Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.

Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 µg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 µg/mL (tested with a fixed vaborbactam concentration of 8 µg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.

Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Noninfected Subjects and Infected Patients.

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated urinary tract infections and in Europe for other serious bacterial infections, including hospital-acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time course of meropenem and vaborbactam using pooled data from two phase 1 and two phase 3 studies. Multicompartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data, and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end-stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different between phase 1 noninfected subjects and phase 3 infected patients. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.

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.

Oral bacitracin vs vancomycin therapy for Clostridium difficile-induced diarrhea. A randomized double-blind trial.

The effectiveness of a ten-day course of either oral bacitracin or oral vancomycin hydrochloride for treatment of Clostridium difficile-induced antibiotic-associated diarrhea was compared in a randomized double-blind study. Bacitracin was as effective as vancomycin in resolving diarrhea; most patients responded within five days of therapy with either drug. Three patients receiving bacitracin worsened during therapy; two of these were considered treatment failures. Neither C difficile nor its toxin was detected in stool samples collected on the final day of therapy in 71% of patients (10/14) receiving vancomycin and in 30% (3/10) receiving bacitracin. Five patients receiving bacitracin and three receiving vancomycin had at least one recurrence. Low but nontoxic concentrations of bacitracin were detected in serum samples collected from 11 patients. Oral bacitracin at this dosage level was as effective as vancomycin in resolving the symptoms of C difficile-induced antibiotic-associated diarrhea in most patients but was less effective in eradicating C difficile and its toxin from patients' stools.

Pharmacologic evaluation of megestrol acetate oral suspension in cachectic AIDS patients.

The objective of our study was to define the pharmacokinetics and pharmacodynamics of megestrol acetate in patients with human immunodeficiency virus (HIV) infection. A new suspension formulation of megestrol acetate (40 mg/ml) was administered as a single oral dose of 800 mg per day in an open label pharmacokinetic study for 21 days. On day 21 of therapy, patients were evaluated for changes in body weight and plasma samples were obtained for steady-state pharmacokinetic analysis. Ten HIV-infected men with an involuntary weight loss of > 10% baseline were evaluated. A high degree of interpatient variability in megestrol acetate pharmacokinetics was observed, with an 8- and 5-fold range in the rate and extent of absorption, respectively. All patients reported an increase in appetite, and 8 of 10 patients gained weight by 3 weeks; the median change in weight in all patients at 3 weeks was 1.8-kg gain (range: 2.3-kg loss to 6.4-kg gain). The two patients who did not gain weight had the lowest area under the curve (AUC), Cmax, and Cmin values. A statistically significant correlation between the ratio of body weight at 3 weeks/initial weight (weight index) and the percentage of the 24-h dosing interval that megestrol acetate concentrations exceeded a 300-ng/ml threshold was observed. These data indicate variable levels of systemic exposure to drug following a fixed dose of a suspension formulation of megestrol acetate. Increase in weight during the early stages of megestrol acetate therapy is related to the extent of in vivo drug exposure above a threshold concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamics and pharmacokinetics of antibiotics with special reference to the fluoroquinolones.

The pharmacodynamic and pharmacokinetic properties of antibiotics have received increased attention in recent years, leading to optimization of dosage regimens. In view of these characteristics, certain fluoroquinolones may prove advantageous compared with other antimicrobials for treatment of selected infections. Several new fluoroquinolone antimicrobial agents have potency equal to or greater than that of beta-lactam antibiotics against gram-negative aerobic bacilli, including Pseudomonas aeruginosa. In vitro bactericidal activity of these compounds is more rapid than that of the beta-lactams, often resembling that for the aminoglycosides. Like the aminoglycosides, but in contrast to the beta-lactams, fluoroquinolones exert a significant in vitro postantibiotic effect against some strains of P. aeruginosa and Enterobacteriaceae. However, unlike many beta-lactam and aminoglycoside antimicrobial agents that have similar in vitro activity, fluoroquinolones are often effective both after oral and parenteral administration. Important pharmacokinetic properties of fluoroquinolones include differences in the extent and variability in oral absorption and clearance, which determine the extent of in vivo exposure to drug. Drugs and dosage regimens that result in a high degree of exposure, particularly high peak levels of drug, may be preferable because of a greater extent of bacterial killing and less selection of drug-resistant bacteria.

Effect of dose and schedule on cefoperazone pharmacodynamics in an in vitro model of infection in a neutropenic host.

Previous studies have shown that cefoperazone given in frequent, large doses is effective in the treatment of infection in patients with cancer. The pharmacodynamics of 2- and 4-g doses of cefoperazone administered either as a single dose or at 12-hour intervals were studied in an in vitro model that simulates infection in a neutropenic patient. One strain each of Pseudomonas aeruginosa (minimal inhibitory concentration [MIC] = 2 micrograms/ml), Staphylococcus aureus (MIC = 1 microgram/ml), Escherichia coli (MIC = 0.06 micrograms/ml), and Klebsiella pneumoniae (MIC = 0.25 micrograms/ml) was studied. The initial dose reduced the inoculum by approximately 3 logs for the Pseudomonas and the staphylococci and 3 to 5 logs for the other organisms. No significant differences in killing were found between the 2- and 4-g doses. Regrowth of Pseudomonas and staphylococci occurred with the single dose but not with the every-12-hour regimen. These data support the clinical use of cefoperazone in doses every 12 hours.

Pharmacokinetics and pharmacodynamics of intravenous ciprofloxacin. Studies in vivo and in an in vitro dynamic model.

The pharmacokinetics and pharmacodynamics of a 200-mg intravenous dose of ciprofloxacin were studied in normal volunteers and in an in vitro dynamic model that exposes bacteria to changing concentrations of the drug in a neutropenic setting. Peak ciprofloxacin concentrations in vivo averaged 3.2 micrograms/ml. The terminal serum elimination half-life averaged 4.2 hours. The volume of distribution of ciprofloxacin was large and consistent with extensive extravascular distribution. Slightly less than half of the dose was recovered unchanged in urine by 48 hours after infusion. The median serum bactericidal titer against a strain of Escherichia coli was 1:16 or more for at least six hours after infusion, but was only 1:2 against a strain of Pseudomonas aeruginosa immediately after the end of the infusion. Pharmacodynamic studies in the in vitro model with a simulated regimen of 200 mg administered intravenously every 12 hours demonstrated rapid and complete killing of this strain of E. coli following the first 200-mg "dose." For the strain of P. aeruginosa, an initial bactericidal effect was observed due to the eradication of susceptible subpopulations of bacteria; however, regrowth of resistant organisms was observed. These data suggest that a regimen of 200 mg administered intravenously every 12 hours results in rapid killing of susceptible bacteria. Higher doses or combination therapy may be required to prevent the emergence of resistant P. aeruginosa in this model and in the setting of neutropenia.

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.

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.

Management of herpesvirus infections in the healthy host.

Human herpesvirus infections continue to be a concern in immunocompetent as well as immunocompromised hosts. They are often life threatening in the immunocompromised patient. In the healthy immunocompetent person the infections tend to be self-limited, although they can directly or indirectly cause periods of severe discomfort and disability, and their treatment can affect productivity, as shown by cost-outcome models. Treatment of primary or secondary episodes in the immunocompetent host is therefore directed toward more rapid resolution of initial and recurrent episodes, thereby limiting the impact of the infections.

Maximizing patient outcomes of antiinfective therapy.

Drug treatment of infectious disease requires consideration of both short- and long-term therapy. Although in most settings patients receive antimicrobials for acute events, long-term management of certain infections with drugs that delay progression of the disease adds a new facet to pharmacotherapy. In the past, broad questions regarding efficacy were posed: a drug was evaluated as either effective or not effective for a particular disorder. The actual question is, in whom is a given drug at a given dosage effective? Antibiotic control, restriction, and pharmacokinetic dosing programs have been useful, but they are reactive as opposed to proactive. The expensive products of biotechnology and the availability of oral drugs with activity exceeding that of parenteral antimicrobials require a more expanded scope of clinical pharmacy practice where patients are identified for these therapies prospectively using statistical models based on disease and other readily identified factors. Predictor variables for patient outcomes such as retreatment with other antibiotics, rehospitalization, toxicity, and mortality following the use of new drugs should be identified. Maximizing these outcome measurements will involve strategies that integrate epidemiology and statistical modeling techniques with principles of pharmaceutical care.

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.

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.

Pharmacokinetics and safety of single rising doses of ofloxacin in healthy volunteers.

The pharmacokinetics, safety, and disposition of the new antimicrobial fluoroquinolone ofloxacin were evaluated after oral administration in 14 healthy, male volunteers in a double-blind, placebo-controlled study. Ofloxacin was administered as 100-, 300-, and 600-mg doses separated by 1 week. Plasma and urine concentrations after each administration were measured using a sensitive and specific high-performance liquid chromatographic procedure. The distribution of ofloxacin was modeled using a two-compartment open-body model with first-order absorption. Maximum plasma concentrations and area under the plasma concentration versus time curve increased in a linear, dose-proportional manner over the range studied. At all levels, within 36 hours after administration, approximately 70% of the dose was recovered in urine as unchanged ofloxacin and only minimal amounts (less than 4%) as metabolites. No significant changes in the distribution or elimination of the compound were found over the 6-fold dose range. No major laboratory toxicities or clinically significant adverse effects were noted in either the ofloxacin or placebo group.

Pharmacoepidemiology of ciprofloxacin: analysis of use patterns and cost impact.

The pharmacoepidemiology and cost impact of ciprofloxacin use were evaluated after unrestricted availability in a 238-bed community teaching hospital. The medical records on all patients treated with oral ciprofloxacin over 6 months were reviewed. To determine if the availability of ciprofloxacin altered antibiotic usage patterns and outcome variables, a group of control patients from a period prior to ciprofloxacin availability were matched and compared to patients who had received the drug. Ciprofloxacin was used as both initial and replacement for parenteral therapy in a variety of infections. A successful clinical outcome was achieved in approximately 90% of patients treated with ciprofloxacin and resulted in an estimated cost avoidance of approximately $165/course. However, comparisons with the matched-control group revealed no differences in overall antibiotic costs or length of hospital stay. These results suggest that unrestricted availability of oral ciprofloxacin does not ensure changes in outcome variables related to cost. Educational and patient targeting programs may be necessary to promote earlier conversion of appropriate patients to newer oral therapies.

Pharmacokinetics and pharmacodynamics of high-dose zidovudine administered as a continuous infusion in patients with cancer.

STUDY OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of high-dose intravenous zidovudine (ZDV). DESIGN: Phase 1, dose-escalating, unblinded study in patients with cancer. SETTING: A university-affiliated cancer treatment center. PATIENTS: Fourteen patients (6 women) with solid tumors that were unresponsive to standard therapy received 31 courses of therapy. INTERVENTIONS: Intravenous ZDV was administered in doses of 2, 3, 4, 5.5, 7, 8.5, 10, 12, 15, or 20 g/m2/day as a continuous infusion over 48 hours. Patients also received fluorouracil plus leucovorin for 24 hours before the start of and during the ZDV infusion. If no dose-limiting toxicities were encountered, subsequent doses were escalated. Blood samples were collected at 24 and 48 hours after the start of the infusion, and hourly for 4 hours after stopping the infusion. Urine was collected in five patients during the infusion and for 24 hours after stopping it. Blood for measuring peripheral white blood cells was collected before and at the end of the infusion in seven patients to measure DNA chain breaks due to incorporation of ZDV. MEASUREMENTS AND MAIN RESULTS: Zidovudine was measured in plasma by high-performance liquid chromatography and in urine fluorescence polarization immunoassay. Its incorporation into DNA was measured by determining DNA strand breakage in peripheral white blood cells using fluorescence analysis. Pharmacokinetic models were fit to plasma ZDV concentrations using extended least squares regression. Short-term high-dose ZDV was generally well tolerated, with adverse effects related to large amounts of free water administered during the infusion. The mean (SD) ZDV pharmacokinetic values were total clearance 1.44 (1.09) L/hr/kg, volume of distribution 2.72 (2.97) L/kg, and half-life 1.2 (0.6) hours. There was considerable interpatient variability in total drug clearance. Although ZDV exposure increased proportionately with increasing dose, two of three patients receiving the highest dose (20 g/m2/day) had markedly low total drug clearances. The relation between the percentage of abnormal DNA in peripheral white blood cells and zidovudine area under the plasma ZDV versus time curve was described by the Emax pharmacodynamic model. CONCLUSIONS: The pharmacokinetics of high-dose ZDV administered by continuous infusion to patients with cancer are similar to those reported with lower doses in patients with infection due to the human immunodeficiency virus. Further study of potential nonlinear pharmacokinetic behavior at doses above 20 g/m2/day is necessary. The high between-patient variability in ZDV clearance results in variable levels of exposure in vivo, and indicates the need for concentration- or effect-controlled study designs in the further evaluation of the agent's antineoplastic effects.

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.

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.