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PubMed1993

How vancomycin is used in Australasia--a survey.

BACKGROUND: Vancomycin serum concentrations have been monitored over the last 30 years in an attempt to avoid dose-dependent toxicity and enhance efficacy. Current literature recommendations for peak and trough concentrations are usually in the range of 20-40 mg/L and 5-10 mg/L, respectively. Literature recommendations regarding the time at which peak concentrations are measured are highly variable, ranging from immediately after the end of the infusion to three hours post-dose. AIMS: To identify how vancomycin dosing is being monitored and assess variability in the current practice. METHODS: A survey of microbiology departments and infectious disease physicians in major Australasian hospitals was undertaken. The variability in the current practice was assessed by fitting mean recommendations to a two compartment Bayesian model. RESULTS: Of the 83 (70%) who replied 71 (86%) monitored vancomycin concentrations. Fifty-four percent targeted peak concentrations within the range of 20-40 mg/L, and 73% targeted trough concentrations < or = 10 mg/L. The time of sampling of peak concentrations varied considerably ranging from immediately (12%) to 120 minutes (12%) post-infusion (median 30 minutes [40%]). The concentration-time curves resulting from three sets of mean recommendations ('peaks' drawn at: 0, 30 and 120 minutes aiming for a concentration of 35 mg/L with a trough concentration of 10 mg/L) were modelled using a two compartment Bayesian programme. The predicted true peak (maximum) concentrations ranged from 30 to 86 mg/L, despite aiming for identical target concentrations, indicating marked variation in the actual dosing practice. CONCLUSIONS: There is thus considerable variation in the practice of vancomycin therapeutic monitoring which has a major effect on dosing. The main contributing factor is the variable timing of sampling peak concentrations.

Australia↗

PubMed1990

Induction of vancomycin resistance in Enterococcus faecium by inhibition of transglycosylation.

Vancomycin resistance has recently been recognized among clinical isolates of enterococci. Resistance is inducible, and associated with production of a novel 39 kDa membrane protein. The mechanism by which exposure to vancomycin, which does not penetrate the cell membrane, induces resistance is unknown. In the vancomycin resistant strain Enterococcus faecium 228, resistance was also inducible by moenomycin, suggesting that inhibition of the transglycosylation step in peptidoglycan synthesis may be required for induction of resistance. Cytoplasmic pools of peptidoglycan precursors were increased after exposure to vancomycin or moenomycin, representing a potential means for regulation of induction.

Cytoplasm↗

PubMed1995

Induction of vancomycin resistance in Enterococcus faecium by non-glycopeptide antibiotics.

Bacitracin and other antibiotics that inhibit late stages in peptidoglycan biosynthesis induce vancomycin resistance in a high-level, inducibly vancomycin-resistant strain of Enterococcus faecium. Exposure to bacitracin led to synthesis of the lactate-containing UDP-MurNAc-pentadepsipeptide precursor required for vancomycin resistance. These findings indicate that inhibition of peptidoglycan biosynthesis can lead to induction of vancomycin resistance and raise the possibility that multiple signals may serve to induce resistance.

Anti-Bacterial Agents↗

PubMed2001

Adhesion of Enterococcus faecalis 1131 grown under subinhibitory concentrations of ampicillin and vancomycin to a hydrophilic and a hydrophobic substratum.

The effect of two subinhibitory antibiotic concentrations of ampicillin and vancomycin during growth on the adhesion of Enterococcus faecalis 1131 to glass and silicone rubber was studied in a parallel plate flow chamber. Initial deposition rates and numbers of adhering bacteria after 4 h were higher on hydrophilic glass than on hydrophobic silicone rubber, regardless of growth conditions. The presence of 1/4 minimal inhibitory concentration (MIC) of ampicillin during growth reduced enterococcal adhesion to both substrata, but growth in the presence of 1/4 MIC vancomycin did not affect the adhesion of E. faecalis. Moreover, enterococcal adhesion increased after growth in the presence of 1/8 MIC vancomycin. The increased adhesion after growth in the presence of subinhibitory concentrations of vancomycin may have strong implications for patients living with implanted biomaterials, as they may suffer adverse effects from use of this antibiotic, especially since bacteria once adhered are less sensitive to antibiotics.

Ampicillin↗

PubMed1983

Population analysis of susceptibility to methicillin, vancomycin, and three cephalosporines in two methicillin-resistant strains of Staphylococcus epidermidis.

Population analyses of susceptibility to methicillin, vancomycin, cephalothin, cefamandole, and cefoxitin were carried out with two strains of Staphylococcus epidermidis (S. epidermidis) resistant to penicillin, streptomycin, and methicillin. Two strains of Staphylococcus aureus (S. aureus), one sensitive to penicillin the other resistant, were used as controls. All strains were clinical isolates. From the strains of S. epidermidis it was possible to select sub-populations highly resistant to methicillin, cephalothin, cefamandole, and cefoxitin. The mutation-rate varied between c. 10(-3) and 10(-7). The two strains were homogeneous as regards vancomycin susceptibility. Methicillin was shown to be more penicillinase-stable than the cephalosporines. Treatment in vivo, with cephalothin and vancomycin did not increase the frequency of highly resistant bacteria against any of the antibiotics, but during treatment with cephalothin the majority-population became eight times more resistant to vancomycin and may explain why the treatment in vivo was not successful.

Cephalosporins↗

PubMed1978

Sensitive bioassay for vancomycin.

An accurate and sensitive assay for vancomycin in serum and body fluids has not been available. This paper reports an assay for vancomycin that can detect serum and fluid levels as low as 0.8 mug/ml. A disk diffusion technique was designed employing buffered glucose minimal salts agar and Bacillus subtilis as an indicator strain. A linear relationship was obtained between zone diameter and concentration for vancomycin standards from 0.8 to 50 mug/ml prepared in pooled human serum. Results were accurate (<10% error) and reproducible (within-sample standard deviation, 0.25 mug/ml) for concentrations of from 0.8 to 25 mug of vancomycin per ml. Zone diameters were at least 6 mm larger on minimal salts agar than on standard assay media. The increased sensitivity and accuracy of the assay make it possible to accurately measure levels in cerebrospinal fluid and dialyzate fluid as well as in serum.

Adult↗

PubMed1978

In vitro activity of rifampin alone and in combination with nafcillin and Vancomycin against pathogenic strains of Staphylococcus aureus.

Twenty strains of Staphylococcus aureus isolated from patients with endocarditis were examined in vitro for susceptibility to rifampin, nafcillin, and vancomycin and to combinations of rifampin with nafcillin or vancomycin. Minimum bactericidal concentrations of rifampin ranged from 0.0031 to 0.0125 mug/ml, of nafcillin ranged from 0.078 to 0.312 mug/ml, and of vancomycin ranged from 0.312 to 1.25 mug/ml. The combination of rifampin with nafcillin was synergistic for 12 strains; the combination of rifampin plus vancomycin was synergistic for 5 of the isolates.

Drug Synergism↗

PubMed1979

Role of vancomycin as a component of oral nonabsorbable antibiotics for microbial suppression in leukemic patients.

A total of 38 adult patients with acute leukemia who were undergoing remission induction chemotherapy in regular patient rooms were randomly allocated to one of two oral nonabsorbable antibiotic regimens for infection prophylaxis (gentamicin, vancomycin, and nystatin [GVN] or gentamicin and nystatin [GN]) to evaluate whether vancomycin was a necessary component. The patient population in both groups were comparable. Tolerance to GVN was less than GN but compliance was approximately equal (>85% in both groups). Patients receiving vancomycin demonstrated greater overall alimentary tract microbial suppression; however, acquisition of potential pathogens was approximately equal in both groups. The incidence of bacteremia, as well as the overall incidence of infection as related to the number of days at various granulocyte levels, was also approximately equal in both groups. Group D Streptococcus species were poorly suppressed by GN compared with GVN, although no patient developed an infection with these organisms. Colonization by newly acquired gram-negative bacilli was significantly less in the GN group (GN, 3 colonizations; GVN, 13 colonizations; P < 0.01). It is concluded that vancomycin may be safely eliminated from the GVN regimen provided microbiological data is monitored to detect resistant organisms.

Adult↗

PubMed1983

Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981.

A retrospective chart review of 98 patients treated with 100 courses of intravenous vancomycin was undertaken to better define its toxicity. Most of the patients carried diagnoses of Staphylococcus aureus or Staphylococcus epidermidis infection. Auditory toxicity was not seen, and fever and rash occurred in only 1 to 3% of the subjects. Phlebitis was noted in 13% of the cases and required discontinuation of therapy in 2%. Therapy was complicated by neutropenia (polymorphonuclear leukocyte count, less than or equal to 1,000 cells per cm3) in 2% of the patients but was rapidly reversible. Nephrotoxicity was uncommon (5%) and reversible in subjects receiving vancomycin alone, even when the therapy was continued. However, 35% of the patients receiving vancomycin with an aminoglycoside developed significant elevations in serum creatinine. Although this high incidence may have been due to the patient population selected or to the aminoglycoside therapy alone, the possibility of additive toxicity between vancomycin and the aminoglycosides should be considered.

Adolescent↗

PubMed1983

Therapy of staphylococcal infections with cefamandole or vancomycin alone or with a combination of cefamandole and tobramycin.

Eighty adult patients with microbiologically demonstrated staphylococcal infections were included in a comparative trial of cefamandole and cefamandole plus tobramycin. Patients with cefamandole-resistant pathogens were treated with vancomycin, if the initial therapy consisted of cefamandole, but were continued on cefamandole plus tobramycin if already started on that combination. Of the patients infected with cefamandole-susceptible strains, 91% (20/22) responded favorably to treatment with cefamandole alone, and 88% (30/34) responded favorably to cefamandole plus tobramycin. Of the patients infected with cefamandole-resistant staphylococci, 70% (7/10) responded to treatment with cefamandole plus tobramycin, and 86% (12/14) responded to treatment with vancomycin, even though vancomycin therapy was started 24 to 48 h later than cefamandole-plus-tobramycin therapy. No major side effects were observed; however, cefamandole plus tobramycin was associated with a rise in the serum creatinine level in 11% (4/44) of the patients. The bactericidal activity of the serum in cefamandole-treated patients and in cefamandole-plus-tobramycin-treated patients was identical against cefamandole-susceptible strains. Against cefamandole-resistant strains, 87% of the vancomycin-containing sera were bactericidal at a dilution of 1:8, whereas only 57% of the cefamandole-plus-tobramycin-containing sera were active at that dilution.

Anti-Bacterial Agents↗

PubMed1983

Effects of hepatic function on vancomycin clinical pharmacology.

Using a recently developed radioimmunoassay, we performed 15 vancomycin pharmacology studies in cancer patients with infections. Vancomycin (500 mg) was infused intravenously for 30 min every 6 h for up to 7 days. The plasma disappearance curve was biphasic, with an initial half-life of less than 30 min. The second half-life (t1/2 beta), not dose related, varied from 1.4 to 231 h among the patients. In six studies of patients with normal hepatic functions, the t1/2 beta was 2.6 h; the rate of total clearance was 162 ml/min. In contrast, nine studies of patients with impaired liver function had a much longer t1/2 beta (37 h) and a decrease in the rate of total clearance to 48 ml/min. These factors resulted in an increase in the value of area under the concentration-time curve from 59 to 3,434 micrograms X h/ml. These results have demonstrated the importance of the effects of liver function on vancomycin disposition. The vancomycin dose and schedule should be adjusted for patients with liver impairment.

Adult↗

PubMed1983

Evaluation of an automated fluorescence polarization immunoassay for vancomycin.

An automated fluorescence polarization immunoassay for the determination of vancomycin levels in serum was evaluated. The vancomycin assay is a homogeneous competitive inhibition immunoassay based on changes in fluorescence polarization that occur with antibody binding. This assay was compared with a liquid chromatographic assay and an agar well diffusion bioassay method by using clinical serum specimens and controls. Linear regression analysis of the data obtained on clinical specimens by the three methods resulted in correlation coefficients of 0.97 for the fluorescence polarization immunoassay versus the liquid chromatographic assay (n = 60), 0.90 for the fluorescence polarization immunoassay versus the bioassay (n = 57), and 0.90 for the liquid chromatographic assay versus the bioassay (n = 57). Repetitive analysis of control sera containing 7, 35, and 75 micrograms of vancomycin per ml by the fluorescence polarization immunoassay yielded coefficients of variation of 3.0, 1.7, and 2.3, respectively. No interference was demonstrated in spiked hemolytic, lipemic, or icteric sera, and the assay was free of matrix effects. The automated fluorescence polarization immunoassay system offers a rapid, efficient, and accurate method for monitoring vancomycin serum levels for both toxicity and efficacy.

Biological Assay↗

PubMed1985

Vancomycin disposition during continuous ambulatory peritoneal dialysis: a pharmacokinetic analysis of peritoneal drug transport.

Expressions are presented to describe the absorption and also clearance of drugs administered into the peritoneal cavity of patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Application of the expressions to vancomycin kinetics in five male CAPD patients showed that therapeutic levels of vancomycin can readily be achieved and maintained in the systemic circulation by administering the appropriate loading and maintenance doses. The intrinsic peritoneal clearance of vancomycin reported here is higher than the apparent clearances reported previously, averaging 300 to 500 ml/min under the conditions used in this study. The low apparent clearances previously reported are useful clinically although they do not represent the true efficiency of vancomycin removal by CAPD. The degree to which apparent clearance underestimates the true intrinsic clearance is exponentially related to the dwell time of dialysate in the peritoneum. Intraperitoneal administration is a practical alternative to other routes for CAPD patients needing antibiotic or other therapy.

Adult↗

PubMed1985

Comparison of penicillin and vancomycin, individually and in combination with gentamicin and amikacin, in the treatment of experimental endocarditis induced by nutritionally variant streptococci.

Six different antibiotic treatment regimens were compared for efficacy in rabbits with endocarditis induced by inoculation with a nutritionally variant strain of streptococcus. Seven untreated animals, sacrificed at day 11, had vegetations containing 8.89 +/- 1.35 log10 CFU/g, none of which was sterile. The vegetations from the rabbits in all treated groups had bacterial titers significantly lower than those of the controls (P less than 0.001). Vegetations from penicillin-treated animals averaged 5.14 +/- 1.00 log CFU/g, and no vegetations were sterile. Treatment with penicillin plus gentamicin or amikacin was more effective than treatment with penicillin alone, resulting in 3.99 +/- 0.94 log CFU/g of vegetation and sterile lesions in 5 of 12 animals. Treatment with vancomycin alone was as least as efficient as that with penicillin plus an aminoglycoside, resulting in an average of 3.33 +/- 0.96 log CFU/g of vegetation and sterile lesions in five of eight animals. Treatment with vancomycin plus an aminoglycoside was not superior to treatment with vancomycin alone, resulting in an average of 3.68 +/- 1.37 log CFU/g of vegetation and sterile lesions in 8 of 13 animals. These in vivo results correlated poorly with the in vitro susceptibility of the strain to the various antibiotics, as measured by the time-kill method. These results support the current practice of using vancomycin as alternative therapy when a penicillin-aminoglycoside combination is ineffective or contraindicated in patients with endocarditis caused by nutritionally variant streptococci.

Amikacin↗

PubMed1987

Vancomycin pharmacokinetics and dose recommendations for preterm infants.

The pharmacokinetics of intravenous vancomycin was studied in 20 preterm infants (gestational age, 26.5 weeks +/- 2.6 weeks [standard deviation]; birthweight, 880 +/- 340 g). At the time of the studies their postconceptional age was 36.4 +/- 4.5 weeks. The drug was infused over 30 min in a dose between 9.2 and 18 mg/kg. A highly significant correlation existed between postconceptional age or body weight and vancomycin t1/2 and clearance. Serum creatinine concentrations correlated with vancomycin t1/2 and clearance. Serum creatinine tended to decrease with increasing postconceptional age. Based on the excellent correlation between age (or weight) and vancomycin pharmacokinetics, dose and dose-interval recommendations are presented.

Drug Administration Schedule↗

PubMed1987

Vancomycin entry into lung lymph in sheep.

The distribution of antibiotics into target tissues is a crucial factor in therapeutic efficacy. To estimate the availability of systemically administered vancomycin to the interstitial fluid in the lung, we have used a sheep model with a chronic pulmonary lymph fistula to collect simultaneously series of plasma and pulmonary lymph specimens during a 6-h period after an intravenous dose of vancomycin (7 mg/kg). After a minor delay in transit from blood to lymph, vancomycin was completely distributed to pulmonary lymph with a ratio of free drug in lymph to free drug in plasma of 0.9. This suggests that vancomycin is an excellent choice for treating pulmonary infections by susceptible organisms.

Animals↗

PubMed1987

Comparative study of intraperitoneal and intravenous vancomycin pharmacokinetics during continuous ambulatory peritoneal dialysis.

The pharmacokinetic characteristics of vancomycin were investigated in eight patients undergoing continuous ambulatory peritoneal dialysis. A crossover design was used. Four noninfected patients received both a 15-mg/kg (body weight) intravenous dose and a 30-mg/kg intraperitoneal (i.p.) dose. Bioavailability ranged from 0.35 to 0.65 after i.p. administration. i.p. absorption was rapid, with concentrations in serum of 8.8 +/- 6 micrograms/ml noted at 1 h peak values of 30.4 +/- 7 micrograms/ml at 6 h. A slow distribution phase was apparent, with a terminal elimination phase emerging after 12 to 24 h. Vancomycin was eliminated slowly, with a mean total clearance of 5.0 +/- 1.3 ml/min, and concentrations in serum were 7.0 +/- 1.2 micrograms/ml at 168 h. The mean serum half-life was 91.7 +/- 28.1 h, and similar pharmacokinetics were noted after intravenous administration. Subsequently, four patients with catheter-related exit site or tunnel infections received a 30-mg/kg i.p. dose of vancomycin and displayed a similar kinetic pattern. This method of administering vancomycin achieved therapeutic serum and end-dwell dialysate concentrations over a 1-week period, represents a simple, cost-effective therapy which avoids the possibility of infusion-related toxicity, and deserves further investigation in patients with continuous ambulatory peritoneal dialysis-related peritonitis.

Humans↗

PubMed1987

Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.

Adult↗