Vancomycin

Symposium on Anti-Infective Therapy

Vancomycin Martin C. McHenry, M.D., M.S.,* and Thomas L. Gavan, M.D.t

Available for more than 20 years, the story of the clinical utility of vancomycin continues to unfold. Discovered in 1956, BI and introduced into clinical medicine in 1958, vancomycin quickly became established as the most effective bactericidal antibiotic for treatment of serious infections caused by penicillin-resistant strains of staphylococci, 42-45, 68-7! but its use was limited by apparent toxicity and the need to be administered intravenously. With improvement in the process of purification, local and systemic reactions were minimized. 1· 24· 30• 34• 41· 68 Nevertheless, with the development and availability of the antistaphylococcal penicillins and cephalosporins in the 1960's, the use of vancomycin declined markedly. In recent years, expanded indications for the use of vancomycin have developed;24· 30 it appears to be better tolerated by patients when careful attention is paid to dosage and method of administration;108 and it is now considered to be an uncommon or rare cause of ototoxicity or nephrotoxicity. 4 Much new information has become available concerning vancomycin in recent years. The chemical structure has been defined, permitting a better understanding of the mechanism of action. New studies have been conducted of the pharmacokinetics in pediatric patients and in adults with impaired renal function. Factors related to the development and the prevention of the "red-neck syndrome" are better understood. Information is accumulating concerning penetration of the drug into the cerebrospinal fluid when meninges are inflamed. The unique value of vancomycin for treatment of infections due to susceptible organisms in anephric patients has been established. The value has also been established for treatment of serious infections due to methicillin-resistant staphylococci, for staphylococcal or streptococcal endocarditis in patients allergic to the penicillins and cephalosporins, and for antibiotic-induced pseudo-membraneous colitis caused by Clostridium difficile. The need to combine an aminoglycoside *Chairman, Department of Infectious Diseases, Cleveland Clinic Foundation; Association Clinical Professor of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio tChairman, Department of Microbiology, Cleveland Clinic Foundation; Assistant Clinical Professor of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio

Pediatric Clinics of North America-Vol. 30, No. 1, February 1983

31

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with vancomycin in the treatment of enterococcal endocarditis is becoming better appreciated.

CHEMISTRY AND MECHANISM OF ACTION Vancomycin is derived from Streptomyces orientalis, an organism which was first isolated in 1956 from a soil sample obtained by a missionary from a jungle in Indonesia. 49a, 81 Produced by fermentation in broths by Streptomyces orientalis, vancomycin was first obtained by precipitation with picric acid. 49• Now it is obtained by passage over an ion-exchange resin, followed by the formation of a crystalline vancomycin-copper complex; upon resolution this compound yields vancomycin hydrochloride. 49• Vancomycin hydrochloride is very soluble and stable in sterile water, acid glucose-containing solutions, and 0. 85 per cent sodium chloride. 92 It is unstable in alkalaine solutions, but it is stable at the pH encountered in body fluids. 92 Unlike any other presently available antibiotic, vancomycin is a tricyclic glycopeptide (Fig. 1) with an empirical formula C 66 H 75 Cl2 N 90 24 and a molecular weight of 1448 daltons. 92 • 110• 135 It exerts a prompt bactericidal effect on multiplying organisms. Rapidly absorbed from solution by susceptible gram-positive bacteria, it binds tightly to peptides that contain D-alanyl-D-alanine at the free carboxyl end, inhibits cell wall synthesis at a stage before that of the penicillins and cephalosporins, and eventually

Figure l. The structure of vancomycin, according to x-ray analysis of the crystalline degradation product, CDP-l,ll0 consists of a disaccharide, two 13-hydroxychlorotyrosine units, three substituted phenylglycine systems, N-methylleucine, and aspartic acid amide. The peptide backbone is shown in heavier type. The atoms involved in hydrogen bonding with acetylD-alanyl-D-alanine are indicated by asterisks. 92

33

VANCOMYCIN

leads to destruction of the bacterial cells by lysis. 2· 89, 92· 128 In addition to inhibition of cell wall synthesis, vancomycin may alter premeability of cell membranes 54• 63 and selectively inhibit ribonucleic acid synthesis. 62

Antibacterial Spectrum Vancomycin is effective in low concentrations in vitro against most gram-positive cocci and bacilli. 3, 5, 29, 32, 3fh37, 39, 42-45, 47, 51h52, 56, 58, 61, 69, 71, 79. 91, 93, 96, 100. 102. 104, 100. m, 117, 120. 12S--134, 141 There has been no evidence of any increased resistance to the drug among susceptible organisms in the last 25 years. 127 It exerts its bactericidal effects primarily against multiplying bacteria and there is little variation in the activity between pH 6.5 and 8.0. It rarely causes L-phase variants, 127 and there is no cross-resistance between vancomycin and other currently available antibiotics. The minimum inhibitory concentrations (MIC's) of vancomycin for 100 per cent of some recent clinical isolates at the Cleveland Clinic are shown in Table 1. Pathogenic strains of Staphylococcus aureus and Staphylococcus epidermidis are almost uniformly susceptible to vancomycin in low concentrations (:55 tJ.g/ml); the minimum bactericidal concentration (MBC) is usually similar to the MIC or differs by only onefold or twofold dilutions. 41 Some strains of staphylococci may be tolerant of the bactericidal action of vancomycin, being inhibited by low concentrations of the drug but requiring inordinately high concentrations for bactericidal effect;33· 48 • 103· 127 this has been attributed to deficiency of autolysins in organisms 103 and has been associated with therapeutic failures in some patients33· 48• 103 but not in others.127 Vancomycin appears to be the most reliably effective antibiotic against methicillin-resistant strains of S. aureus. 10• 17· 72, B2, 95, 105 Some strains of S. epidermidis resistant to vancomycin have been described. 140 Bacteria other than staphylococci that are susceptible to vancomycin include group A streptococci, Streptococcus pneumoniae including the multiply resistant strains from South Africa, 60 S. viridans, S. bovis, enterococci, and most strains of group B streptococci. 127 Although most entero-

Table 1.

In Vitro Susceptibility of Some Recent Clinical Isolates to Vancomycin.

MICROORGANISM

Staphylococcus aureus Staphylococcus epidennidis Enterococcus spp. Streptococcus bovis Streptococcus viridans Streptococcus pneumoniae Group A streptococcus Listeria monocytogenes

NUMBER OF ISOLATES

MIC 100 (f.LGIML)

734 488 927 32 21 7 3 3

sLOt :S2.0 :S4.0 :S2.0 :Sl.O :Sl.O :Sl.O sl.O

*Minimum inhibitory concentration of 100 per cent of strains tested. tLowest concentration of vancomycin tested.

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cocci are inhibited by low concentrations of vancomycin, MBC"s are much higher, and the drug usually is not bactericidal for enterococci in concentrations that can safely be achieved in the body. 5.?, 56· 129· 134 Because of this, vancomycin should not be administered alone for treatment of enterococcal endocarditis. 41 · 46 · 79 • 13:>-- 134 Vancomycin may also have relatively high MBC values for occasional strains of S. viridans, group B streptococci, and S. bovis.41, 46.128 . 131 Most strains of clostridia, including Clostridium difficile, are susceptible to vancomycin, but some strains of C. ramosum are slightly resistant.l 27 Most strains of Corynebacteria (diphtheroids) are susceptible. 75 Some strains of Neisseria gonorrhoeae are susceptible, 61 · 138 but other gram-negative bacteria and fungi are resistant. Streptomycin and vancomycin or penicillin G produce a synergistic bactericidal effect in vitro against approximately 60 per cent of enterococci, 128 whereas virtually 100 per cent of enterococcal strains are killed by a combination of gentamicin and vancomycin or penicillin G at concentrations that can be safely achieved in patients. 127• 128 A simple test114 has been devised to differentiate between those enterococcal strains likely to be susceptible to the bactericidal effects of the combination of streptomycin and vancomycin or penicillin G and those strains likely to be resistant. 56 It is based upon the fact that enterococci likely to be resistant to the synergistic effect of the combinations are highly resistant in vitro to streptomycin (MIC2:2000 j.Lg/ml)56 · 114 in contrast to "synergistic" strains, which have much lower MIC' s. Thus, the presence or absence of growth of an enterococcal strain in a single test tube containing 2000 j.Lg/ml of streptomycin is used to predict whether or not the strain is likely to show synergism between the combination of streptomycin and vancomycin or penicillin G. However, recently the simplified MIC test failed to uncover an enterococcus resistant to the penicillin-gentamicin synergism. 84•

PHARMACOKINETICS After oral administration, vancomycin is not usually absorbed from the gastrointestinal tract, 22· 44 • 49 and high concentrations are achieved in the stooL 44 Occasionally, small amounts of the drug are excreted in the urine after oral administration to patients with normal or impaired renal function, 22 indicating minimal absorption from the gastrointestinal tract. However, even in patients with severely impaired renal function, repetitive oral administration of vancomycin does not result in clinically significant concentrations in serum. 22 Intramuscular administration causes severe pain, 52,69 and the drug must be administered intravenously. A single intravenous dose of 500 mg or 1 gm of vancomycin in adults with normal renal function yields peak serum concentrations at the end of the infusion (Table 2), and serum concentrations remain above 1 to 2 1-1-g/ml for 8 to 12 or more hours. In infants and children with normal renal function, single doses of 10 to 15 mg of vancomycin per kg of body weight given intravenously over 30 to 60 minutes yield peak serum concentrations at the end of the infusions (Table 2), and serum concentrations remain above 1 to 2 j.Lg/ml for at least 6 hours.l 00 • 108 Vancomycin is about 55 per cent bound to serum pro-

~ Table 2.

Some Microbiologic and Pharmacokinetic Data Concerning Vancomycin In Adults, Children, Infants, and Premature Infants

USUAL MIC*

MEAN PEAK SERUM CONCENTRATION*

Concentrations, tJ-g/ml (time after dose, hr)

( tJ-g/ml of Susceptible Organisms)

Dose and Routet of Administration

:55.0

0.5 g 1V in 4 to 30 min {adults)

7.3--10 (1-3)

1.0 g 1V in 4 to 30 min (adults) 2.0 g 1V in 4 to 30 min (adults) 10 mg/kg IV in 30 min (premature infants) 15 mg/kg IV in 30 min {premature infants) 15 mg/kg IV in 30 min (full term infants) 10 mg/kg IV in 60 min (older infants) 15 mg/kg IV in 60 min {older infants) 10 mg/kg IV in 60 min (children) 10 mg/kg IV in 30 min (children) 15 mg/kg IV in 60 min {children)

25-33 {0.02-2)

SERUM HALF-LIFE, HR

Serum Protein Binding%

Normal Renal Function

Anuria or Oliguria

55

4. 7-11.2 (adults)

168--216 (adults)

0

a:

z~

References 7,26,31,41,44,68--69, 71,77,83-85, 87,106,108

50 {2) 16.8± 1.3{0) 25.2±2.1(0)

5.9--9.8 (newborn infants)

29.8± 1.4{0) 26.1 ± 1.2(0)

4.1 (older infants)

28.0 ± 1.1(0) 27.2± 1.2{0) 30.5 ± 3.1{0)

2.2-3.0 {children)

32.5±2.0{0)

*MIC = Minimum inhibitory concentration. tiV =Intravenous. *Mean peak serum concentrations in patients with normal renal function.

~

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teins,7 3 and readily diffuses into pleural, pericardia!, ascitic, and synovial fluids. 44 It does not diffuse well into the cerebrospinal fluid when the meninges are not inflamed, but adequate concentrations may be achieved in the cerebrospinal fluid of some, but not all, patients with meningitis. 53 • 83 Vancomycin is not excreted in high concentrations in bile, 44 is not metabolized in the body, and is excreted primarily in the urine. 44 · 52 , 69· 108 The clearance of vancomycin is approximately two thirds that of the clearance of creatinine. 73 Eighty to 90 per cent of an administered dose appears in the urine within 24 hours. 44 · 49 The serum half-life of elimination of vancomycin in adults with normal renal function ranges from about 5 to 11 hours. 73• 84 The half-life in newborn infants with normal renal function ranges from 5. 9 to 9. 8 hours; in older infants it averages 4.1 hours, and in children it ranges from 2.2 to 3.0 hours.l06- 108 In adults with severely impaired or absent renal function, the half-life ranges from 7 to 9 days; 26· 41 similar data are not available for infants or small children, but comparable prolongations might be expected when renal function is severely impaired. In patients with renal failure, potentially toxic concentrations of vancomycin may accumulate in the body when dosage is not adjusted. 26 Although some vancomycin is removed by hemodialysis, the drug is so slowly dialyzable that this route can be neglected when dosage schedules are being considered. 77 However, sufficient vancomycin is removed by peritoneal dialysis to take this into consideration when devising dosage regimens. 7, 88, 113

UNFAVORABLE SIDE EFFECTS Early preparations of vancomycin contained impurities; solutions of the drug were referred to as "Mississippi mud"; 49a and pain at sites of intravenous administration, chemical thrombophlebitis, chills, and fever occurred quite frequently 1· 23 • 30• 34· 41 -45. 69· 71 With elimination of the impurities, solutions of the drug became clear and colorless 49• and side effects became much less common. 1· 23 · 30• 41 · 68 Even today, however, rapid intravenous administration of vancomycin produces a histamine-like reaction characterized by: flushing; tingling; pruritus; tachycardia; an erythematous macular rash involving the face, neck, upper trunk, back, and arms with sparing of the rest of the body; and systemic arterial hypotension or shock (so-called "red-neck syndrome"). It is important to be aware of this potential adverse reaction, first described a number of years ago, 98 • 140 and reemphasized recently,13 · 86• 108 because it appears to be caused by rapid or bolus intravenous infusion and reportedly has caused death; 139 it can be prevented by slow intravenous administration without altering the concentration of the drug. 73 · 86· 106 For infants and children, the reaction may be prevented by administration of recommended doses of 10 to 15 mg of vancomycin per kilogram of body weight intravenously over at least 30 to 60 minutes. 106 For adults, the rate of infusion should not exceed 500 mg of vancomycin intravenously in 30 minutes. 73 Vancomycin does not appear to be nephrotoxic. 4 Early reports of nephrotoxicity may have been related to impurities in the early lots of the drug41-45, 68-71 or to rapid intravenous infusion, but signs of nephrotoxicity

37

VANCOMYCIN

have not been encountered in recent years. 4· 68-$, 71 Although vancomycin does not cause ototoxicity in guinea pigs, 21 it has caused occasional cases of ototoxicity in man. 27· 42-43, 74· 78· 118· 140 It appears to have caused ototoxicity most frequently when patients received other potentially ototoxic drugs concomitantly or antecedently, or when serum concentrations of vancomycin exceeded 80 to 100 IJ.g/ml. 27· 43· 74 Transient neutropenia19, 131 or eosinophilia has been observed in some patients. Maculopapular or erythematous skin rashes have been observed in 4 to 5 per cent of patients treated with vancomycin by some physicians. 41-45 Drug fever may be a complication of vancomycin therapy. When vancomycin is administered orally, it has an unpleasant taste and may cause nausea.11. 15-16

THERAPEUTIC USES Vancomycin is effective for treatment of serious or life-threatening infections caused by Staphylococcus au reus and S. epidermidis. It is indicated especially when the organisms are resistant to or the patients are unable to tolerate antistaphylococcal penicillins or cephalosporins. Vancomycin appears to be the drug of choice for treatment of serious infections caused by methicillin-resistant S. au reus .1°· 17· 72· 82· 95• 105· 136 Caution must be used in treating serious infections caused by S. epidermidis with vancomycin because occasional strains may be resistant.l39 Members of our group observed a renal transplant patient who had persistent bacteremia due to S. epidermidis despite vancomycin therapy; the pathogen waS resistant to vancomycin but susceptible to clindamycin in vitro; the administration of vancomycin was discontinued and the infection was eradicated with clindamycin therapy. Vancomycin has been effective for treatment of S. aureus septicemia and endocarditis, with cure rates in the range of 60 to 70 per cent or more.23, 28,45-46,59, 70 Some failures of therapy of S. aureus endocarditis have recently been reported; 33• 48 • 80• 94 some of these patients eventually responded to combined therapy with vancomycin and rifampin.so, 94 Vancomycin administered intravenously has been successful for treatment of staphylococcal meningitis, 45• 53• 57 but published experience is limited, therapeutic concentrations of vancomycin are not always achieved in the cerebrospinal fluid, and some authors advocate administration of small doses of the drug intrathecally. When administered either intravenously or intraperitoneally, vancomycin may be effective for treatment of staphylococcal peritonitis developing in patients on chronic peritoneal dialysis; 7· 88 when vancomycin is administered by intraperitoneal route, systemic absorption of the drug may result in therapeutic serum concentrations. 88 Vancomycin appears to be the drug of choice for treatment of enterococcal endocarditis in patients allergic to penicillin G. 38• 136 Since vancomycin is bacteriostatic and not bactericidal for enterococci, ss. 56, 128, 130, 134 it should be administered conjointly with streptomycin or gentamicin for treatment of enterococcal endocarditis. 79· 133 In the event that in vitro testing indicates that the enterococcal pathogen is likely to be susceptible to a bactericidal effect of the combination of streptomycin and vancomycin, 56, 114

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streptomycin would be preferable to gentamicin because, in contrast to gentamicin, streptomycin is not nephrotoxic when administered in conventional therapeutic doses. Recently, vancomycin administered intrathecally and intravenously along with rifampin given orally were used to treat successfully a patient with enterococcal meningitis. 99 Vancomycin has been used as an alternative agent for treatment of endocarditis caused by S. viridans, S. bovis, and Corynebacteria (diphtheroid) organisms in patients allergic to the penicillins and cephalosporins. 46 Vancomycin alone may be sufficient for eradication of endocarditis due to S. viridans and S. bovis when the MBC of the drug for the pathogen is less than 10 J.Lg/ml. When the MBC is greater than 10 J.Lg/ml, streptomycin should be administered conjointly with vancomycin. 46 Vancomycin appears to be the drug of choice for treatment of endocarditis caused by Corynebacteria strains resistant to the penicillins and cephalosporins. 46· 120 Vancomycin is recommended for prophylaxis of endocarditis in patients allergic to penicillins when they are undergoing dental treatment, surgical procedures, or instrumentations likely to be associated with intrusion of bacteria into the bloodstream. 64 In adult patients undergoing dental procedures or surgery or instrumental procedures on the upper respiratory tract, vancomycin is given in a dose of one gm intravenously over 60 minutes before the procedures; in children the dosage is 10 mg/kg intravenously over 30 to 60 minutes before the procedure; in both adults and children, erythromycin is then given orally every 6 hours for a total of 8 doses. For patients undergoing surgical or instrumentational procedures on the genitourinary or gastrointestinal tracts, vancomycin is administered conjointly with streptomycin or gentamicin. Shortly after vancomycin became available, it was found to be highly effective for treatment of staphylococcal enterocolitis when administered orally.45, 67 , 125 More recently, it has been found to be effective, when administered orally, for treatment of antibiotic-induced pseudomembranous colitis caused by Clostridium difficile both in experimental animals 11-13, 20. 115 and humans.11. 14, 34, 40, 65--ffl, 112. 116 Clostridium difficile is usually susceptible to concentrations of vancomycin:56.0 J.Lg/ml. 34 Oral administration of vancomycin 500 mg four times daily results in mean stool concentrations of 3100 J,Lg/gm, 41 which are far in excess of the concentrations required to inhibit the growth of Clostridium difficile. When vancomycin is administered in a dose of I25 mg orally four times daily, the mean concentration of the drug in the stool is approximately 350 J.Lg/gm, which is also much more than is necessary to inhibit the growth of the pathogen. 65 Although oral administration of vancomycin is associated with an unpleasant taste, 11 · 15-16 it is followed by prompt clinical and histologic improvement in patients with pseudomembranous colitis due to Clostridium difficile. In a controlled study, administration of vancomycin 500 mg orally four times daily was significantly better than treatment with a placebo. 65 A lower dose of I25 mg of vancomycin orally every 6 hours may be equally effective. 34 Treatment for 5 days may be all that is required, 34· 65 but relapses occur in approximately 20 per cent of the patients; retreatment with vancomycin often appears to be successful in those

39

VANCOMYCIN

patients. Cholestyramine should not be administered in conjunction with vancomycin because it binds the drug and may interfere with its therapeutic effect. us Vancomycin has been incorporated into oral, nonabsorbable, antibiotic prophylactic regimens for prevention of infections in patients undergoing chemotherapy for treatment of malignant neoplasms, 15· 16• 18• 18• but unpleasant taste and nausea have been a significant problem. 15, 16 Vancomycin appears to have a unique value for treatment or prevention of infections due to susceptible organisms in patients with severe renal failure. 31, 77· 85 Therapeutic concentrations of the drug persist for at least 7 days in anephric adults after a single one gm intravenous dose of vancomycin, and it is not removed appreciably by hemodialysis. Because of persistence of therapeutic concentrations of the drug, vancomycin has a significant clinical advantage over other antistaphylococcal drugs in patients with severe renal failure when access to veins is a problem for frequent intranveous therapy. It is possible to eradicate staphylococcal endocarditis in those patients with less than 10 one gm intravenous doses of vancomycin given at weekly intervals (Fig. 2). Furthermore, it has been possible to prevent staphylococcal infections of arteriovenous shunts in patients with end-stage renal disease by intravenous administration of one gram every 14 days. 85 Because vancomycin is not removed significantly by hemodialysis, intravenous administration may be performed at the time of hemodialysis, thereby minimizing manipulations of veins. As much as 54 grams of vancomycin have been administered to patients with severe renal failure over a two-year period without ototoxicity or other untoward effects. 85

DOSAGE Vancomycin hydrochloride is available as a dry, sterile, white powder in 10 ml rubber-stoppered ampules containing 500 mg of the drug. The powder is stable when stored at room temperature and is very soluble in water. At the time of use, 10 ml of sterile water for injection is added to the ampules of vancomycin, and this solution must be further diluted 10fold to 20-fold in 5 per cent of glucose solution or in normal saline to concentrations of 2.5 to 5 mg/ml for intravenous administration. Recommended doses for adults with normal renal function are 500 mg intravenously over at least 30 minutes every 6 hours, or 1 gm intravenously over 60 minutes every 12 hours. For newborn infants, the recommended dose is 15 mg per kilogram of body weight intravenously over 30 to 60 minutes every 12 hours during the first week of life (30 mg/kg/day), 15 mg/kg intravenously over 30 to 60 minutes every 8 hours in those 8 to 30 days of age (45 mg/kg/day), and 10 mg!kg intravenously over 60 minutes every 6 hours to older infants and children (40 mg/kg/day). For infants and children with infections of the central nervous system, larger doses may be required (for example, 15 mg/kg intravenously every 6 hours, or 60 mg/kg!day). In patients with meningitis, when there is no response to intravenous therapy after 48 hours, vancomycin has been administered intrathecally in doses of 3 to 5 mg.s3. 57

~

0

TEMPERATURE (DEGREES F)

JULY 197 3

AUGUST 197 3

26 28 30

I

104l· 102

100....,

9896 +

VANCOMYCIN IG IV SERUM LEVEL OF

SEPTEMBER 1973

7

·1 ~\

- + +++ STAPHYLOCOCCUS AUREUS PHAGE TYPE WH-1

-

13

15

17

19

21

OUT ON PASS

I__I

I__I

23 25 27

29

31

2

4 5

7

9

II

13

15

17

19

21

23 25 27

29

OUT ON PASS

U l_I

HEMODIALYSIS AT HOME (AFEBRILE AND ASYMPTOMATIC)

~

> ~

l M.I.C. VANCOMYCIN= 4 p.o/ml

z (")

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ONE DOSE ONLY

lJ

::I:

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'·-~~~:~~~---~~~

50 40

10

MAXIMUM 1•32 SERUM 1•16 BACTERICIDAL 1•8 ACTIVITY 1>4 (TITER) 1•2

II

..... + +++

VANCOMYCIN~ p.g/ml

9

.~,,\~ 0.:~~,.. ~~,] :

-

-

+

ERYTHROMYCIN 2SO mg PO 06H LINCOMYCIN 600 mg IV

5

ADMITTED HOSPITAL

106-

BLOOD CULTURES

3

z

~

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0

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~

Figure 2. Graphic representation of clinical course of patient at the Cleveland Clinic.: with staphyloeoeeal endoearditis and chronic renal failure. Patient was cured with 9 one-gram doses vancomycin intravenously. (Reprinted by permission from Hewitt, W. L., and McHenry, M. C.: Blood level determinations of antimicrobial drugs: Some clinical considerations. Med. Clin. North Am., 62:11191140, 1978.)

li0 ;::: > [JJ

r C"l

~

41

VANCOMYCIN

Several methods are available for administration of vancomycin to patients with impaired renal function. In one scheme, 87 the daily parenteral dose of vancomycin for adults is 150 mg plus 15 times the value of the endogenous creatinine clearance in milliliters per minute. Another approach is to give 1 gm intravenously to adults every 36 hours when the serum creatinine concentration is 1.5 to 5 mg per dl and 1 gm intravenously every 10 to 14 days when the value of the serum creatinine concentration is greater than 5 mg per dl. 34 Still another method is based upon a recently published nomogram for estimating dosage in renal failure. 84 For anephric adult patients, it is our practice to administer two doses of 1 gm of vancomycin intravenously at 12-hour intervals followed by 1 gm intravenously every 7 days. We monitor serum concentrations of the drug to ensure that the peak serum concentration is <50 j.Lg/ml and the trough concentration (immediately before next dose) is 2::10 j.Lg/ml. For anephric infants and children, we advise two doses of 15 mg/kg of body weight intravenously at 12 hour-intervals followed by 15 mg/kg intravenously every 7 days with adjustments in dosage based upon clinical response to therapy and the results of serum vancomycin assays. For oral administration, vancomycin hydrochloride is supplied in glass bottles containing 10 gm of dry powder. The powder is mixed with 115 ml of distilled or deionized water; when reconstituted with 115 ml, each 6 ml of solution contains approximately 500 mg of vancomycin. For therapy of C. difficile colitis, vancomycin is administered in doses of 125 to 500 mg orally every 6 hours for 5 to 10 days. Intravenous vancomycin therapy in this condition is inferior to oral therapy because adequate concentrations of the drug may not be achieved in the gastrointestinal tract. Intravenous therapy should be reserved for those patients with C. difficile colitis in whom nausea and vomiting prevent oral intake of the drug.

REFERENCES l. Alexander, M. R.: A review of vancomycin after 15 years of use. Drug Intell. Clin. Pharm., 8:52~525, 1974. 2. Anderson, J. S., Matsuhashi, M., Haskin, M. A., et al.: Lipid-phosphoacetylmuramylpentapeptide and lipid-phosphodisaccharide-pentapeptide: Presumed membrane transport intermediates in cell wall synthesis. Proc. Nat!. Acad. Sci. U.S.A., 53:881-

889, 1965. 3. Andriole, V. T., and Lyons, R. W.: Coagulase-negative staphylococcus. Ann. N.Y. Acad. . Sci., 174:53~544, 1970. 4. Appel, G. B., and Neu, H. C.: The nephrotoxicity of antimicrobial agents (second of three parts). N. Engl. J. Med., 296:722-728, 1977. 5. Archer, G. L.: Antimicrobial susceptibility and selection of resistance among Staphylococcus epidermidis isolates recovered from patients with infectious of indwelling foreign devices. Antimicrob. Agents Chemother., 14:35~359, 1978. 6. Austin, T. W., Leake, J., Coles, J. C., et al.: Vancomycin blood levels during cardiac bypass surgery. Can. J. Surg., 24:42~25, 1981. 7. Ayus, J. C., Eneas, J. F., Tong, T. G., et al.: Peritoneal clearance and total body elimination of vancomycin during chronic intermittent peritoneal dialysis. Clin. Nephrol. 11:129--132, 1979.

42

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