of peak and trough serum concentrations tion of therapy is 7 to 10 days.
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ADVERSE EFFECTS Soon after its introduction; vancomycin developed a reputation as being a relatively toxic antibacterial agent. Early preparations, often referred to as "Mississippi mud," contained many ;mpurities that apparently contributed to the frequency of adverse effects. Improved purification procedures have diminished the toxicity associated with vancomycin. When its concentration is monitored in the serum, the frequency of serious toxicity is low. The most important potential adverse effect associated with use of vancomycin is damage to the auditory nerve and consequent hearing loss. Ototoxicity has primarily been noted in patients with extremely high serum concentrations of vancomycin (80 to 100 ug/ml); it is rarely encountered when concentrations in serum are maintained at 30 ug/ml or lower (Table 3). Recent reviews suggest that the potential for vancomycin to cause significant ototoxicity, as perpetuated in the medical literature, has been exaggerated.P-" Although hearing occasionally improves when drug therapy is terminated, more commonly it is permanent. The risk of ototoxicity seems to be increased when vancomycin is administered in combination with an aminoglycoside. An infusion-associated reaction that is peculiar to vancomycin is referred to as the "red man" or "red neck" syndrome." Typically, it consists of pruritus, an erythematous rash that involves the face, neck, and upper torso, and occasionally hypotension. This reaction may occur within minutes after initiation of the drug infusion or may begin soon after its completion. Its manifestations are due to the nonimmunologically mediated release of histamine. This complication can be avoided by administering vancomycin over at least a l-hour period. Smaller doses of vancomycin administered at shorter intervals (relative to the standard regimen) may also decrease the occurrence of this reaction. Because the red man syndrome is usually related to a rapid rate of infusion, vancomycin may be administered at a slower rate in a patient who has previously experienced these symptoms. Antihistamines such as hydroxyzine have been shown to be protective when given before infusion of vancomycin." Vasopressors may be needed if severe hypotension occurs. Pain and muscle spasms in the chest and back may occur after rapid infusion of vancomycin; these findings have been referred to as the "pain and spasm" syndrome. Symptoms resolve after the infusion is terminated." The new preparations of vancomycin are rarely associated with clinically significant nephrotoxicity. As with ototoxicity, however, the concomitant use of an aminoglycoside seems to enhance the risk of nephrotoxicity." Chemical thrombophlebitis occurs in as many as 13% of patients with peripheral venous cannulas. Hypersensitivity maculopapular or urticarial drug eruptions and drug-induced fever occur rarely. Reversible neutropenia has been noted in
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Table 3.-Adverse Effects Associated With Use of Vancomycin Ototoxicity Hearing loss: often irreversible; rare; associatedwith drug levels >30 ug/ml Enhanced risk with concomitantaminoglycoside therapy Infusion-relatedside effects "Red man" syndrome "Pain and spasm" syndrome Hypotension Thrombophlebitis-associated with peripheral venous cannulas Hypersensitivity reactions Drug fever (rare) Allergic rash (rare) Neutropenia Reversible Develops after prolonged use Nephrotoxicity Rare Enhanced risk with concomitantaminoglycoside therapy Reversible
approximately 2% of vancomycin-treated patients. Its onset is usually delayed; the neutrophil nadir occurs 15 to 40 days after initiation of therapy."
OTHER GLYCOPEPTIDE ANTIBIOTICS Several other glycopeptide antibiotics of the vancomycin group have been obtained from various species of actinomycetes. Ristocetin, which is also bactericidal against grampositive bacteria, is no longer considered for use as an antibiotic because of its propensity to cause aggregation of platelets."? Teicoplanin (formerly known as teichomycin A 2) has been studied extensively and is available for clinical use in several European countries; currently, however, it is not commercially available in the United States. Teicoplanin is a complex mixture of closely related compounds that share certain structural and antimicrobial properties with vancomycin." It has a longer elimination half-life (40 to 70 hours) than does vancomycin and may be administered every 24 hours. Its spectrum of activity, like vancomycin, is restricted to gram-positive bacteria. Overall, its minimal inhibitory concentrations tend to be lower. It is more active than vancomycin and ampicillin against enterococci, although concomitant aminoglycoside therapy is necessary for a bactericidal effect. Several strains of S, haemolyticus and S. epidermidis have been shown to be substantially less susceptible to teicoplanin than to vancomycin." Although serious adverse effects have seldom been encountered, rare ototoxicity has been reported. Concern about the occurrence of teicoplanin-resistant staphylococci and reports of clinical
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failures with use of teicoplanin in patients with bacteremic staphylococcal infections have prompted serious questions about the overall advantages of teicoplanin over vancomycin. 40 ,4 1 Currently, it seems unlikely that teicoplanin will usurp the prominent and important role of vancomycin in clinical practice.
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18. 19.
20.
REFERENCES 1. 2.
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Griffith RS: Vancomycin use-an historical review. J Antimicrob Chemother 14 (Suppl 0):1-5,1984 Reynolds PE: Structure, biochemistry and mechanism of action of glycopeptide antibiotics. Eur J Clin Microbiol Infect Dis 8:943-950, 1989 Jordan DC, Mallory HOC: Site of action of vancomycin on Staphylococcus aureus. Antimicrob Agents Chemother, 1964, pp 489-494 Jordan DC, Inniss WE: Selective inhibition of ribonucleic acid synthesis in Staphylococcus aureus by vancomycin. Nature 184:1894-1895, 1959 Watanakunakorn C, Tisone JC: Synergism between vancomycin and gentamicin or tobramycin for methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother 22:903-905,1982 Watanakunakorn C, Bakie C: Synergism of vancomycingentamicin and vancomycin-streptomycin against enterococci. Antimicrob Agents Chemother 4: 120-124, 1973 Tedesco F, Markham R, Gurwith M, Christie 0, Bartlett JG: Oral vancomycin for antibiotic-associated pseudomembranous colitis. Lancet 2:226-228, 1978 Moellering RC Jr: Pharmacokinetics of vancomycin. J Antimicrob Chemother 14 (Suppl 0):43-52, 1984 Fekety R: Vancomycin. Med Clin North Am 66:175-181, January 1982 Redfield DC, Underman A, Norman 0, Overturf GO: Cerebrospinal fluid penetration of vancomycin in bacterial meningitis. In Current Chemotherapy and Infectious Disease. Vol I. Edited by JD Nelson, C Grassi. Washington, DC, American Society for Microbiology, 1980, pp 638-641 De Bock V, Verbeelen 0, Maes V, SennesaelJ: Pharmacokinetics of vancomycin in patients undergoing haemodialysis and haemofiltration. Nephrol Dial Transplant 4:635-639, 1989 Geraci JE, Hermans PE: Vancomycin. Mayo Clin Proc 58:88-91, 1983 Jaffe HW, Lewis JS, Wiesner PJ: Vancomycin-sensitive Neisseria gonorrhoeae (letter to the editor). J Infect Dis 144:198-199,1981 Watanakunakorn C: Mode of action and in-vitro activity of vancomycin. J Antimicrob Chemother 14 (Suppl 0):7-18, 1984 Rubin LG, Vellozzi E, Shapiro J, Isenberg HD: Infection with vancomycin-resistant "streptococci" due to Leuconostoc species (letter to the editor). J Infect Dis 157:216, 1988 Schwalbe RS, Stapleton JT, Gilligan PH: Emergence of vancomycin resistance. in coagulase-negative staphylococci. N Eng! J Med 316:927-931,1987 Uttley AHC, Collins CH, Naidoo J, George RC: Vancomycin-resistant enterococci (letter to the editor). Lancet 1:5758, 1988
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Small PM, Chambers HF: Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 34:1227-1231,1990 Evans RC, Holmes CJ: Effect of vancomycin hydrochloride on Staphylococcus epidermidis biofilm associated with silicone elastomer. Antimicrob Agents Chemother 31:889-894, 1987 Swayne R, Rampling A, Newsom SWB: Intraventricular vancomycin for treatment of shunt-associated ventriculitis. J Antimicrob Chemother 19:249-253,1987 Appelbaum PC: World-wide development of antibiotic resistance in pneumococci. Eur J Clin Microbiol 6:367-377, 1987 Dajani AS, Bisno AL, Chung KJ, Durack DT, Freed M, Gerber MA, Karchmer AW, Millard HD, Rahimtoola S, Shulman ST, Watanakunakorn C, Taubert KA: Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 264:2919-2922,1990 Moellering RC Jr, Krogstad OJ, Greenblatt OJ: Vancomycin therapy in patients with impaired renal function: a nomogram for dosage. Ann Intern Med 94:343-346, 1981 Matzke GR, McGory RW, Halstenson CE, Keane WF: Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob Agents Chemother 25:433437, 1984 Rybak MJ, Boike SC: Individualized adjustment of vancomycin dosage: comparison with two dosage nomograms. Drug Intell Clin Pharm 20:64-68, 1986 Banner W Jr, Ray CG: Vancomycin in perspective (editorial). AmJDisChild 138:14-16,1984 Teresi M, Allison J: Interaction between vancomycin and ticarcillin (letter to the editor). Am J Hosp Pharm 42:2420; 2422, 1985 Barg NL, Supena RB, Fekety R: Persistent staphylococcal bacteremia in an intravenous drug abuser. Antimicrob Agents Chemother 29:209-211,1986 Fekety R, Silva J, Kauffman C, Buggy B, Deery HG: Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens. Am J Med 86:15-19, 1989 Bailie GR, Neal 0: Vancomycin ototoxicity and nephrotoxicity: a review. Med Toxicol Adverse Drug Exp 3:376-386, 1988 Brummett RE, Fox KE: Vancomycin- and erythromycininduced hearing loss in humans. Antimicrob Agents Chemother 33:791-796,1989 Davis RL, Smith AL, Koup JR: The "red man's syndrome" and slow infusion of vancomycin (letter to the editor). Ann Intern Med 104:285-286, 1986 Sahai J, Healy DP, Garris R, Berry A, Polk RE: Influence of antihistamine pretreatment on vancomycin-induced red-man syndrome. J Infect Dis 160:876-881, 1989 Gatterer G: Spasmodic low back pain in a patient receiving intravenous vancomycin during continuous ambulatory peritoneal dialysis. Clin Pharm 3:87-89, 1984 Sorrell TC, Collignon PJ: A prospective study of adverse reactions associated with vancomycin therapy. J Antimicrob Chemother 16:235-241, 1985 Henry K, Steinberg I, Crossley KB: Vancomycin-induced neutropenia during treatment of osteomyelitis in an outpatient. Drug Intell Clin Pharm 20:783-785, 1986
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37. 38. 39.
Barna JCJ, Williams DH: The structure and mode of action of glycopeptide antibiotics of the vancomycin group. Annu Rev Microbiol 38:339-357, 1984 Williams AH, Griineberg RN: Teicoplanin revisited. J Antimicrob Chemother 22:397-401, 1988 Goldstein FW, Coutrot A, Sieffer A, Acar JF: Percentages and distributions of teicoplanin- and vancomycin-resistant strains among coagulase-negative staphylococci. Antimicrob Agents Chemother 34:899-900,1990
40.
41.
Brunet F, Vedel G, Dreyfus F, Vaxelaire JF, Giraud T, Schremmer B, Monsallier JF: Failure of teicoplanin therapy in two neutropenic patients with staphylococcal septicemia who recovered after administration of vancomycin. Eur J Clin Microbiol Infect Dis 9:145-147, 1990 Gilbert DN, Wood CA, Kimbrough RC, Infectious Diseases Consortium of Oregon: Failure of treatment with teicoplanin at 6 miUigrams/kilogramJday in patients with Staphylococcus aureus intravascular infection. Antimicrob Agents Chemother 35:79-87, 1991
End of Symposium on Antimicrobial Agents, Part III. Part IV will appear in the December issue.
Vancomycin is a glycopeptide antibiotic that is active against staphylococci, streptococci, and other gram-positive bacteria. It is the drug of choice for the treatment of infections due to methicillinresistant staphylococci, Corynebacterium jeikeium, and multiply resistant strains of Streptococcus pneumoniae. Vancomycin is an alternative treatment for serious staphylococcal and streptococcal infections, including endocarditis, when allergy precludes the use of penicillins and cephalosporins. Vancomycin is bactericidal against most strains of staphylococci and nonenterococcal streptococci. Although rare strains of stapbylococci and enterococci that .are resistant to vancomycin have been reported, bacterial resistance has thus far not emerged as a major clinical problem despite widespread use of vancomycin. When therapy is monitored by periodic determinations of serum concentrations of the drug and rapid infusion rates are avoided, vancomycin is rarely associated with serious toxicity.
Recent years have seen a considerable increase in the use of vancomycin, a glycopeptide antibiotic first isolated from a strain of Streptomyces (now Amycolatopsis) orientalis found in a Borneo jungle in 1956.1 After the introduction of this drug, it rapidly became an important agent for use against increasingly prevalent penicillin-resistant staphylococci. Its widespread clinical application was soon eclipsed by the arrival of the semisynthetic antistaphylococcal penicillins and the toxicity encountered with early impure preparations of vancomycin. The past decade has witnessed a resurgence of interest in vancomycin, primarily because of the increasing frequency of infections caused by ~-lactam-resistant gram-positive organisms.
MECHANISM OF ACTION Vancomycin is a complex tricyclic glycopeptide with a molecular weight of approximately 1,500. It exerts its main bactericidal effect by inhibiting the biosynthesis of the major structural polymer of the bacterial cell wall, peptidoglycan.' Vancomycin complexes with the o-alanyl-o-alanine portion Individual reprints of this article are not available. The entire Symposium on Antimicrobial Agents will be available for purchase as a bound booklet from the Proceedings Circulation Office at a later date. Mayo Clin Proc 66:1165-1170,1991
of peptide precursor units at the crucial site of attachment and thereby inhibits vital peptidoglycan polymerase and transpeptidation reactions. It inhibits the second stage of synthesis of peptidoglycan at a site earlier than the site of action of penicillin; thus, no cross-resistance occurs. In addition, vancomycin affects the permeability of cytoplasmic membranes' and may impair synthesis of RNA.4 Vancomycin is bactericidal against most gram-positive organisms except enterococci. The combination of gentamicin and vancomycin is synergistic against essentially all strains of Staphylococcus aureus and enterococci.>" The emergence of secondary resistance with prolonged use is exceedingly rare. The remarkable stability of susceptibility among organisms observed during the past 3 decades may be due to the multiple sites of antibacterial action.
PHARMACOLOGIC PROPERTIES Vancomycin is poorly absorbed from the gastrointestinal tract. Patients with normal renal function who receive 500 mg of vancomycin every 6 hours orally can be expected to have stool concentrations of vancomycin in the range of 900 to 9,000 ug/g.' Only small amounts of the drug have been detected in serum, even in patients with advanced renal failure. The presence of an inflammatory bowel disease may result in increased absorption of orally administered van-
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comycin. Because intramuscular injection of vancomycin causes considerable local. pain, only the intravenous route can be used for parenteral administration. Vancomycin is approximately 55% bound to plasma proteins. Its half-life in patients with normal renal function is approximately 6 hours. In the presence of anuria, however, the half-life is prolonged to approximately 7.5 days." In patients with normal renal function, the intravenous administration of 1 g of vancomycin usually yields peak levels of 20 to 50 ug/ml and trough levels of 5 to 10 ug/rnl.? After intravenous administration of vancomycin, 90% of the dose is excreted unchanged by glomerular filtration in a 24-hour period. Vancomycin diffuses well across serous membranes into pleural, pericardial, synovial, and ascitic fluids. Only small amounts appear in the bile after intravenous administration. Injection of vancomycin into serous cavities may produce an irritant effect. Although therapeutic levels can be obtained in the cerebrospinal fluid in patients with inflamed meninges, only low levels in the cerebrospinal fluid are achieved in those with noninflamed meninges.'? Vancomycin is not removed by conventional hemodialysis or peritoneal dialysis, but highflux methods of hemodialysis may remove substantial amounts of the drug. II Therapy should be monitored in individual patients by periodic determinations of serum concentrations of vancomycin.
SPECTRUM OF ACTIVITY The antibacterial spectrum of vancomycin is limited to aerobic and anaerobic gram-positive organisms. Vancomycin inhibits growth of almost all strains of S. aureus and coagulase-negative staphylococci (both methicillin-sensitive and methicillin-resistant organisms) at concentrations of 1 to 5 ug/ml or less (Table l). Although it is bactericidal at clinically achievable concentrations against S. aureus, coagulasenegative staphylococci, corynebacteria (including Corynebacterium jeikeium), Bacillus species, ~-hemolytic streptococci, viridans streptococci, anaerobic cocci, and clostridia, it is only bacteriostatic against most strains of enterococci. For Enterococcus faecium and Ei faecalis, concentrations of 100 ug/ml or greater are usually needed for a bactericidal effect.'? The addition of streptomycin provides a synergistic bactericidal effect against 40 to 70% of enterococcal isolates. Excluding rare isolates that exhibit high-level gentamicin resistance (500 ug/ml or more), the combination of vancomycin and gentamicin is bactericidal against essentially all enterococcal isolates. The susceptibility of lactobacilli and Actinomyces species to vancomycin is variable. Listeria monocytogenes is usually susceptible; thus, vancomycin may be considered a reasonable alternative to ampicillin or trimethoprim-sulfamethoxazole in patients who are intolerant of these agents.
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Table I.-Minimal Inhibitory Concentrations (MIC) of Vancomycin for Various Organisms Organism
MIC (ug/ml)
Staphylococcus aureus Methicillin-sensitive Methicillin-resistant S. epidermidis Streptococcus pyogenes S. pneumoniae Viridans streptococci Si faecalis Clostridium difficile Listeria monocytogenes Corynebacterium jeikeium
0.8-5.0 0.06-2.0 0.39-3.12 0.25-0.5 0.25-1.0 0.06-8.0 0.2-6.25 1.0-8.0 0.625-5.0 0.20-6.25
From Kucers A, Bennett NM: The Use of Antibiotics. Fourth edition. Philadelphia, JB Lippincott Company, 1987, pp 10451068. By permission.
Gram-negative bacteria are generally resistant except for occasional isolates of Neisseria gonorrhoeae," Although vancomycin has been used successfully to treat. infections attributable to Flavobacterium meningosepticum, these organisms are usually resistant in vitro. 14 Leuconostoc species are also usually resistant to vancomycin. They are rarely recovered in clinical specimens but should be suspected when the laboratory recovers "streptococci" that are resistant to vancomycin. IS Vancomycin-resistant strains of gram-positive microorganisms encountered in clinical practice remain exceedingly rare. Recent reports of resistant isolates of S. haemolyticus'? and enterococci," however, may portend a serious emerging clinical problem. High-level vancomycin resistance is plasmid mediated and therefore may be transferred between strains.
CLINICAL INDICATIONS Vancomycin is the drug of choice for treatment of serious infections due to methicillin-resistant strains of S. aureus and coagulase-negative staphylococci (Table 2). It is also used to treat serious infections caused by methicillin-susceptible staphylococci in patients who cannot tolerate penicillins or cephalosporins. Although vancomycin is effective for the treatment of staphylococcal endocarditis, it may be considerably less effective than nafcillin for the treatment of endocarditis due to methicillin-susceptible S. aureusP When clinical failures are encountered with vancomycin in treating infections due to rare staphylococcal isolates that show tolerance to its bactericidal effect, the addition of gentamicin, rifampin, or both should be considered. The combination of vancomycin and rifampin, with gentamicin added for the first 2 weeks, is used in the treatment of
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Table 2.-Therapeutic Indications for Vancomycin prosthetic valve endocarditis due to methicillin-resistant coagulase-negative staphylococci. Seriousinfections causedby methicillin-resistant strains of Infections that involve indwelling prosthetic material are Staphylococcus aureus and coagulase-negative staphylococci commonly due to coagulase-negative staphylococci. Slime Serious infections causedby S. aureus or streptococci in patients biofilms produced by these organisms may enhance bacterial intolerant of ~-lactam antibiotics persistence." Although S. epidermidis bacteremia associ- Endocarditis treatment-as alternative therapy in ~-lactamated with indwelling Hickman or Broviac catheters usually intolerant patients S. aureus can be eradicated with vancomycin alone, removal of the Coagulase-negative staphylococci indwelling foreign body may be necessary for cure. Usually, Streptococci cerebrospinal fluid shunt-related infections due to coagu~-Hemolytic streptococci lase-negative staphylococci can be successfully treated with Viridans streptococci a combination of intravenously and intraventricularly adNonenterococcal group D streptococci Enterococci (in combination withgentamicin) ministered vancomycin and removal of the shunt. 20 Staphylococcal peritonitis associated with an indwelling catheter Infections causedby multiply resistant gram-positive organisms (for example, Corynebacteriumjeikeium and resistant strains of for peritoneal dialysis can usually be cured without removal Streptococcus pneumoniae) of the catheter. Vancomycin can be used alone for treatment of strepto- Clostridium difficile colitis (oraladministration) coccal infections, including endocarditis, in patients who are Endocarditis prophylaxis (in combination withgentamicin) for selected genitourinary and gastrointestinal procedures in allergic to penicillin. When endocarditis due to enterococci penicillin-intolerant patients is treated, however, vancomycin must be used in conjunction with an aminoglycoside. Vancomycin is the drug of choice for infections due to resistant corynebacteria, including C. jeikeium, and rarely encountered multiply resistant strains of Streptococcus pneumoniae. 21 of the drug. Desirable ranges for therapeutic peak and Vancomycin is recommended for prevention of endocar- trough concentrations are 20 to 40 ug/ml and 5 to 10 ug/ml, ditis in patients at risk who are allergic to penicillin and must respectively. The dose of vancomycin must be modified in patients with undergo selected invasive genitourinary or gastrointestinal procedures likely to be associated with transient bacter- impaired renal function. On the basis of the linear relationernia." It may be effective prophylaxis during selected car- ship between the clearance of vancomycin and creatinine diac and neurosurgical procedures at medical centers where clearance, nomograms have been formulated to guide the methicillin-resistant staphylococcal infections are common, alteration of doses in the presence of renal failure.P:" These guidelines are not valid in the functionally anephric patient, particularly when foreign bodies are implanted. Orally administered vancomycin is generally considered however. Vancomycin dosing should be individualized on the drug of choice for treating seriously ill patients with the basis of pharmacokinetic data derived from measured antibiotic-associated Clostridium dijficile colitis. This or- concentrations in the serum." Regardless of renal function, ganism is uniformly susceptible to vancomycin. Less expen- an initial dose of 15 mg/kg should be given to achieve sive alternatives, such as metronidazole or bacitracin, should prompt therapeutic concentrations. Vancomycin has been used effectively in many patients on hemodialysis by the be considered in patients who are less seriously ill. administration of 1 g every 7 to 10 days. A similar dosage schedule can be used in patients on continuous ambulatory peritoneal dialysis. DOSAGE AND ADMINISTRATION Several drugs, including chloramphenicol, methicillin, The usual daily intravenous dosage of vancomycin in adults with normal renal function is 1 g every 12 hours (30 mg/kg and ticarcillin, may be incompatible with vancomycin in for a 70-kg adult). In seriously ill patients, 1 g of vancomy- intravenous solutions.P-" High concentrations of heparin cin can be administered every 8 hours for the first few days have been shown to cause inactivation of vancomycin and of therapy. Each dose should be administered during at least resultant persistent bacteremia when the two agents were a 60-minute interval to minimize infusion-related toxicity. administered through the same intravenous line." Although the optimal oral dose of vancomycin has not Vancomycin pharmacokinetics may be altered in elderly or been established for the treatment of antibiotic-associated C. obese patients. Individual patient factors may necessitate difficile colitis, a dosage of 125 mg every 6 hours has been modification of the dose, which is difficult to predict accurately. Therefore, therapy should be monitored by periodic shown to be as effective as higher doses." The usual duradeterminations of peak and trough serum concentrations tion of therapy is 7 to 10 days.
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ADVERSE EFFECTS Soon after its introduction; vancomycin developed a reputation as being a relatively toxic antibacterial agent. Early preparations, often referred to as "Mississippi mud," contained many ;mpurities that apparently contributed to the frequency of adverse effects. Improved purification procedures have diminished the toxicity associated with vancomycin. When its concentration is monitored in the serum, the frequency of serious toxicity is low. The most important potential adverse effect associated with use of vancomycin is damage to the auditory nerve and consequent hearing loss. Ototoxicity has primarily been noted in patients with extremely high serum concentrations of vancomycin (80 to 100 ug/ml); it is rarely encountered when concentrations in serum are maintained at 30 ug/ml or lower (Table 3). Recent reviews suggest that the potential for vancomycin to cause significant ototoxicity, as perpetuated in the medical literature, has been exaggerated.P-" Although hearing occasionally improves when drug therapy is terminated, more commonly it is permanent. The risk of ototoxicity seems to be increased when vancomycin is administered in combination with an aminoglycoside. An infusion-associated reaction that is peculiar to vancomycin is referred to as the "red man" or "red neck" syndrome." Typically, it consists of pruritus, an erythematous rash that involves the face, neck, and upper torso, and occasionally hypotension. This reaction may occur within minutes after initiation of the drug infusion or may begin soon after its completion. Its manifestations are due to the nonimmunologically mediated release of histamine. This complication can be avoided by administering vancomycin over at least a l-hour period. Smaller doses of vancomycin administered at shorter intervals (relative to the standard regimen) may also decrease the occurrence of this reaction. Because the red man syndrome is usually related to a rapid rate of infusion, vancomycin may be administered at a slower rate in a patient who has previously experienced these symptoms. Antihistamines such as hydroxyzine have been shown to be protective when given before infusion of vancomycin." Vasopressors may be needed if severe hypotension occurs. Pain and muscle spasms in the chest and back may occur after rapid infusion of vancomycin; these findings have been referred to as the "pain and spasm" syndrome. Symptoms resolve after the infusion is terminated." The new preparations of vancomycin are rarely associated with clinically significant nephrotoxicity. As with ototoxicity, however, the concomitant use of an aminoglycoside seems to enhance the risk of nephrotoxicity." Chemical thrombophlebitis occurs in as many as 13% of patients with peripheral venous cannulas. Hypersensitivity maculopapular or urticarial drug eruptions and drug-induced fever occur rarely. Reversible neutropenia has been noted in
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Table 3.-Adverse Effects Associated With Use of Vancomycin Ototoxicity Hearing loss: often irreversible; rare; associatedwith drug levels >30 ug/ml Enhanced risk with concomitantaminoglycoside therapy Infusion-relatedside effects "Red man" syndrome "Pain and spasm" syndrome Hypotension Thrombophlebitis-associated with peripheral venous cannulas Hypersensitivity reactions Drug fever (rare) Allergic rash (rare) Neutropenia Reversible Develops after prolonged use Nephrotoxicity Rare Enhanced risk with concomitantaminoglycoside therapy Reversible
approximately 2% of vancomycin-treated patients. Its onset is usually delayed; the neutrophil nadir occurs 15 to 40 days after initiation of therapy."
OTHER GLYCOPEPTIDE ANTIBIOTICS Several other glycopeptide antibiotics of the vancomycin group have been obtained from various species of actinomycetes. Ristocetin, which is also bactericidal against grampositive bacteria, is no longer considered for use as an antibiotic because of its propensity to cause aggregation of platelets."? Teicoplanin (formerly known as teichomycin A 2) has been studied extensively and is available for clinical use in several European countries; currently, however, it is not commercially available in the United States. Teicoplanin is a complex mixture of closely related compounds that share certain structural and antimicrobial properties with vancomycin." It has a longer elimination half-life (40 to 70 hours) than does vancomycin and may be administered every 24 hours. Its spectrum of activity, like vancomycin, is restricted to gram-positive bacteria. Overall, its minimal inhibitory concentrations tend to be lower. It is more active than vancomycin and ampicillin against enterococci, although concomitant aminoglycoside therapy is necessary for a bactericidal effect. Several strains of S, haemolyticus and S. epidermidis have been shown to be substantially less susceptible to teicoplanin than to vancomycin." Although serious adverse effects have seldom been encountered, rare ototoxicity has been reported. Concern about the occurrence of teicoplanin-resistant staphylococci and reports of clinical
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failures with use of teicoplanin in patients with bacteremic staphylococcal infections have prompted serious questions about the overall advantages of teicoplanin over vancomycin. 40 ,4 1 Currently, it seems unlikely that teicoplanin will usurp the prominent and important role of vancomycin in clinical practice.
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18. 19.
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End of Symposium on Antimicrobial Agents, Part III. Part IV will appear in the December issue.