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Biomedical subjects

M J Rybak

Publications and source records attributed to M J Rybak.

At least 73 records · Page 4Linked to original sources
PubMed1995

Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus alone and in combination with single daily-dose amikacin against Pseudomonas aeruginosa in an in vitro infection model.

We compared the pharmacodynamics and killing activity of ceftazidime, administered by continuous infusion and intermittent bolus, against Pseudomonas aeruginosa ATCC 27853 and ceftazidime-resistant P. aeruginosa 27853CR with and without a single daily dose of amikacin in an in vitro infection model over a 48-h period. Resistance to ceftazidime was selected for by serial passage of P. aeruginosa onto agar containing increasing concentrations of ceftazidime. Human pharmacokinetics and dosages were simulated as follows: half-life, 2 h; intermittent-bolus ceftazidime, 2 g every 8 h (q8h) and q12h; continuous infusion, 2-g loading dose and maintenance infusions of 5, 10, and 20 micrograms/ml; amikacin, 15 mg/kg q24h. There was no significant difference in time to 99.9% killing between any of the monotherapy regimens or between any combination regimen against ceftazidime-susceptible P. aeruginosa. Continuous infusions of 10 and 20 micrograms/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 micrograms/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regrowth at 48 h, while a continuous infusion of 5 micrograms/ml resulted in the most regrowth. All of the combination regimens exhibited a synergistic response, with rapid killing of ceftazidime-susceptible P. aeruginosa and no regrowth. Against ceftazidime-resistant P. aeruginosa, none of the ceftazidime monotherapy regimens achieved 99.9% killing. The combination regimens exhibited the same rapid killing of the resistant strain as occurred with the susceptible strain; however, regrowth occurred with all regimens. The combination regimens of continuous infusion of 20 micrograms/ml plus amikacin and intermittent bolus q8h or q12h plus amikacin continued to be synergistic. Overall, continuous infusion monotherapy with ceftazidime at concentrations 4 to 5 and 10 to 15 times the MIC was as effective as an intermittent bolus of 2 g q12h (10 to 15 times the MIC) and q8h (25 to 35 times the MIC), respectively, against ceftazidime-susceptible P. aeruginosa. Combination therapy with amikacin plus ceftazidime, either intermittently q8h or by continuous infusion of 20 micrograms/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.

Amikacin↗
PubMed1995

Quinupristin/dalfopristin (RP 59500): a new streptogramin antibiotic.

OBJECTIVE: To review the current knowledge on RP 59500 (quinupristin/dalfopristin, Synercid), a new streptogramin antibiotic, with respect to its pharmacology, pharmacokinetics, pharmacodynamics, mechanism of resistance, and in vitro inhibitory and bactericidal activity. DATA SOURCES: A MEDLINE search using keywords RP 59500, pristinamycin, virginiamycin, and streptogramin was performed. Relevant abstracts presented at recent scientific conferences also were consulted. STUDY SELECTION: Because RP 59500 is a relatively new investigational agent, relevant in vitro and animal studies were selected. All available human studies were included as well. DATA EXTRACTION: Data from in vitro and in vivo studies were included, with particular emphasis on human studies. DATA SYNTHESIS: RP 59500 is a new injectable streptogramin antibiotic consisting of a mixture o 2 synergistic pristinamycin compounds. RP 59500 possesses in vitro inhibitory and bactericidal activity against most isolates of gram-positive organisms including vancomycin-resistant Enterococcus faecium, selected gram-negative bacteria, and most anaerobic organisms. Based on preliminary data, the drug appears to be metabolized rapidly and extensively while exhibiting a significant postantibiotic effect. Data from ongoing clinical trials suggests that RP 59500 is well-tolerated except for mild injection site irritations. However, before the role of RP 59500 within the vast armamentarium of antimicrobials can be elucidated, additional studies need to be conducted to document its clinical efficacy. CONCLUSIONS: Based on in vitro susceptibility testing, in vivo studies, and preliminary clinical data, RP 59500 may be an alternative to the glycopeptides, especially for inherently resistant organisms. Further studies are needed to confirm this agent's in vitro activity and to establish its clinical efficacy.

Anti-Bacterial Agents↗
PubMed1994

Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model.

The pharmacodynamic properties of levofloxacin (an optically active isomer of ofloxacin), ofloxacin, and ciprofloxacin, alone and in combination with rifampin, were evaluated over 24 to 48 h against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA 1199 and MRSA 494, respectively) in an in vitro infection model. The incidence of the emergence of resistance among the test strains was also determined. The fluoroquinolones were administered to simulate dosage regimens of 200 mg, 400 mg given intravenously (i.v.) every 12 h (q12h), and 400 and 800 mg given i.v. q24h. Rifampin was dosed at 600 mg i.v. q24h. Although the MICs and MBCs of the quinolones were similar (< or = 0.49 microgram/ml), levofloxacin was the most potent agent in time-kill studies on the basis of the time required to achieve a 99.9% reduction in the number of log10 CFU per milliliter (e.g., with the regimen of levofloxacin [400 mg q24h, 6.5 h] versus ofloxacin [12.5 h], P < 0.024, and levofloxacin versus ciprofloxacin [6.5 versus 9.0 h], P < 0.0017) against MSSA 1199. The killing activity of levofloxacin was similar to that of ofloxacin against MRSA 494 (time to achieve a 99.9% reduction in the number of log10 CFU per milliliter, 11.1 versus 13.8 h, respectively). Levofloxacin and ofloxacin dosed once daily demonstrated greater bactericidal activity than when they were dosed twice daily against MSSA 1199. Resistance to levofloxacin or ofloxacin was not observed with any dosage regimen. Furthermore, resistance to ofloxacin was not detected when the half-life was reduced from 6 to 3 h. Regrowth and stable resistance (65-fold increase in the MIC for MSSA 1199; 16-fold increase in the MIC for MRSA 494) were noted within 24 h of exposure to ciprofloxacin at 200 mg q12h. Combination therapy with rifampin prevented the emergence of resistance to ciprofloxacin. Neither DNA gyrase alteration nor an energy-dependent efflux process mediated by the norA gene appeared to be responsible for the resistance observed. Our data suggest that with levofloxacin there is a more rapid onset of bactericidal activity than with ofloxacin or ciprofloxacin against MSSA 1199 and that the activity of levofloxacin is similar to that of ofloxacin but better than that of ciprofloxacin against MRSA 494. Resistance was noted only after exposure to the low dose of ciprofloxacin. Resistance to ofloxacin did not develop even when the pharmacokinetics of the drug were set to equal those of ciprofloxacin, suggesting that ofloxacin differs from ciprofloxacin irrespective of time of exposure. The resistance to ciprofloxacin that developed in our vitro model may be mediated by the cfx-ofx locus, which has been shown to be associated with low-level fluoroquinolone resistance. Overall, levofloxacin demonstrated potent bactericidal activity against S. aureus, without the emergence of resistance in our infection model. Quinolones dosed once daily were more effective than equivalent dosages administered twice daily. The addition of rifampin was not synergistic but prevented the emergence of ciprofloxacin resistance.

Ciprofloxacin↗
PubMed1994

Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis.

We adapted an in vitro pharmacodynamic model of infection to incorporate simulated endocardial vegetations. The bactericidal activities of teicoplanin, vancomycin, gentamicin, and various combinations of these drugs were studied against a strain of methicillin-susceptible Staphylococcus aureus obtained from a patient being treated for endocarditis at Detroit Receiving Hospital. Bacteria were grown overnight, concentrated, and added to a mixture of cryoprecipitate (80%) and thrombin (10%) to achieve approximately 5 x 10(9) CFU/g. Fibrin clots (8 to 10) were suspended into the model, removed at 24, 48, and 72 h in duplicate, weighed, and homogenized in 1.25% trypsin. Control experiments were conducted to characterize the growth kinetics. The following antibiotics were administered to simulate the pharmacokinetics of the drugs in humans: teicoplanin at 3 and 15 mg/kg of body weight, vancomycin at 15 mg/kg, and gentamicin at 1 mg/kg. Fibrin clot samples used to detect resistance were plated on antibiotic-containing tryptic soy agar plates. For the teicoplanin and vancomycin regimens, protein binding to cryoprecipitate, thrombin, and fibrin clot was determined to be 32, 43, and 50% and 26, 28, and 29%, respectively. In comparison with no treatment, vancomycin or teicoplanin at 15 mg/kg or either of these regimens combined with gentamicin significantly reduced bacterial counts (P < 0.0001). Monotherapy with teicoplanin at 3 mg/kg or gentamicin resulted in no killing activity. Combination treatment with teicoplanin at 3 mg/kg and gentamicin resulted in the killing of approximately 2 log10 CFU/g by 72 h and the development of resistance to gentamicin. The results obtained with the in vitro model of endocarditis are similar to the results reported by several investigators with the rabbit model of infective endocarditis. This unique infection model is useful for designing initial drug dosage regimens and may be predictive of drug efficacy against infective endocarditis.

Blood Proteins↗
PubMed1993

Prospective evaluation of red man syndrome in patients receiving vancomycin.

The incidence of red man syndrome (RMS) and its relationship to histamine were investigated in patients receiving vancomycin or an aminoglycoside (control). During the 60-min infusions, patients were observed for signs or symptoms consistent with RMS, including pruritus, erythema, angioedema, and cardiovascular depression. Four blood samples were obtained at 30-min intervals for determination of histamine concentrations. One (3.4%) of 29 vancomycin- and none of 8 aminoglycoside-treated patients had documented RMS. The mean maximum changes in blood pressure and heart rate were not significant and were similar between groups. Increases in histamine concentrations to > 1 ng/mL occurred only in 25% (2/8) of the aminoglycoside patients. Vancomycin induced minimal changes in histamine concentrations despite the occurrence of RMS. From these observations, it appears that RMS is not closely associated with histamine release, and elevated histamine concentrations do not predict RMS. Further investigation is needed to elucidate other mediators of RMS.

Abdomen↗
PubMed1993

Teicoplanin and daptomycin bactericidal activities in the presence of albumin or serum under controlled conditions of pH and ionized calcium.

Teicoplanin and daptomycin bactericidal rates (BRs) were measured from standard kill curves in supplemented Mueller-Hinton broth (B), B with 3 g of albumin per dl (BA), B with 50% pooled human serum (BS), and in broth to simulate free concentrations (BF) under controlled physiologic conditions of pH (7.4) and ionized calcium (1.15 to 1.17 mM) against two clinical Staphylococcus aureus strains. Total concentrations of teicoplanin and daptomycin, respectively, were 45 and 12.5 micrograms/ml in B, BA, and BS and 4.5 and 1.25 micrograms/ml in BF. All BRs are reported as log10 CFU per milliliter per hour. There was a trend for the teicoplanin BR to be inhibited by serum for strain 67 (BR in B was -0.26 +/- 0.08 versus a BR in BS of -0.19 +/- 0.08 [P > 0.05]). The teicoplanin BRs for strain 135 were unaffected by the type of medium used (range, -0.17 to -0.20). For both strains, daptomycin BRs were adversely affected by lower concentrations, albumin, and serum. The BR of daptomycin was significantly faster in B (-4.53 +/- 1.92) (P < 0.05) than it was in BF (-0.58 +/- 0.04), BA (-1.68 +/- 0.28), or BS (-1.02 +/- 0.16) against strain 67. BA and BS resulted in BRs more than twice that in BF (P > 0.05). Against strain 135, daptomycin again produced the highest BR in B; however, the BRs in BF, BA, and BS were almost identical, indicating that only free daptomycin was active. After correcting for the influence of protein binding, pH, and ionized calcium, teicoplanin appeared to be inhibited by serum, and daptomycin demonstrated enhanced BRs against different S. aureus strains in the presence of albumin or serum.

Anti-Bacterial Agents↗
PubMed1993

Pharmacodynamic effects of extended dosing intervals of imipenem alone and in combination with amikacin against Pseudomonas aeruginosa in an in vitro model.

The pharmacodynamic effects of extended imipenem dosing intervals were studied against two strains of Pseudomonas aeruginosa (ATCC 27853 and an imipenem-resistant mutant, 27853R) in an in vitro model of infection. Imipenem was administered as monotherapy (simulated 1-g bolus every 8 or every 12 h) and in combination with amikacin (7.5-mg/kg bolus every 12 h or a 15-mg/kg bolus once). Monotherapy with imipenem administered every 8 h was equally bactericidal at 24 h compared with regimens combined with amikacin for ATCC 27853. Imipenem administered every 12 h against the sensitive strain and both imipenem monotherapy regimens against the resistant strain demonstrated regrowth at 24 h. Although both amikacin regimens administered as monotherapy resulted in rapid bacterial killing activity with respect to time to a 99.9% reduction in log10 CFU/milliliter, regrowth at 24 h was observed at levels reaching or exceeding the initial inoculum. All combination regimens resulted in no detectable growth by 24 h regardless of dosing interval for either drug or initial susceptibility to imipenem. Results from this study indicate the potential for several novel dosing regimens against P. aeruginosa. Monotherapy with imipenem, 1 g every 8 h, was effective against a sensitive strain of P. aeruginosa. Combination therapy with imipenem and once-daily or twice-daily amikacin resulted in increased killing activity against imipenem-resistant P. aeruginosa. Once-daily or twice-daily amikacin in combination therapy, regardless of P. aeruginosa susceptibility, allowed for extension of imipenem dosing intervals.

Amikacin↗
PubMed1993

Enterococcus, an emerging pathogen.

OBJECTIVE: To review the bacterial genus Enterococcus with respect to its epidemiology, specific infections in humans, mechanisms of resistance and tolerance, and antimicrobial treatment. DATA SOURCES: A MEDLINE search of English-language journal articles published from 1977 to 1992 was completed. Articles published prior to 1977 were identified through Index Medicus and from references appearing in the bibliographies of other journal articles. Information also was acquired from abstracts, personal communication with infectious disease specialists with active research in the area of enterococcal infection, and conference proceedings. STUDY SELECTION: In vitro data; animal models of enterococcal infection; case reports; and case-controlled, cohort, and randomized controlled trials in humans were evaluated for relevant information. DATA EXTRACTION: Studies were evaluated by their methodologic strength (e.g., randomized controlled trial), reporting of clinically relevant outcomes (e.g., clinical response to antimicrobial therapy), statistical analyses, and accountability of all patients who entered the study. DATA SYNTHESIS: The incidence of enterococcal infections has increased in recent years and enterococci are now the second most frequently reported nosocomial pathogens. Enterococcus faecalis is the pathogen responsible for most enterococcal infections seen today; it has been implicated as an important cause of endocarditis, bacteremia, urinary tract infections, and intraabdominal infections. CONCLUSIONS: Enterococcal infection is of particular concern clinically because of its resistance to several antibiotics. Controlled comparative clinical trials of antimicrobial therapy in humans are lacking for several enterococcal infections. Therefore, the recommendations for antimicrobial therapy presented in this review are guidelines that reflect our current understanding of antibiotics used for enterococcal infection.

Abdomen↗
PubMed1993

Teicoplanin vs vancomycin: cost-effectiveness comparisons.

The rising incidence of methicillin-resistant staphylococci and resistant enterococci in recent years has led to increased use of vancomycin as an active combatant in the treatment of gram-positive infections. Teicoplanin is an investigational glycopeptide that shares a similar spectrum of activity with vancomycin and appears to have similar efficacy. Teicoplanin offers several theoretical advantages compared with vancomycin including once-daily dosing, fewer side effects, and the option for intramuscular administration. While these may be perceived as substantial advances in the glycopeptide class of antibiotics, teicoplanin will probably not replace the now generically available vancomycin on hospital formularies. If competitively priced as a once-daily dosing regimen, teicoplanin will likely gain initial acceptance as an alternative in patients with an intolerance to vancomycin infusion-related side effects or in patients placed on combination aminoglycoside therapy for extended periods of treatment, as an intramuscular antibiotic in patients with poor venous access, and for routine antibiotic prophylaxis where protection from resistant gram-positive pathogens is important. The use of teicoplanin in the hospital may become more widespread as its side effect profile and economic advantages of less frequent dosing compared with vancomycin become better understood.

Cost-Benefit Analysis↗
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↗