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PubMed2003

Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children.

BACKGROUND: Pediatric infections caused by resistant Gram-positive infections are an increasing concern with limited treatment options. Linezolid, a new oxazolidinone, is active against staphylococci, streptococci and enterococci. OBJECTIVE: To assess clinical efficacy and safety of linezolid vs.vancomycin in antibiotic-resistant Gram-positive infections in children. DESIGN Hospitalized children (birth to 12 years of age) with nosocomial pneumonia, complicated skin/skin structure infections, catheter-related bacteremia, bacteremia of unknown source or other infections caused by Gram-positive bacteria were randomized 2:1 to receive linezolid intravenously followed by oral linezolid or vancomycin and then by an appropriate oral agent. Treatment duration was 10 to 28 days. RESULTS: There were 321 patients enrolled (linezolid 219, vancomycin 102). Clinical cure rates were 79% vs.74% (P = 0.36) and 89% vs.85% (P = 0.31) for linezolid and vancomycin in intent-to-treat and clinically evaluable patients, respectively. Cure rates were similar by age and infection diagnosis. Pathogen eradication rates in microbiologically evaluable patients were high for linezolid and vancomycin, respectively, for methicillin-susceptible S. aureus (95% vs.94%; P = 0.82), methicillin-resistant S. aureus (88% vs.90%; P = 0.89) and methicillin-resistant coagulase-negative staphylococci (85% vs.83%, P = 0.87). In clinically evaluable patients, linezolid-treated patients required significantly fewer days of intravenous therapy compared with vancomycin-treated patients (8.0 +/- 4.8; 10.9 +/- 5.8 days, respectively; P < 0.001). In addition significantly fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19% vs.34%, respectively; P = 0.003). Hematologic events were uncommon and similar between treatment groups. CONCLUSIONS: Linezolid was well-tolerated and as effective as vancomycin in treating serious Gram-positive infections in children.

Acetamides↗

PubMed2003

Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates.

BACKGROUND: Gram-positive infections caused by susceptible and resistant strains of Staphylococcus aureus, coagulase-negative staphylococci and enterococci are increasing problems in neonates. Linezolid, a new oxazolidinone, is active against these pathogens and has recently been approved by the Food and Drug Administration for treating Gram-positive infections in pediatric patients. OBJECTIVE: To compare the clinical efficacy and safety of intravenous and oral linezolid with vancomycin (10 to 15 mg/kg every 6 to 24 h) in neonates (age 0 to 90 days). METHODS: Hospitalized infants with known or suspected hospital-acquired pneumonia, complicated skin or skin structure infections, bacteremia or other infections (e.g. pyelonephritis, abdominal abscess) were eligible. Test-of-cure clinical response was evaluated at follow-up. RESULTS: Sixty-three neonates, randomized 2:1 to linezolid (n = 43) or vancomycin (n = 20) were included in the intent-to-treat group. Clinical cure rates at follow-up in the intent-to-treat group were higher, but not significantly different, for linezolid vs. vancomycin (78% vs. 61%; P = 0.196). Corresponding cure rates in clinically evaluable patients were 84% vs. 77% (P = 0.553) for linezolid and vancomycin, respectively. Pathogen eradication rates were as follows in the linezolid and vancomycin groups, respectively: S. aureus (67% vs. 60%; P = 0.850); coagulase-negative staphylococci (88% vs. 100%; P = 0.379); and enterococci (71% vs. 0%; P = 0.168). Results for hematology and chemistry assays were similar between treatment groups. Fewer linezolid-treated neonates had drug-related adverse events than vancomycin-treated neonates (12% vs. 32%; P = 0.058). CONCLUSIONS: Linezolid is well-tolerated and as effective as vancomycin in the treatment of resistant Gram-positive infections in neonates.

Acetamides↗

PubMed2005

Vancomycin elimination in human infants with intrauterine growth retardation.

BACKGROUND: Intrauterine growth retardation (IUGR) results in substantial decrease in nephron number and renal and hepatic organ mass in experimental animals and newborn infants. Because the liver and the kidneys are the major organs for drug biotransformation and elimination, any decrease in their size and function may lead to impaired metabolism and elimination of drugs in newborns with IUGR. Our objective was to test the hypothesis that IUGR results in prolonged renal elimination of vancomycin in newborns. METHODS: Small for gestational age (SGA) infants (n = 20) were matched with appropriate for gestational age (AGA) infants (n = 123). Steady state peak and trough serum concentrations were used to calculate vancomycin clearance (Cl), volume of distribution (Vd) and half-life (t(1/2)) for each subject. Pharmacokinetic profiles were compared between groups. RESULTS: Overall, Cl, Vd and t(1/2) of vancomycin were the same between groups. However, stratification showed decreased Cl in those SGA versus AGA newborns 3-4 weeks old and in those newborns with a postconceptional age of 27-29 weeks. There was no difference in Vd, normalized for weight, between SGA and AGA babies. The half-life of vancomycin was similar across most groups but was prolonged in SGA newborns aged 3-4 weeks. CONCLUSIONS: Vancomycin Cl differs between SGA and AGA newborns. This difference is greatest early in life and normalizes between groups after the fourth week of life or after 29 weeks postconceptionally. Normalized Vd is similar between SGA and AGA newborns. The elimination of vancomycin is comparable between SGA and AGA infants, except before the fifth week of life, when SGA newborns may eliminate the drug more slowly. Specific vancomycin dose recommendations for SGA versus AGA neonates may therefore be justified during the first month of life.

Area Under Curve↗

PubMed1995

The effect of oral vancomycin on chronic idiopathic constipation.

BACKGROUND: A case study reporting the efficacy of oral vancomycin in a patient with chronic idiopathic constipation prompted this prospective trial of oral vancomycin in eight female patients (aged 21-61 years) with severe constipation resistant to the action of dietary fibre. METHODS: The trial was divided into two consecutive 14-day periods. During the first period, each patient was given ispaghula, 3.5 g twice a day, and during the subsequent period they took 250 mg vancomycin t.d.s. per os, as well as the fibre supplement. During both periods they collected stools and recorded daily bowel symptoms (stool frequency, straining, stool consistency, subjective stool volume) in a diary. At the end of each period whole gut transit time and the breath hydrogen response to a standard meal, giving oro-caecal transit time, were measured along with gastrointestinal symptoms which were assessed on visual analogue scales. RESULTS: Vancomycin caused a significant improvement in stool frequency, consistency, ease of defecation and the amount of stool patients felt they produced (all P < 0.05), but objective measures of daily stool weight and whole gut or oro-caecal transit time were not significantly different. Basal breath hydrogen levels were higher after vancomycin treatment in seven out of eight patients. One patient experienced a complete remission of symptoms when she took vancomycin and remains in remission after 14 months. This patient showed no elevation in basal breath hydrogen level. CONCLUSION: Although this study does not support the use of vancomycin for most patients with constipation, the results suggest that modification of the intraluminal flora may be of value in the treatment of the occasional case of idiopathic constipation.

Administration, Oral↗

PubMed2006

Population pharmacokinetic modelling of gentamicin and vancomycin in patients with unstable renal function following cardiothoracic surgery.

AIMS: To describe the population pharmacokinetics of gentamicin and vancomycin in cardiothoracic surgery patients with unstable renal function. METHODS: Data collected during routine care were analyzed using NONMEM. Linear relationships between creatinine clearance (CL(Cr)) and drug clearance (CL) were identified, and two approaches to modelling changing CL(Cr) were examined. The first included baseline (BCOV) and difference from baseline (DCOV) effects and the second allowed the influence of CL(Cr) to vary between individuals. Final model predictive performance was evaluated using independent data. The data sets were then combined and parameters re-estimated. RESULTS: Model building was performed using data from 96 (gentamicin) and 102 (vancomycin) patients, aged 17-87 years. CL(Cr) ranged from 9 to 172 ml min(-1) and changes varied from -76 to 58 ml min(-1) (gentamicin) and -86 to 93 ml min(-1) (vancomycin). Inclusion of BCOV and DCOV improved the fit of the gentamicin data but had little effect on that for vancomycin. Inclusion of interindividual variability (IIV) in the influence of CL(cr) resulted in a poorly characterized model for gentamicin and had no effect on vancomycin modelling. No bias was seen in population compared with individual CL estimates in independent data from 39 (gentamicin) and 37 (vancomycin) patients. Mean (95% CI) differences were 4% (-3, 11%) and 2% (-2, 6%), respectively. Final estimates were: CL(Gent) (l h(-1)) = 2.81 x (1 + 0.015 x (BCOV(CLCr)-BCOV(CLCr Median)) + 0.0174 x DCOV(CLCr)); CL(Vanc) (l h(-1)) = 2.97 x (1 + 0.0205 x (CL(Cr)-CL(Cr Median))). IIV in CL was 27% for both drugs. CONCLUSIONS: A parameter describing individual changes in CL(cr) with time improves population pharmacokinetic modelling of gentamicin but not vancomycin in clinically unstable patients.

Adolescent↗

PubMedDate not supplied

Medullary plasma pharmacokinetics of vancomycin after intravenous and intraosseous perfusion of the proximal phalanx in horses.

OBJECTIVE: To study the pharmacokinetics of vancomycin in plasma obtained from the medullary sinusoids of the proximal phalanx (P1) after intravenous (IV) and intraosseous (IO) regional limb perfusion (RLP). STUDY DESIGN: Experimental study. ANIMALS: Twelve horses. METHODS: IV and IO RLP were performed in 2 groups (n = 6) of horses. Vancomycin hydrochloride (300 mg in 60 mL 0.9% NaCl) was randomly infused in 1 front limb, with the contralateral limb as control (60 mL 0.9% NaCl). A hole was drilled in the lateral cortex of P1, and blood samples from the medullary sinusoids of P1 were collected before infusion, and 15, 30, 45, 65, and 90 minutes after beginning infusion. Samples were centrifuged and plasma vancomycin concentrations determined. Vancomycin concentrations were compared over time and between routes using a 2-way repeated measures ANOVA. Pharmacokinetic variables were compared with a Kolmogorov-Smirnov test. Significance was set at P<.05. RESULTS: No vancomycin-induced clinical side effects such as lameness or swelling were observed. Both techniques, IV and IO, produced high vancomycin concentrations in the sinusoidal plasma of the P1, which remained above the minimum inhibitory concentration value for methicillin-resistant Staphylococcus aureus (MRSA) during the 90 minutes study. Concentrations and pharmacokinetic variables were not significantly different comparing both routes. CONCLUSIONS: IV and IO routes produced similar antimicrobial perfusion of the medullary cavity of P1. CLINICAL RELEVANCE: Either IV or IO routes for perfusion are likely to be equally selected when planning RLP with vancomycin.

Analysis of Variance↗

PubMed1993

Teicoplanin versus vancomycin in the empirical treatment of febrile neutropenic patients.

Gram-positive infections have become prevalent among neutropenic patients with cancer. A prospective, randomized, double-blind trial of teicoplanin, 6 mg/kg every 12 h for three doses then every 24 h, versus vancomycin hydrochloride, 15 mg/kg every 12 h, in the empirical treatment of febrile neutropenic patients was undertaken among 50 consecutive patients with haematological malignancy. The patients also received piperacillin sodium, 3 g every 4 h, and tobramycin sulphate, 1.5-2 mg/kg every 8 h. Both groups (25 teicoplanin and 25 vancomycin) were comparable in age, sex, renal function, underlying disease and concurrent therapy. Among 22 patients (44%) with culture-proven infection, Gram-positive organisms were isolated in 15 (9 with bacteraemia) and Gram-negative in 11 (4 with bacteraemia). Mixed or polymicrobial infection occurred in 8 patients. Serum 1-h peak and trough levels at steady state were 41 +/- 15 and 12 +/- 3 mg/l for teicoplanin (at 14 +/- 4 days), and 40 +/- 10 and 8 +/- 5 mg/l for vancomycin (at 0.9 +/- 0.6 days). Mean elimination half-life and apparent volume of distribution at steady state were 80.5 +/- 21.5 h and 1.4 +/- 0.8 l/kg for teicoplanin, and 5.6 +/- 1.8 h and 0.6 +/- 0.2 l/kg for vancomycin. Empirical antimicrobial therapy was successful in 23 teicoplanin and 21 vancomycin patients, respectively (p = 0.67; two-tailed Fisher's exact test). Nephrotoxicity (serum creatinine > 110 mmol/l), however, was more common among vancomycin patients (10 versus 2; p = 0.02), while termination of treatment due to adverse effects was also more common among vancomycin patients (10 versus 2; p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1996

In-vivo clearance study of vancomycin in rats.

The renal handling of vancomycin in rats and the effects of various drugs (probenecid, cimetidine and quinidine) on urinary excretion of the antibiotic were investigated by in-vivo clearance. The vancomycin-to-inulin excretion ratio (ER) was greater than unity at various infusion rates of vancomycin. Quinidine, co-administered with vancomycin, significantly decreased the total, renal and net secretory clearance of the antibiotic. Cimetidine also decreased, though not significantly, the secretory clearance of vancomycin by about 20%, but probenecid did not. These results suggested that vancomycin is secreted in renal tubules in rats, and that quinidine decreases the total clearance of vancomycin partly by inhibiting its tubular secretion in the kidney.

Analysis of Variance↗

PubMed2001

[Epidemiological study on vancomycin-resistant enterococci from fecal samples in the east area of Japan].

Recently, Vancomycin-resistant enterococci (VRE) have become important nosocomial pathogens in the world. In Japan, the VRE-infection was first reported in 1996. However, an epidemiological study on VRE has not been aggressively done in Japan. We conducted a survey study to explore the incidence and antimicrobial susceptibility of vancomycin-resistant enterococci isolated from fecal samples at 45 hospitals in the east area of Japan (Kanto, Koshinetsu, Tohoku, and Hokkaido) during June 1998 to March 1999. The Enterococcosel agar containing vanocomycin (BBL) was used for screening VRE from fecal samples in each hospital. The susceptibilities of the isolates to 8 antimicrobials were determined by the broth microdilution method and the definitions of resistance were based on current standards of the NCCLS standards. The VRE genotypes (vanA, vanB, vanC1, and van C2/3) were confirmed by amplifying the respective genes by PCR. Eight hundred and ninety four strains of enterococci were tested by the microtiter plates hybridization method (WAKUNAGA SEIYAKU, Japan). One thousand five hundred eighty three strains of enterococci were collected from 6,914 patients in 45 hospitals. These strains included 72 (4.5%) strains Enterococcus faecalis, 33 (2.1%) strains Enterococcus faecium, 17 (1.1%) strains Enterococcus avium, 1,040 (65.7%) strains Enterococcus gallinarum, 386 (24.4%) strains Enterococcus cassliflavus, and 35 (2.2%) strains Enterococcus flavescens. These strains of vancomycin-resistant E. faecalis were isolated from 3 patients, two of these 3 strains had van A gene and other one had van B gene. Those 3 strains were in the Kanto area, and 2 of 3 strains were in Tokyo, Generally, though van A type VRE was highly resistaant to both vancomycin and teicoplanin. In our study, two strains of van A type E. faecalis were highly resistant to vancomycin (MICs > 128 micrograms/ml) and susceptible to teicoplanin with MICs 4 micrograms/ml. Those two strains were different in susceptibilities of minocycline and ofloxacin. The result of the analysis of PFGE had also different patterns. VanB type E. fecalis was highly resistant to vancomycin and susceptible to teicoplanin (MICs 0.25 microgram/ml). For ampicillin and imipenem, 3 strains of E. faecalis were susceptible (MIC < or = 1 microgram/ml). One of 562 strains of E. gallinarum had vanB and vanC1 genes and was moderately resistant to vancomycin and susceptible to teicoplanin. All strains of E. casseliflavus and E. flavescens had vanC2/C3 gene only. All strains of E. faecium and E. avium did not detect van genes. From this result, it was supposed that VRE were very rare in the east of Japan.

Enterococcus↗

PubMed1986

Bactericidal activity and killing rate of serum in volunteers receiving ciprofloxacin alone or in combination with vancomycin.

Ten healthy volunteers received the following regimen on different days: vancomycin, 500 mg intravenously; ciprofloxacin, 200 mg intravenously; vancomycin plus ciprofloxacin. Concentrations in serum measured microbiologically at the end of infusion and 1 and 6 h after the end of infusion were, respectively (mean [standard deviation] in milligrams per liter): 32.3 (5.5), 14.2 (2.6), and 4 (0.9) for vancomycin and 3.12 (0.86), 0.78 (0.18), and 0.19 (0.05) for ciprofloxacin. Vancomycin concentration was not affected by the simultaneous administration of ciprofloxacin. The serum bacteriostatic and bactericidal (SBA) activities were measured 1 and 6 h after the end of infusion against five strains each of Staphylococcus aureus susceptible and resistant to oxacillin, Staphylococcus epidermidis susceptible and resistant to oxacillin, Corynebacterium strain JK, and Listeria monocytogenes and three strains of Mycobacterum fortuitum. Ciprofloxacin alone provided low SBAs against the tested strains even 1 h after administration. Vancomycin provided adequate SBAs against staphylococci and Corynebacterium strain JK 1 h after administration. None of the regimens tested showed adequate bactericidal activity against L. monocytogenes and M. fortuitum. The combination of vancomycin with ciprofloxacin was indifferent. This was confirmed by studying the rate of killing in serum. Vancomycin plus ciprofloxacin appeared to be promising for the empiric treatment of infection in immunocompromised patients.

Ciprofloxacin↗

PubMed1989

In vitro susceptibility studies of vancomycin-resistant Enterococcus faecalis.

Vancomycin resistance exhibited by Enterococcus faecalis isolates V583, V586, and V587 is described. The vancomycin MICs ranged from 32 to 64 micrograms/ml. Although resistant to vancomycin, the isolates were susceptible to teicoplanin (MIC, less than or equal to 0.5 micrograms/ml). Such a glycopeptide susceptibility profile has not been previously described for E. faecalis. Time kill studies showed that vancomycin resistance adversely affected the synergistic activity that vancomycin and aminoglycoside combinations usually demonstrate against enterococci. However, the ability to detect vancomycin resistance varied with the susceptibility testing method used. Whereas broth microdilution, broth macrodilution, and agar dilution methods detected resistance, disk-agar diffusion and the AutoMicrobic system Gram-Positive GPS-A susceptibility card (Vitek Systems Inc., Hazelwood, Mo.) did not. To detect vancomycin resistance reliably and establish the incidence of such E. faecalis isolates, adjustments in some susceptibility testing methods may be necessary.

Anti-Bacterial Agents↗

PubMed1990

Effects of daptomycin and vancomycin on tobramycin nephrotoxicity in rats.

Daptomycin is a new biosynthetic antibiotic which belongs to a new class of drugs known as lipopeptides. The objective of this study was to evaluate the effects of daptomycin and vancomycin on tobramycin-induced nephrotoxicity. Female Sprague-Dawley rats were treated during 4 and 10 days with either saline (NaCl, 0.9%) or tobramycin at doses of 4 and 40 mg/kg per day (given every 12 h [q12h] intraperitoneally). Each treatment was combined with saline, daptomycin at a dose of 20 mg/kg per day (given q12h subcutaneously), and ancomycin at a dose of 50 mg/kg per day (given q12h subcutaneously). Daptomycin and vancomycin had no effect on the intracortical accumulation of tobramycin. Daptomycin did not accumulate in renal tissue even after 10 days of treatment. Tobramycin given at a dose of 40 mg/kg per day during 10 days induced a significant inhibition of sphingomyelinase activity in the renal cortex (P less than 0.01) and increased cellular regeneration (P less than 0.01), as measured by the incorporation of [3H]thymidine into DNA of the renal cortex. These changes were minimal when daptomycin was combined with tobramycin. Histologically, signs of tobramycin toxicity were also less severe in the presence of daptomycin. The intracortical accumulation of vancomycin was not modified by tobramycin. The sphingomyelinase activity was significantly more inhibited (P less than 0.01) when vancomycin was associated with tobramycin (4 and 40 mg/kg) without affecting the rate of [3H]thymidine incorporation into DNA. Histologically, signs of tobramycin toxicity were not affected by vancomuycin, but the cellular vacuolizations which were also observed in vancomycin-treated animals were still present in the proximal tubular cells of animals that were treated with the combination vancomycin-tobramycin. This study strongly suggests that daptomycin protects animals from tobramycin-induced nephrotoxicity but that vancomycin may enhance the effect of tobramycin. We conclude that daptomycin is safe and protects kidney cells from tobramycin-induced nephrotoxicity.

Animals↗

PubMed1990

Application of a modified bioassay for monitoring serum teicoplanin and vancomycin in febrile neutropenic patients.

Teicoplanin is a glycopeptide antibiotic with a mode of action and spectrum of activity similar to those of vancomycin. Its efficacy and tolerability as empiric therapy and its pharmacokinetic properties in neutropenic patients are being studied in a double-blinded, randomized trial in comparison with those of vancomycin. We report here a modified agar diffusion bioassay which is suitable for monitoring levels of either teicoplanin or vancomycin in serum during combination therapy with beta-lactams, aminoglycosides, and amphotericin B. Serum samples spiked with either teicoplanin or vancomycin gave reproducible results (mean coefficient of variation, 8.8%) regardless of the presence of tobramycin, amikacin, piperacillin, ceftazidime, amphotericin B, or their combinations. Among 25 patients who received teicoplanin at a dosing schedule of 6 mg/kg every 24 h intravenously, steady state was reached after 14.2 +/- 4.0 days, and 1-h peak and trough concentrations of teicoplanin in serum at steady state were 40.8 +/- 15.0 and 12.5 +/- 3.2 mg/liter, respectively. In contrast, among 25 patients who received vancomycin at a dosing schedule of 15 mg/kg every 12 h intravenously, steady state was reached by 24 h, and the 1-h peak and trough concentrations in serum were 37.5 +/- 15.6 and 8.3 +/- 3.8 mg/liter, respectively. The elimination half-lives for teicoplanin estimated by two separate approaches agreed closely with each other: 80.5 +/- 21.5 h by an accumulation model (M. Gilbaldi and D. Perrier, Pharmacokinetics, 2nd ed., p. 121, 1982) and 87.3 +/- 19.3 h as predicted from the degree of renal function (M. Rowland, Clin. Pharmacokinetic 18:184-209, 1990). These values were 14- to 15-fold higher than that for vancomycin (5.6 +/- 1.8 h). Since considerable variability was noted in the pharmacokinetic parameters for both teicoplanin and vancomycin among the individual patients, our data further emphasized the need for frequent monitoring of these drugs during empiric therapy of the febrile neutropenic patient.

Adult↗

PubMed1992

Subcellular localization of tobramycin and vancomycin given alone and in combination in proximal tubular cells, determined by immunogold labeling.

The subcellular localization of tobramycin and vancomycin in the renal cortices of rats was determined with ultrathin sections by immunogold labeling. Four groups of four rats each were treated for 10 days with saline (NaCl, 0.9%), tobramycin at dosages of 20 mg/kg of body weight per 12 h intraperitoneally, vancomycin at dosages of 25 mg/kg/12 h subcutaneously, or the combination tobramycin-vancomycin. On day 11, the animals were killed, and cubes of renal cortex were fixed overnight in phosphate-buffered glutaraldehyde (0.5%), dehydrated in ethanol, and embedded in Araldite 502 resin. Ultrathin sections were made and incubated with sheep antitobramycin antibody followed by protein A-gold (15-nm diameter) complex or rabbit antivancomycin antibody followed by gold (30-nm diameter)-labeled goat anti-rabbit antibody. For the double labeling, incubations were made on opposite sides of the grid. Tobramycin was detected over the lysosomes of proximal tubular cells, but the labeling was concentrated into small areas in the matrix of the lysosomes. Vancomycin was seen over the lysosomes of proximal tubular cells and was distributed uniformly throughout the matrix of the lysosomes. In rats treated with tobramycin-vancomycin, both drugs were still detected in lysosomes of proximal tubular cells. It is concluded that tobramycin and vancomycin accumulate in lysosomes of proximal tubular cells throughout 10 days of treatment and that vancomycin has no effect on the subcellular distribution of tobramycin.

Animals↗

PubMed1992

Effects of amino acids on expression of enterococcal vancomycin resistance.

The effects of various amino acids on vancomycin MICs obtained with resistant enterococci was investigated by using broth dilution testing. For both the type A (i.e., possessing transferable resistance to teicoplanin and vancomycin) and the type B (i.e., possessing teicoplanin susceptibility and nontransferable vancomycin resistance) resistant strains, vancomycin MICs in the presence of glycine were substantially lower than those in unsupplemented broth (range of MIC decrease, 8- to 128-fold). No such effect was seen with Enterococcus gallinarum AIB-39 or with the susceptible control Enterococcus faecalis ATCC 29212. Further testing of two type B strains (E. faecalis V583 and V583-2) showed that certain other amino acids (i.e., D-methionine, D-serine, D-alanine, and D-phenylalanine) had effects similar to that of glycine. Results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis with membrane preparations from these strains revealed the production of vancomycin-inducible proteins of sizes comparable to those describe for other enterococcal isolates that exhibit acquired vancomycin resistance. Even in the presence of 0.2 M glycine, the inducible proteins were produced. These results indicate that certain amino acids specifically interfere with the mechanism(s) of acquired vancomycin resistance in enterococci and that the nature of interference probably involves inhibition or circumvention of the inducible proteins' functions.

Amino Acids↗

PubMed1992

Vancomycin resistance in Enterococcus gallinarum.

The vancomycin resistance expressed by several strains of Enterococcus gallinarum was studied. Resistance was expressed constitutively, as demonstrated by analysis of growth and inhibition of peptidoglycan synthesis. E. gallinarum strains were moderately resistant to vancomycin (MIC, 16 micrograms/ml) but were as susceptible as vancomycin-susceptible enterococci to the glycopeptides, teicoplanin, A35512B, A47934, A4103A, and A41030E and the glycopeptide actaplanins A1, B2, and C1. Vancomycin resistance in E. gallinarum was inhibited by beta-lactam antibiotics at concentrations that saturated penicillin-binding protein 6 (PBP 6), as demonstrated by binding competition experiments. Spontaneous mutants (frequency, 10(-8)) were two- to fourfold more resistant to beta-lactam inhibition of vancomycin resistance than the parent strain. PBP binding competition experiments suggested that PBP 6 in the mutants bound less cefotaxime, while binding of penicillin and cefoxitin was unaffected. Both a bioassay method and high-performance liquid chromatography showed that E. gallinarum membranes have enzymatic activity which modifies a model pentapeptide yielding a product that is thought to be a tetrapeptide. This activity could be a D,D-carboxypeptidase. In both the parent E. gallinarum strain and its derivatives that were resistant to the synergistic drug combination, the activity was inhibited by beta-lactams at concentrations which correlated with those that inhibit vancomycin resistance and those that saturate PBP 6. These results suggest the possibility that PBP 6 may be involved in the vancomycin resistance of E. gallinarum and that the putative D,D-carboxypeptidase activity seen in E. gallinarum membranes may be attributable to PBP 6.

Anti-Bacterial Agents↗

PubMed1993

Effect of obesity on vancomycin pharmacokinetic parameters as determined by using a Bayesian forecasting technique.

Few data exist concerning the effect of obesity on the pharmacokinetic parameters of vancomycin. The purpose of this investigation was to assess the effect of obesity on vancomycin pharmacokinetic parameters in 95 nonobese and 135 obese adult patients (age range, 18 to 92 years) receiving vancomycin. All subjects had normal renal function as defined by a creatinine concentration in serum of < or = 1.5 mg/dl (mean estimated creatinine clearance +/- 1 standard deviation, 76 +/- 34; range, 23 to 215 ml/min). Vancomycin concentrations in serum were determined by the fluorescence polarization immunoassay. All data for vancomycin concentration in serum versus time for each course of therapy were fitted by using a two-compartment Bayesian forecasting program. Subjects were stratified into nine groups on the basis of the percent difference between actual body weight (ABW) and lean body weight (LBW) (> -10%, -10 to 0%, > 0 to 10%, > 10 to 20%, > 20 to 30%, > 30 to 40%, > 40 to 50%, > 50 to 60%, > 60%). Analysis of variance with post hoc Scheffe's testing revealed that statistically significant differences occurred in terminal disposition half-life (t1/2 beta) between the extremes of modestly obese (group 4) and morbidly obese (group 9, P < 0.05) patients. Similar analysis with distribution volume (V) identified significant differences in patients at or near their LBW (groups 2 to 4) and patients who were morbidly obese (groups 8 and 9, P < 0.05). Multiple regression models for the pharmacokinetic parameters V, t1/2beta, and vancomycin total body clearance were developed to assess the joint predictive power of LBW, ABW, and percent over LBW, controlling for the effects of age, initial creatinine concentration in serum, initial creatinine clearance, and gender. In the final model for V, both ABW and percent over LBW were independent and significant predictors. For total body clearance, only ABW was significant and predictive. Percent over LBW was a significant and independent predictor of t1/2beta. LBW is not predictive of these pharmacokinetic parameters and should not be used for initial dosing. On the basis of these data, ABW appears to be superior to LBW for calculating initial dose requirements for vancomycin.

Adolescent↗

PubMed1993

Constitutively vancomycin-resistant Enterococcus faecium resistant to synergistic beta-lactam combinations.

Vancomycin resistance among enterococci has recently been recognized. Synergy between vancomycin and penicillin has been shown in vitro for isolates of Enterococcus faecium resistant to both of these antibiotics. We describe three isolates of vancomycin-resistant E. faecium which demonstrate unique phenotypic characteristics. The isolates exhibited high-level resistance to both vancomycin and teicoplanin, consistent with the VanA phenotype. However, resistance in these isolates could not be induced or cured, and mating experiments failed to detect a transfer of resistance. The combination of vancomycin and penicillin did not significantly change the MIC of penicillin for any of the three isolates. Immunoblotting with polyclonal anti-VanB antibody showed no reaction with the cellular proteins of these strains. Probing with a vanA oligonucleotide revealed hybridization with chromosomal but not plasmid DNA. The mechanism of constitutive resistance of those strains remains unclear. A second mutational change, perhaps involving PBP 5, may explain the presence of resistance to synergistic combination penicillin-vancomycin therapy. In vitro evaluation of penicillin-vancomycin should be carried out in all clinical cases where this therapeutic regimen is being considered.

Adult↗