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M N Dudley

Publications and source records attributed to M N Dudley.

At least 19 recordsLinked to original sources
PubMed2001

In vitro activities of RWJ-54428 (MC-02,479) against multiresistant gram-positive bacteria.

RWJ-54428 (MC-02,479) is a new cephalosporin with a high level of activity against gram-positive bacteria. In a broth microdilution susceptibility test against methicillin-resistant Staphylococcus aureus (MRSA), RWJ-54428 was as active as vancomycin, with an MIC at which 90% of isolates are inhibited (MIC(90)) of 2 microg/ml. For coagulase-negative staphylococci, RWJ-54428 was 32 times more active than imipenem, with an MIC(90) of 2 microg/ml. RWJ-54428 was active against S. aureus, Staphylococcus epidermidis, and Staphylococcus haemolyticus isolates with reduced susceptibility to glycopeptides (RWJ-54428 MIC range, < or = 0.0625 to 1 microg/ml). RWJ-54428 was eight times more potent than methicillin and cefotaxime against methicillin-susceptible S. aureus (MIC(90), 0.5 microg/ml). For ampicillin-susceptible Enterococcus faecalis (including vancomycin-resistant and high-level aminoglycoside-resistant strains), RWJ-54428 had an MIC(90) of 0.125 microg/ml. RWJ-54428 was also active against Enterococcus faecium, including vancomycin-, gentamicin-, and ciprofloxacin-resistant strains. The potency against enterococci correlated with ampicillin susceptibility; RWJ-54428 MICs ranged between < or = 0.0625 and 1 microg/ml for ampicillin-susceptible strains and 0.125 and 8 microg/ml for ampicillin-resistant strains. RWJ-54428 was more active than penicillin G and cefotaxime against penicillin-resistant, -intermediate, and -susceptible strains of Streptococcus pneumoniae (MIC(90)s, 0.25, 0.125, and < or = 0.0625 microg/ml, respectively). RWJ-54428 was only marginally active against most gram-negative bacteria; however, significant activity was observed against Haemophilus influenzae and Moraxella catarrhalis (MIC(90)s, 0.25 and 0.5 microg/ml, respectively). This survey of the susceptibilities of more than 1,000 multidrug-resistant gram-positive isolates to RWJ-54428 indicates that this new cephalosporin has the potential to be useful in the treatment of infections due to gram-positive bacteria, including strains resistant to currently available antimicrobials.

Anti-Bacterial Agents↗
PubMed2000

Pharmacodynamics in the study of drug resistance and establishing in vitro susceptibility breakpoints: ready for prime time.

Considerable advancements have been made in providing informative, relevant interpretations of the results of antimicrobial susceptibility tests to clinicians, clinical microbiologists, epidemiologists, and researchers. At the same time, the science of pharmacokinetics has flourished, and the importance of drug exposure in vivo on outcome is now recognized by researchers and clinicians alike. More recently, pharmacokinetic and quantitative measures of antimicrobial susceptibility have been integrated using pharmacokinetic-pharmacodynamic (PK-PD) models to forecast clinical and microbiological outcomes. Stochastic methods utilizing patient population pharmacokinetics, target organism minimum inhibitory concentration (MIC) distributions, and PK-PD targets from non-clinical models of infection or clinical data have established a new paradigm for determining in vitro susceptibility breakpoints and selection of empirical therapy in clinical practice. Given the increasing problem of antimicrobial resistance, these new tools are valuable additions for clinicians, researchers, and regulatory authorities.

Anti-Infective Agents↗
PubMed2000

A population pharmacokinetic analysis of nelfinavir mesylate in human immunodeficiency virus-infected patients enrolled in a phase III clinical trial.

A population pharmacokinetic analysis was conducted on nelfinavir in patients infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations from 174 patients who received nelfinavir at a dose of 500 or 750 mg three times a day. The analysis was performed using nonlinear mixed-effect modeling as implemented in NONMEM (version 4.0; double precision). A one-compartment model with first-order absorption best described the data. The timing and small number of early postdose blood levels did not allow accurate estimation of volume of distribution (V/F) and the absorption rate constant (k(a)). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F), V/F, and k(a) were estimated, and model 2, in which V/F and k(a) were fixed to known values and only CL/F was estimated. Estimates of CL/F ranged from 41. 9 to 45.1 liters/h, values in close agreement with previous studies. Neither body weight, age, sex, race, dose level, baseline viral load, metabolite-to-parent drug plasma concentration ratio, history of liver disease, nor elevated results of liver function tests appeared to be significant covariates for clearance. The only significant covariate-parameter relationship was concomitant use of fluconazole on CL/F, which was associated with a modest reduction in interindividual variability of CL/F. Patients who received concomitant therapy with fluconazole had a statistically significant reduction in nelfinavir CL/F of 26 to 30%. Since serious dose-limiting toxicity and concentration-related toxicities are not apparent for nelfinavir, this effect of fluconazole is unlikely to be of clinical significance.

Adult↗
PubMed2000

SAR studies of anti-MRSA non-zwitterionic 3-heteroarylthiocephems.

SAR studies in a series of 3-heteroarylthio substituted cephalosporins established that high activity against methicillin-resistant Staphylococcus aureus (MRSA) can be achieved with various heteroaryl substituents. Early results showed that highly lipophilic 3-heteroarylthio substituents, which were necessary for anti-MRSA activity, caused high affinity of such cephems toward serum proteins. Our earlier published efforts described discovery of zwitterionic cephems MC-02,331 and RWJ-54428 (MC-02,479), where serum binding was reduced by employing basic, positively charged functionalities attached to the 3-heteroarylthio substituent. In order to avoid low solubility problems associated with most such zwitterionic cephalosporins a wide variety of non-basic heteroaryl substituents was tested (non-zwitterionic cephems are more easily formulated as water soluble sodium salts for intravenous administration). Considerable reduction in serum binding was obtained in some analogs while maintaining high anti-MRSA potency.

Animals↗
PubMed1999

Human immunodeficiency virus protease inhibitors.

Human immunodeficiency virus (HIV) protease inhibitors have revolutionized the treatment of individuals infected with this pathogen. The protease is an enzyme that is essential for viral replication because it cleaves both structural and functional proteins from precursor viral polyprotein strands. Inhibition of this process suppresses viral replication, which produces immature noninfectious virions. When combined with reverse transcriptase inhibitors, these agents are very potent in suppressing viral replication. Pharmacologic properties, toxic profile, drug interactions, and resistance patterns differ among protease inhibitors, and all must be considered when selecting the drugs for therapeutic use in humans. The best combination, sequence of use, durability of response, and magnitude of immune reconstitution and function are issues that have yet to be fully elucidated.

Clinical Trials as Topic↗
PubMed1999

Intracellular phosphorylation of zidovudine in an in vitro hollow fiber model.

Combination antiretroviral therapy that includes zidovudine has proved much better in treating human immunodeficiency virus infection than monotherapy Diminished responses to zidovudine, especially when it was given alone, was likely due to factors including interpatient variability in pharmacokinetics, nonadherence, emergence of resistant mutants, and reduced cellular enzymatic processes to phosphorylate the drug. This study evaluated the intracellular metabolism of zidovudine up to 6 weeks using a hollow fiber cellular model system that simulated exposure of cells to steady-state concentrations achieved in humans. The CEM-T4 lymphocytes were exposed to simulated 200-, 600-, and 1200-mg daily doses of zidovudine. Samples were analyzed for monophosphate, diphosphate, and triphosphate metabolites of zidovudine by high-performance liquid chromatography separation and radiochemical detection. The monophosphate metabolite increased as simulated doses increased, but no corresponding increases in the active triphosphate metabolite occurred. In addition, intracellular metabolism of zidovudine did not change after exposure for 6 weeks. These results suggest that the active triphosphate metabolite of zidovudine does not change much when doses are increased or when exposed for at least 6 weeks. Hollow fiber models may be used effectively to investigate intracellular metabolism of antiviral agents and for some duration of time.

Anti-HIV Agents↗
PubMed1998

Beta-lactam/beta-lactamase inhibitor combinations: pharmacodynamic considerations and possible role in the management of bacterial infections in the neutropenic host.

Morbidity and mortality in febrile neutropenic patients result mainly from complications attributable to infectious diseases. Both Gram-negative and Gram-positive bacterial infections have been implicated. The use of antibiotics in combating bacterial infections has been hampered by production by many bacterial pathogens of beta-lactamases that render them resistant to beta-lactam antibiotics. Since susceptibility to the beta-lactam appears crucial in attaining a clinical response in Gram-negative bacteraemia in febrile neutropenic patients, regimens that inhibit the activity of beta-lactamases are desirable. Although many beta-lactamase inhibitors, such as tazobactam, can result in irreversible inhibition of bacterial beta-lactamase in vitro, careful selection of dosage, as well as testing in models of infection mimicking that in patients, is required. Experimental studies in in-vitro models of infection that mimic conditions of absent host response, show that tazobactam restores the activity of piperacillin against beta-lactamase-producing bacteria. Optimal dosage regimens of beta-lactamase inhibitors will provide mean concentrations of beta-lactamase inhibitor at or above those used in in-vitro testing.

Anti-Bacterial Agents↗
PubMed1998

Activity of trovafloxacin (with or without ampicillin-sulbactam) against enterococci in an in vitro dynamic model of infection.

Antibiotic-resistant enterococci are being increasingly identified as causal agents of infection. Trovafloxacin is a new fluoronaphthyridone with enhanced activity against gram-positive cocci and variable activity reported against Enterococcus spp. Twenty-one strains of vancomycin-resistant Enterococcus faecium and two strains of Enterococcus faecalis (one vancomycin resistant) were studied at an initial inoculum of 10(6) CFU/ml in time-kill assays with trovafloxacin (3 mg/liter), ampicillin-sulbactam (100/50 mg/liter), and the combination. Six strains of E. faecium (five vancomycin resistant) also were studied in an in vitro two-compartment dynamic model that mimics human pharmacokinetics with trovafloxacin simulated at 300 mg every 12 h (q12h), ampicillin-sulbactam at 2/1 g q6h, and the combination. Peripheral compartments were sampled q2h for 30 h for bacterial counts. Trovafloxacin MICs ranged from 0.5 to 32 mg/liter, and the nine strains of vancomycin-resistant E. faecium for which MICs were < or =2 mg/liter were more likely to show a reduction of 2 log units or more in viable counts in time-kill assays than were strains for which MICs were higher. Synergism with ampicillin-sulbactam was found for only one strain (trovafloxacin MIC, 16 mg/liter). Similar results were obtained in the pharmacokinetic model, with 2- to 4-log-unit reductions in viable bacteria for trovafloxacin-susceptible strains. Although no convincing evidence of synergism was found, ampicillin-sulbactam in combination minimized late bacterial regrowth of two trovafloxacin-susceptible strains. These data suggest that this high dose of trovafloxacin (with or without ampicillin-sulbactam) might be useful against strains of vancomycin-resistant E. faecium for which MICs were < or =2 mg/liter.

Ampicillin↗
PubMed1997

Microbiologic and pharmacodynamic principals applied to the antimicrobial susceptibility testing of ampicillin/sulbactam: analysis of the correlations between in vitro test results and clinical response.

The correlation between various ampicillin/sulbactam in vitro antimicrobial susceptibility test results and the clinical outcome of patients treated with this agent have been examined. A survey of over 29,000 clinical isolates of the family Enterobacteriaceae found that the proportion of susceptible pathogens as assessed by current susceptibility testing interpretive guidelines (NCCLS) for disk diffusion and dilution (MIC) assays was significantly less than the proportion of patients cured or clinically improved in ampicillin/sulbactam clinical trials. Also, the results of two NCCLS methods differ greatly in the perceived percentages of susceptible strains (63.9% versus 72.2%; unacceptable variation). Furthermore, the current interpretive criteria resulted in high false-susceptible (4.2%) and total (19.7%) error rates. When proposed interpretive guidelines were applied, approximately 73 to 87% of the Enterobacteriaceae strains were observed to be susceptible, the variation between methods was minimized, and the error rates were reduced. A retrospective analysis of data from clinical trials with ampicillin/sulbactam indicated that the proportion of patients who were cured or clinically improved and bacterially eradicated was not appreciably different in patients having baseline Enterobacteriaceae pathogens with MICs of 16 or 32 micrograms/ml (ampicillin MIC component) as compared to those with pathogens having MICs of < or = 8 micrograms/ml. Studies in animals, in vitro models, and pharmacokinetic considerations indicate that a change in the MIC breakpoint for ampicillin/sulbactam should be considered. The proposed interpretive guideline revisions for ampicillin/sulbactam susceptibility testing of the Enterobacteriaceae were 1) use current diagnostic reagents with criteria of < or = 16/8 micrograms/ml (> or = 14 mm) as susceptible and > or = 64/32 micrograms/ml (< or = 10 mm) as resistant; e.g., 75.9 to 76.0% spectrum and 1.3% false-susceptible error; 2) use alternative diagnostic reagents (1:1 ratio MIC; 20/20 micrograms disks) with criteria of < or = 8/8 micrograms/ml (> or = 18 mm) as susceptible and > or = 32/32 micrograms/ml (< or = 14 mm) as resistant; e.g., 73.3 to 76.9% spectrum and 1.8% false-susceptible error; or 3) use alternative diagnostic reagents with criteria of < or = 16/16 micrograms/ml (> or = 14 mm) as susceptible and > or = 64/64 micrograms/ml (< or = 10 mm) as resistant; e.g., 84.7 to 86.9% spectrum and 1.3% false-susceptible error. Data from a comprehensive in vitro survey of clinical isolates, retrospective analyses of clinical trials, and studies of animal models support the modification of contemporary interpretive guidelines for ampicillin/sulbactam antimicrobial susceptibility tests. The best short-term criteria would apply current in vitro diagnostic reagents and a modified susceptible breakpoint (< or = 16/8 micrograms/ml as susceptible; option 1 above) until new diagnostic reagents can be qualified by means of studies needed for quality assurance of standardized methods (NCCLS M23-A and FDA procedures). These changes would provide a better in vitro prediction of ampicillin/sulbactam efficacy in clinical practice.

Ampicillin↗
PubMed1997

Clinical pharmacokinetics of stavudine.

Stavudine (d4T) is a pyrimidine nucleoside analogue used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase as do zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) and lamivudine (3TC), which comprise the family of nucleoside HIV-reverse transcriptase inhibitors. Stavudine is currently approved by the US Food and Drug Administration for the treatment of patients who have become intolerant to or have failed to response to zidovudine, didanosine or zalcitabine therapy. Oral administration of stavudine results in maximal concentrations within 2 hours and increases linearly as doses increase. The absolute oral bioavailability is high, approaching 100%. There is evidence to suggest that stavudine does not accumulate in the plasma. It distributes into total body water and appears to enter cells by non-facilitated diffusion. Penetration into the cerebrospinal fluid occurs, as does the transfer of the drug across human placental tissue. Stavudine is cleared quickly by both renal and nonrenal processes. The pharmacokinetic properties of stavudine in children are similar to those of adults. The pharmacokinetic parameters of stavudine were not affected by simultaneous administration of didanosine. It appears that stavudine at doses < 2 mg/kg/day is most efficient at increasing CD4 + cell numbers. While stavudine is reported to be less cytotoxic than zidovudine, the principal toxicity in humans is peripheral neuropathy and appears to be related to daily, but not cumulative, doses.

Adult↗
PubMed1996

Electronic compliance assessment of antifungal prophylaxis for human immunodeficiency virus-infected women.

Several prophylactic medications for opportunistic or recurrent infections are used in human immunodeficiency virus-infected individuals. Essential to the efficacy evaluation of these agents is the accurate reporting of medication compliance. We hypothesized that poor patient compliance with thrice-weekly fluconazole prophylaxis would correlate with the occurrence of clinical events. Fluconazole compliance was monitored electronically by using the Medication Event Monitoring Systems with 19 women receiving fluconazole at 50 mg thrice weekly for prophylaxis of recurrent mucocutaneous candidiasis. During 202 patient-months of follow-up, eight breakthrough episodes of mucocutaneous candidiasis developed in four women; compliance data were available for seven of these episodes. At 6 months of therapy, more women with greater than or equal to 80% compliance were disease free compared with women with less than 80% compliance (P < 0.05; the Fisher exact test). These data suggest that documentation of medication compliance is essential in studies of chronic prophylaxis in human immunodeficiency virus-infected patients to properly evaluate drug efficacy and to avoid erroneous conclusions concerning drug failure.

AIDS-Related Opportunistic Infections↗
PubMed1996

Clarithromycin does not affect phosphorylation of zidovudine in vitro.

Zidovudine (ZDV) and clarithromycin (CLR) are often used simultaneously in the management of patients with AIDS. While pharmacokinetic studies show decreased absorption of ZDV when it is administered with CLR, it is unknown if CLR affects the intracellular metabolism of ZDV. We investigated the effects of CLR on the intracellular metabolism of ZDV in vitro. CEM-T4 cells were coincubated with a microM ZDV ([3 H] ZDV, 3 microCi/ml) either alone or with 1 or 10 microM CLR. Cells were also grown in the presence of CLR for 48 h prior to exposure to ZDV. Samples were analyzed for mono-, di-, and triphosphate metabolites of [3 H] ZDV by high-performance liquid chromatography separation and radiochemical detection. There were no significant differences in levels of intracellular metabolites of ZDV following exposure to ZDV, either alone or with 1 or 10 microM CLR and under both coincubated and preincubated conditions. These results show that treatment with CLR does not alter the formation of phosphorylated metabolites of ZDV in this cell line.

Anti-Bacterial Agents↗
PubMed1995

Combination beta-lactam and beta-lactamase-inhibitor therapy: pharmacokinetic and pharmacodynamic considerations.

Pharmacokinetic and pharmacodynamic considerations in in vitro susceptibility testing are described, and the integration of pharmacokinetic and pharmacodynamic concepts in dosage-regimen design is explored. Both the amount of beta-lactamase produced per unit of time and the amount of beta-lactamase inhibitor supplied greatly influence susceptibility to beta-lactam antibiotics. The goal should be to supply enough beta-lactamase to render the bacteria functionally beta-lactamase negative. In susceptibility testing, the amount of inhibitor may be more important than the ratio between the beta-lactam antibiotic and the inhibitor. Irreversible inactivation of beta-lactamases by inhibitors allows for a period of killing of bacteria by beta-lactams, even when concentrations of the inhibitor fall to concentrations below those tested in vitro. The integration of pharmacokinetic and pharmacodynamic concepts allows for comparisons between in vitro and in vivo drug exposure. With some antibiotic-inhibitor combinations, it may be possible to extend the dosage interval if an adequate amount of inhibitor is provided over the course of therapy.

Anti-Bacterial Agents↗
PubMed1995

Clinical pharmacokinetics of nucleoside antiretroviral agents.

The rapid clinical evaluation of new drugs active against human immunodeficiency virus (HIV) requires that pharmacologic properties be carefully considered to determine optimal exposure profiles in patients. The published pharmacokinetic data for the nucleoside antiretroviral agents zidovudine, didanosine, zalcitabine, stavudine, and lamivudine show that administration of fixed doses of certain agents results in a considerable degree of between-patient variability in in vivo drug exposure. Pharmacologic treatment of HIV infection requires development of strategies for individualized adjustment of doses of certain agents with a high degree of interpatient variability.

Animals↗
PubMed1995

Population pharmacokinetics of stavudine (d4T) in patients with AIDS or advanced AIDS-related complex.

The population pharmacokinetics and bioavailability of oral stavudine (d4T; 2',3'-dideoxy-3'-deoxythymidine) was determined in 81 patients with AIDS or AIDS-related complex (ARC) enrolled in phase I and phase I/II dose-ranging trials. Each patient underwent inpatient pharmacokinetic studies following administration of the first oral stavudine dose; 59 patients were restudied after chronic therapy for an average of 19 days. Thirty-three of these patients also received a single intravenous stavudine dose prior to starting an oral regimen. A two-compartment model with first-order absorption and elimination was used as the structural pharmacokinetic model. A basic model provided the following population parameter estimates (interpatient variability expressed in parentheses as percent coefficient of variation): clearance/bioavailability = 30.9 (24.5%) liters/h; volume of distribution/bioavailability = 8.42 (not modeled) liters; volume of distribution at steady state/bioavailability = 68.9 (105%) liters; intercompartmental clearance/bioavailability = 12.4 (26%) liters/h; and first-order absorption rate constant = 1.32 (78.9%) liters/h. In the subset of 33 patients receiving both intravenous and oral doses, the bioavailability of stavudine was estimated to be 99.1% (18.5%). Total body weight, stage of disease (AIDS versus ARC), and an oral stavudine dose of > or = 200 mg were found to have a statistically significant but a clinically marginal effect on the estimate of the oral clearance of stavudine. This analysis shows the high degree of bioavailability of stavudine in patients with AIDS and ARC and the relatively low degree of interpatient variability in oral drug clearance compared with those of other nucleosides. Population pharmacokinetic analysis is a useful tool for assessing the combined effects of several patient variables on the pharmacokinetic properties of drugs in human immunodeficiency virus-infected patients.

AIDS-Related Complex↗
PubMed1995

Efficacy of constant infusion of A-77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, in limiting acute HIV-1 infection in vitro.

A-77003, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is effective for both acute and chronic infection in vitro and was evaluated clinically by continuous intravenous infusion administration. The minimum effective dose (the concentration required to completely inhibit viral replication) was determined in vitro in a population of uninfected (99%) and HIV-infected (1%) cells exposed to A-77003 by continuous infusion in hollow-fiber bioreactors. The production of infectious HIV and release of p24 antigen from infected cells were completely inhibited in cultures exposed to A-77003 at or above a concentration of 0.5 microM. Measurement of unintegrated HIV-1 DNA synthesis and flow cytometric analysis for cells expressing HIV p24 antigen demonstrated that the spread of HIV to uninfected cells was also blocked at 0.5 microM A-77003. Dose deescalation to 0.25 microM or removal of A-77003 resulted in the limited spread of the virus throughout the culture, the resumption of viral DNA synthesis, and release of p24. HIV produced after exposure to 0.5 microM A-77003 was noninfectious for a period of 72 h after the removal of the drug. Addition of 1 mg of alpha 1-acid glycoprotein per ml to this in vitro system completely ablated the anti-HIV effect of 0.5 microM A-77003. These data suggest that determination of the minimum effective dose under conditions which simulate human pharmacodynamic patterns may be useful in determining the initial dose and schedule for clinical trials. However, other factors, such as serum protein binding, may influence the selection of a therapeutic regimen.

Antiviral Agents↗
PubMed1994

Pharmacodynamics of piperacillin alone and in combination with tazobactam against piperacillin-resistant and -susceptible organisms in an in vitro model of infection.

The pharmacodynamics of dosage regimens of piperacillin alone or in combination with tazobactam against piperacillin-resistant or -susceptible bacteria were studied in an in vitro model of infection. Experiments were conducted by using a fixed daily exposure of 12 g of piperacillin, given as 3 g alone or in combination with tazobactam at 0.375 g every 6 h, or the same total dose of the combination given as 4 g of piperacillin plus 0.5 g of tazobactam every 8 h. The addition of tazobactam to piperacillin, irrespective of the dosing interval, did not alter the killing of piperacillin-susceptible organisms (Escherichia coli J53 and Pseudomonas aeruginosa ATCC 27853). In contrast, experiments with an isogenic TEM-3-containing transconjugant of E. coli J53 (E. coli J53.2-TEM-3) that was resistant to piperacillin (MIC, 128 micrograms/ml) showed that the addition of tazobactam resulted in bacterial killing similar to that observed with the wild-type strain. Although tazobactam concentrations fell to less than 4 mg/liter (the concentration associated with a reduction in the piperacillin MIC from 128 to 2 mg/liter) 2 to 3 h after a dose, a similar degree of bacterial killing was observed when the same total 24-h dose of piperacillin-tazobactam was fractionated into dosing intervals of every 6 or 8 h. Investigations with Staphylococcus aureus 7176 (piperacillin MIC, 128 micrograms/ml) showed that the addition of tazobactam, again irrespective of dosing interval, also resulted in net bacterial killing which was not seen with piperacillin alone. These data support the use of extended dosing intervals (every 8 h) of piperacillin-tazobactam in the treatment of infections caused by piperacillin-resistant bacteria.

Bacteria↗