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M J Rybak

Publications and source records attributed to M J Rybak.

At least 19 recordsLinked to original sources
PubMed1992

In vitro pharmacodynamic effects of concentration, pH, and growth phase on serum bactericidal activities of daptomycin and vancomycin.

Clinical trials with daptomycin were halted in December 1990 because of treatment failures including two resistant Staphylococcus aureus strains. High protein binding of daptomycin (> 90%) and the lower-than-expected concentrations in serum with the dosage regimen of 3 mg/kg of body weight every 12 h may have contributed to these failures. To evaluate the effect that higher concentrations would have on bactericidal activity measured by time-kill curves, peak and trough concentrations were estimated for dosage regimens of 3, 5, and 10 mg/kg every 12 h. MICs, MBCs, and killing curves for daptomycin and vancomycin were performed by using the estimated concentrations with four S. aureus strains obtained from patients who failed daptomycin therapy for endocarditis. MICs and MBCs of daptomycin demonstrated a greater inoculum effect than those of vancomycin; MICs and MBCs of daptomycin increased three- to fourfold, but those of vancomycin increased only one- to twofold when the inoculum was increased from 5 x 10(5) to 5 x 10(7) CFU/ml. No pH-dependent effect on MICs or MBCs was seen. Strenuous experimental conditions were chosen: high inoculums (5 x 10(7) CFU/ml), extremes of pH (6.4, 7.4, and 8), and stationary and exponentially growing organisms; and all experiments completed in the presence of pooled human serum. Daptomycin exhibited concentration-dependent killing and statistically faster kill rates than vancomycin against stationary- or exponential-growth-phase organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. The results indicate that the use of higher dosage regimens with compounds similar to daptomycin may be capable of overcoming the effects of pH, high inoculum, and protein binding.

Blood Bactericidal Activity↗
PubMed1992

Pharmacodynamics of once-daily amikacin in various combinations with cefepime, aztreonam, and ceftazidime against Pseudomonas aeruginosa in an in vitro infection model.

The pharmacodynamics of once-daily amikacin administered as monotherapy and in combination with aztreonam, ceftazidime, and cefepime against Pseudomonas aeruginosa ATCC 27853 and clinical isolate 16690 (moderately susceptible to ceftazidime) were investigated with an in vitro model of infection over a 24-h period. Monotherapy with aztreonam, ceftazidime, and cefepime and combinations of aztreonam with cefepime or ceftazidime were also studied. MICs and MBCs were determined for viable organisms at 24 h to test for the development of resistance. Once-daily amikacin demonstrated killing activity over the initial 8 h superior to those of all other drugs administered as monotherapy against both strains tested (P < 0.01). Regrowth by 24 h was greatest for the amikacin regimen (P < 0.01) but was apparent for all monotherapy regimens against both strains. No changes in susceptibilities were observed. All combination therapies containing once-daily amikacin achieved 99.9% reductions in log10 CFU/ml by 2.0 h against both strains, with no regrowth of organisms at 24 h. Aztreonam-cefepime and -ceftazidime combinations required approximately 5 to 6 h to achieve a 99.9% reduction in log10 CFU/ml. Although there was no difference in time to the 99.9% kill between the aztreonam-cefepime and -ceftazidime regimens against either strain, the killing activity of these combinations was significantly less than those of regimens containing once-daily amikacin (P < 0.01). Minor differences in the initial susceptibilities of beta-lactams and the monobactam aztreonam against P. aeruginosa may not be important for therapeutic outcomes when used in combination with single-daily aminoglycoside therapy.

Amikacin↗
PubMed1992

Pharmacokinetics and bactericidal rates of daptomycin and vancomycin in intravenous drug abusers being treated for gram-positive endocarditis and bacteremia.

The pharmacokinetics and bactericidal killing rates (BR) of daptomycin (D) and vancomycin (V) in 12 intravenous drug abusers (6 treated with daptomycin and 6 treated with vancomycin) were evaluated. Pharmacokinetic parameters were determined from multiple serum samples drawn at steady state over a 12-h dosing interval after intravenous infusions of 3 mg of D per kg of body weight and 1,000 mg of V. The BRs were determined from the 1- and 6-h serum samples by using four isolates of Staphylococcus aureus (three methicillin susceptible and one methicillin resistant) obtained from the patients enrolled in the study. Peak serum daptomycin concentrations were lower and volumes of distribution were higher than reported in healthy volunteers. Although not statistically different, D clearance was 22% higher than reported in healthy volunteers. V pharmacokinetics were similar to those reported in previous studies. Daptomycin's BRs, although comparable to those of V in patients' serum, were significantly decreased compared with those found in broth. This may be related to the high degree of protein binding of D (93% versus 50% for V). Conversely, the BRs of V in serum were significantly greater than those in broth. The BRs of D and V in broth were greater when killing curves were performed with test strains in logarithmic versus stationary-phase growth. The ability to kill organisms in stationary phase may be an important factor in determining the performance of an antibiotic in deep-seated infections such as endocarditis.3+

Adult↗
PubMed1992

CI-960, a new fluoroquinolone, for therapy of experimental ciprofloxacin-susceptible and -resistant Staphylococcus aureus endocarditis.

CI-960 is a new fluoroquinolone with enhanced in vitro activity against gram-positive pathogens. The efficacy of the drug was compared with that of vancomycin by using the rabbit model of nafcillin- and ciprofloxacin-susceptible and -resistant Staphylococcus aureus endocarditis. Animals received intravenous therapy with CI-960, 20 mg/kg of body weight every 8 h, or vancomycin, 17.5 mg/kg every 6 h, for 4 days. In a comparison with the effects on untreated controls, both antimicrobial agents effectively cleared bacteremia and significantly reduced bacterial counts in vegetations and tissues of animals infected with any of the test strains. In some cases, the efficacy of CI-960 was superior to that of vancomycin. The therapeutic activity of CI-960 was reduced, but still very good, against ciprofloxacin-resistant strains. One rabbit infected with such a strain and treated with CI-960 was found to harbor a small number of vegetation-associated organisms resistant to the drug at fivefold its original MIC; this was associated with a microbiological, but not a clinical, failure of therapy. We conclude that CI-960 is as effective as vancomycin is in this model of a serious systemic S. aureus infection, including that caused by strains resistant to ciprofloxacin. Increases in CI-960 MICs may develop during therapy of infections caused by strains highly resistant to ciprofloxacin, but they appear unlikely to occur in ciprofloxacin-susceptible strains.

Animals↗
PubMed1992

Absence of "red man syndrome" in patients being treated with vancomycin or high-dose teicoplanin.

Twenty-five febrile patients with a history of intravenous drug use who were receiving either vancomycin (15 patients) or teicoplanin (10 patients) as part of a multicenter, double-blind, randomized, clinical efficacy trial were enrolled, upon receipt of their first dose of antibiotic, into a study to evaluate the effect of 1 g of vancomycin and high-dose teicoplanin (30 mg/kg of body weight) on histamine release and the occurrence of "red man syndrome" (RMS). In addition, 10 healthy volunteer subjects (HVS) were randomized to receive either 1 g of vancomycin intravenously or a saline infusion in a double-blind, crossover design study. Patients and HVS were observed for the presence of erythema, flushing, pruritus, and hypotension during and for up to 1 h postinfusion by a blinded investigator. Histamine concentrations in plasma were measured at baseline and during and after drug infusion. No significant differences were noted in baseline temperature between patients (vancomycin recipients, 102.3 degrees F [39.1 degrees C]; teicoplanin recipients, 102.4 degrees F [39.1 degrees C]) or incidence of bacteremia (7 of 15 vancomycin recipients; 5 of 10 teicoplanin recipients). There were no significant differences in peak vancomycin concentrations in the sera of patients (40.8 micrograms/ml) and HVS (49.9 micrograms/ml). There were no reactions consistent with RMS in any patient who received teicoplanin (0 of 10); there was a significant difference in the occurrence of RMS in patients in comparison with that in HVS (0 of 15 patients, 9 of 10 HVS; P less than 0.001) who received vancomycin. The predominant reaction was erythema and pruritus. Histamine concentrations in plasma and the area under the histamine plasma concentration-time curve were highly variable within groups and were not statistically different between patients and HVS. The incidence of RMS secondary to vancomycin or teicoplanin in our patient population appears to be low and consistent with clinical observations. Similar to previous investigations, RMS secondary to vancomycin in HVS was high (90%). However, we found no relationship between the histamine concentration in plasma or the area under the plasma histamine concentration-time curve and the severity of RMS in HVS. The reason for the discrepancy of RMS in patients versus that in HVS in unknown, but it may be related to a blunted effect of glycopeptides to produce the reaction in the presence of infection or it may be specific to our patient population.

Adult↗
PubMed1992

Ofloxacin clinical pharmacokinetics.

Ofloxacin is a new fluoroquinolone with a spectrum of activity similar to other fluoroquinolones with activity which includes Chlamydia trachomatis, Mycobacterium spp., Mycoplasma spp. and Legionella pneumophila. Through its additional mechanisms of action, ofloxacin may be less susceptible to the development of resistance from Staphylococcus aureus commonly seen with currently available fluoroquinolones. The impact of these findings cannot be evaluated without further clinical experience. The pharmacokinetics of ofloxacin are characterised by almost complete bioavailability (95 to 100%), peak serum concentrations in the range of 2 to 3 mg/L after a 400mg oral dose and an average half-life of 5 to 8h. In comparison with other available quinolones, elimination is more highly dependent on renal clearance, which may lead to more frequent dosage adjustments in patients with impaired renal function. Ofloxacin appears less likely to affect the pharmacokinetics of drugs (e.g. theophylline) which commonly interact with fluoroquinolones such as ciprofloxacin and enoxacin. The properties of ofloxacin make it a therapeutic alternative to currently available fluoroquinolones.

Absorption↗
PubMed1992

Pharmacy-based antimicrobial-monitoring service.

A pharmacy-based antimicrobial-monitoring service at a university teaching hospital is described. The service was developed and implemented by the pharmacy department in 1987. Antimicrobial drugs that can be misused, that are expensive, or for which bacterial resistance is a concern were targeted. When a pharmacist receives an order for a targeted antimicrobial, an antimicrobial-monitoring card is completed. Monitored drugs meeting approved criteria are dispensed as ordered. When the antimicrobial does not meet the criteria, the pharmacist contacts the physician and suggests an alternative. If the alternative is not accepted, the infectious diseases service is contacted and then informs the pharmacy department about the status of the drug. The agent is dispensed if no response is received within two hours. Qualified staff pharmacists rotate through the position of antimicrobial pharmacist, whose responsibilities include reviewing antimicrobial use throughout the hospital, checking relevant laboratory test results, and recommending adjustments to regimens. From July 1989 to June 1990, 3546 orders for monitored antimicrobials were reviewed; of these, 86% met the criteria, 9% did not meet the criteria but were approved, 2% were for drugs that were replaced by alternative therapies, 1% were for agents that were dispensed because the pharmacist was not contacted, and 2% represented medical staff overrides or drugs dispensed inappropriately. Pharmacist and physician compliance with the monitoring policy has been high. A positive, constructive, and educational relationship exists between pharmacists and physicians vis-à-vis the service. A pharmacy-based antimicrobial-monitoring service has been accepted by pharmacists and physicians and appears to be having a positive impact on prescribing habits.

Anti-Infective Agents↗
PubMed1991

Influence of subject age on the inhibition of oxidative metabolism by ciprofloxacin.

Case reports suggest that the magnitude of inhibition of oxidative metabolism produced by ciprofloxacin may be greater in elderly subjects. We examined the effect of oral ciprofloxacin on antipyrine disposition in 13 young (ages, 23 to 34 years) and 9 elderly (ages, 65 to 82 years) healthy volunteers. Ciprofloxacin decreased antipyrine oral clearance in young and elderly subjects (P less than 0.05), with the average decreases being similar in both groups (23.3% for the young subjects and 27.9% for the elderly subjects). Ciprofloxacin concentrations in serum were significantly higher (mean, 57%) in the elderly. The formation clearance of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was also significantly decreased in both groups of subjects; however, norantipyrine formation, accounting for 15 to 20% of antipyrine clearance, was reduced only in the elderly. These results suggest that elderly subjects are not more sensitive to the inhibitory effect of ciprofloxacin on antipyrine metabolism. However, careful clinical monitoring is necessary with all patients, irrespective of age, taking ciprofloxacin concomitantly with drugs primarily eliminated by the cytochrome P-450 system.

Adult↗
PubMed1991

Teicoplanin pharmacokinetics in intravenous drug abusers being treated for bacterial endocarditis.

The pharmacokinetics of teicoplanin were determined after multiple 30-min intravenous infusions of 10 to 15 mg/kg every 12 to 24 h in 11 intravenous drug abuse (IVDA) patients being treated for bacterial endocarditis. Multiple serum samples were obtained over 7 to 14 days. Twenty-four-hour urine collections were obtained on days 1 and 5. Serum concentration-time data were analyzed by using multiple-dose pharmacokinetic analysis (NONLIN84). Results were compared with pharmacokinetic parameters derived from previous studies in normal healthy volunteers following multiple intravenous infusions of teicoplanin (3 to 6 mg/kg/day). Total and renal clearances of teicoplanin in IVDA patients were found to be significantly greater and more highly variable than those observed previously in normal healthy volunteers. As a result, predicted steady-state trough concentrations in serum may vary up to fivefold. The mechanism responsible for this variation appears to be related to the glomerular filtration rate. In IVDA patients, individualized teicoplanin dosage may be required in the treatment of bacterial endocarditis.

Adult↗
PubMed1991

Comparative effect of protein binding on the killing activities of teicoplanin and vancomycin.

The effect of protein binding on the activity of teicoplanin against Staphylococcus aureus was evaluated. Bactericidal rates of teicoplanin in cation-supplemented Mueller-Hinton broth (SMHB) and in a 1:1 mixture of pooled human serum and cation-supplemented Mueller-Hinton broth (PHS-SMHB) were compared with those of vancomycin. Eight concentrations of each drug ranging from 15 to 150 micrograms/ml were studied in two series which correspond to the concentrations in serum achieved with low- (6 mg/kg of body weight once daily) and high-dose (30 mg/kg once daily) teicoplanin. Overall, the bactericidal rate of teicoplanin was lower than that of vancomycin. In the presence of serum, the bactericidal rate of teicoplanin in PHS-SMHB was lower than that in SMHB, often resulting in only one log10 drop in CFU over a 24-h period. There was no statistical difference in the bactericidal rates of high- and low-concentration teicoplanin in either medium. Additionally, concentration-dependent killing in SMHB was not evident with either agent. The bactericidal rates of teicoplanin and vancomycin in a 1:1 mixture of serum ultrafiltrate and SMHB at 60 micrograms/ml were also studied. It was noted that the bactericidal rate of neither agent was affected by the presence of serum ultrafiltrate. This finding is consistent with teicoplanin's high degree of protein binding (reported to be greater than 90% in undiluted serum) and further substantiates the hypothesis that only the free drug is active against microorganisms. These data support protein binding as being a factor in teicoplanin activity against S. aureus.

Anti-Bacterial Agents↗
PubMed1991

Development of resistance to fleroxacin during therapy of experimental methicillin-susceptible Staphylococcus aureus endocarditis.

The efficacy of fleroxacin was compared with that of vancomycin by using the rabbit model of methicillin-susceptible Staphylococcus aureus endocarditis. Animals received intravenous therapy with fleroxacin, 30 mg/kg every 8 h, or vancomycin, 17.5 mg/kg every 6 h, for 4 days. Both antimicrobial agents effectively cleared bacteremia and significantly reduced bacterial counts in vegetations and tissues compared with those in untreated controls. However, resistance to fleroxacin at 5- and 10-fold the MIC arose in the test strain of S. aureus in 73 and 27%, respectively, of animals that received the drug. Resistant isolates were found mainly in vegetations and were composed of up to 7% of the residual population recovered from that site. We conclude that fleroxacin is as effective as vancomycin in this model of a serious systemic S. aureus infection, but resistance to the drug may develop during therapy. If similar results are found with other strains of S. aureus during therapy with this or other fluoroquinolones, such data, when they are combined with the high incidence of fluoroquinolone resistance among S. aureus isolates being reported from selected institutions, would support the contention that these drugs should not be used as first-line therapeutic agents for S. aureus infections.

Animals↗
PubMed1991

Clinical evaluation of teicoplanin fluorescence polarization immunoassay.

A teicoplanin fluorescence polarization immunoassay (FPIA) developed by International BioClinical (IBC) was evaluated by using serum samples from patients who had been receiving teicoplanin at Detroit Receiving Hospital (DRH) as part of a clinical investigation. Patient samples collected over a 1-year span were assayed at DRH and at IBC, and the results were compared with those of a standard microbiological assay performed at Merrell Dow Research Institute, Indianapolis, Ind. The FPIA has a rapid turnaround time (circa 20 min), utilizes small sample volumes (less than 100 microliters) and is sensitive and accurate in determining concentrations in the range of 5 to 100 micrograms/ml. The intra-assay and interassay coefficient of variation for controls (7, 35, and 75 micrograms/ml) was less than or equal to 13%. Concentrations greater than 100 micrograms/ml must be diluted prior to the assay, which may introduce additional error in determination. The FPIA compared well with the bioassay (r = 0.901) for 193 clinical samples. The results obtained utilizing the FPIA system were reproducible at two different sites, as illustrated by the high degree of correlation between the results at DRH and IBC (r = 0.92). There was less than 7% interference noted when teicoplanin was assayed in the presence of other antibiotics. Patient samples stored for up to 1 year retained their potency: the mean recovery rate in these samples was 107%. The FPIA should be useful for monitoring and adjusting teicoplanin dosage regimens in patients.

Anti-Bacterial Agents↗
PubMed1990

Nephrotoxicity of vancomycin, alone and with an aminoglycoside.

The incidence of nephrotoxicity in patients receiving vancomycin alone or in combination with an aminoglycoside was prospectively evaluated. A total of 231 courses of antibiotic therapy in 224 patients were consecutively monitored over 28-month period. One hundred and sixty-eight patients received vancomycin alone, 63 patients received vancomycin with an aminoglycoside, and 103 patients received gentamicin. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or a 50% increase above baseline, whichever was greater. Eight patients (5%) receiving vancomycin alone, 14 patients (22%) receiving vancomycin with an aminoglycoside, and 11 patients (11%) receiving gentamicin alone were found to have nephrotoxicity. Factors found to be associated with increased risk of nephrotoxicity in patients receiving vancomycin were concurrent therapy with an aminoglycoside, length of treatment with vancomycin (greater than 21 days), and vancomycin trough serum concentration (greater than 10 mg/l). Although the incidence of vancomycin nephrotoxicity is low, patients receiving vancomycin therapy with the above risk factors should be closely monitored.

Adult↗
PubMed1990

Daptomycin compared with teicoplanin and vancomycin for therapy of experimental Staphylococcus aureus endocarditis.

The efficacies of daptomycin, teicoplanin, and vancomycin were compared in the therapy of experimental Staphylococcus aureus endocarditis. Rabbits infected with either of two methicillin-susceptible strains (SA-12871 or its moderately teicoplanin-resistant derivative SA-12873) or a methicillin-resistant S. aureus strain (MRSA-494) were treated with daptomycin, 8 mg/kg of body weight, every 8 h; teicoplanin, 12.5 mg/kg (low-dose teicoplanin [teicoplanin-LD], excluding MRSA-494) or 40 mg/kg (high-dose teicoplanin [teicoplanin-HD]) every 12 h; or vancomycin, 17.5 mg/kg every 6 h, for 4 days. Compared with no treatment daptomycin, teicoplamin-HD, and vancomycin significantly reduced bacterial counts of all test strains in vegetations and renal and splenic tissues (P less than 0.001). Teicoplanin-LD was equally effective against SA-12871 but failed against SA-12873, with three of six animals still being bacteremic at the end of therapy. For SA-12871, daptomycin was as effective as teicoplanin-HD and was superior to teicoplanin-LD and vancomycin (P = 0.02) in lowering vegetation bacterial counts. There were no differences between daptomycin, teicoplanin-HD, or vancomycin in the reduction of bacterial counts in tissues for any of the test strains. In rabbits infected with SA-12871, vegetations from 33% of teicoplanin-LD-treated, 6% of teicoplanin-HD-treated, and 13% of daptomycin-treated animals yielded organisms for which there were up to eightfold increases in the MICs. Resistance may have contributed to early death in one daptomycin-treated animal. No increases in the MICs for the test strain were detected in animals infected with SA-12873 or MRSA-494. We conclude that in this model and against these strains of S. aureus, daptomycin and teicoplanin-HD are as efficacious as vancomycin, but diminished susceptibility to both can develop during therapy.

Animals↗
PubMed1990

Efficacy of ofloxacin in experimental Staphylococcus aureus endocarditis.

The efficacy of ofloxacin was compared with that of vancomycin in the therapy of experimental Staphylococcus aureus endocarditis. Rabbits infected with either a methicillin-susceptible (MSSA-1199) or a methicillin-resistant (MRSA-494) test strain were treated with ofloxacin (20 mg/kg of body weight every 8 h) or vancomycin (17.5 mg/kg of body weight every 6 h) for 4 days. The antimicrobial agents were found to be equally effective in clearing bacteremia and in reducing bacterial counts in vegetations and in renal and splenic tissue of animals infected with either test strain. The drugs were of equal efficacy in curing MRSA-494 endocarditis. No resistance to ofloxacin emerged in either test strain during therapy. We conclude that in this model ofloxacin is as efficacious as vancomycin and that, unlike for other fluoroquinolones we have evaluated, resistance to the drug does not develop during therapy of this serious S. aureus infection.

Animals↗
PubMed1990

Vancomycin pharmacokinetics in burn patients and intravenous drug abusers.

The pharmacokinetics of vancomycin were evaluated in 34 patients (10 burn patients, 14 intravenous drug abusers [IVDA], and 10 controls). Multiple serum samples were drawn following a 1-h vancomycin infusion at steady state over an 8- to 12-h dosing interval. Pharmacokinetic parameters were derived by noncompartmental analysis. There were no significant differences among the groups with respect to age, weight, serum creatinine, volume of distribution, or protein binding. Burn patients had a significantly higher creatinine clearance than did IVDA or controls. Vancomycin clearances averaged 142.8, 98.0, and 67.7 ml/min in burn patients, IVDA, and controls, respectively. The renal clearance of vancomycin was also higher in burn patients than in the other groups. IVDA tended to have a higher vancomycin clearance (31% higher) than did controls, but the difference was not statistically significant. Vancomycin clearance was much higher in burn patients requiring dosage individualization and close monitoring. A considerable amount of vancomycin was eliminated through renal tubular secretion, making dosage predictions based on creatinine clearance more difficult. Further work with IVDA will be needed to determine if they represent a group requiring aggressive vancomycin dosages.

Adolescent↗
PubMed1990

Cefixime.

Cefixime is a new orally active third-generation cephalosporin with a broad spectrum of activity against a variety of both gram-positive and -negative bacteria including many beta-lactamase-producing strains of streptococci, Haemophilus influenzae, Neisseria gonorrhoeae, and the majority of the Enterobacteriaceae. Activity of cefixime against Staphylococcus aureus, enterococci, Listeria monocytogenes, and Pseudomonas spp. is poor. The relatively long elimination half-life of cefixime (approximately 3.0 h) has made possible once- to twice-daily administration with the potential added benefit of improved patient compliance. Clinical trials indicate that cefixime is at least as effective as standard agents in the treatment of genitourinary and upper respiratory tract infections. The incidence of resistant organisms reported during clinical trials with cefixime was low. Adverse reactions observed during clinical trials were relatively uncommon and generally mild and transient in nature. The most significant adverse reactions reported were diarrhea and stool changes occurring in up to 20 percent of patients.

Bacteria↗