Comparative in vivo efficacy of meropenem, imipenem, and cefepime against Pseudomonas aeruginosa expressing MexA-MexB-OprM efflux pumps.

To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and DeltaK767 (knockout strain). Efficacy (Delta log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (10(5) CFU/thigh) and high (10(7) CFU/thigh) inoculums. At 10(5) CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (-2.82, -1.88) and K767+ (-2.24, -2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (-2.74 and -2.19, respectively). Similar magnitudes of kill were observed at the 10(7) inocula. Except for DeltaK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against DeltaK767. DeltaK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on beta-lactam agents in vivo warrant further research.

Impact of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species on clinical outcomes and hospital costs: a matched cohort study.

OBJECTIVES: To evaluate the economic and clinical impact of infection with extended-spectrum beta -lactamase (ESBL)-producing Escherichia coli and Klebsiella species (ESBL-EK). DESIGN: A matched-cohort analysis of the cost of illness. SETTING: An 810-bed, urban, community hospital in Hartford, Connecticut. PATIENTS: Twenty-one case patients infected with ESBL-EK at a site other than the urinary tract were matched with 21 control subjects infected with a non-ESBL-producing organism on the basis of pathogen species, age, anatomic site of infection, hospitalization in the intensive care unit (ICU) during the time of infection, date of hospitalization, and initial antibiotics received. RESULTS: Mean infection-related costs per patient were significantly greater for case patients than for control patients ($41,353 vs $24,902; P=.034). Infection-related length of stay was the main driver of cost, which was prolonged for case patients, compared with control patients (21 vs 11 days; mean difference, 9.7 days [95% confidence interval {CI}, 3.2-14.6 days]; P=.006). The additional cost attributed to the presence of an ESBL-EK infection was $16,450 per patient (95% CI, $965-$31,937). Case patients were more likely than control patients to have clinical failure (P=.027), and the rate of treatment success for case patients whose initial treatment involved antibiotics other than carbapenems was lower than that for their matched control patients (39% vs 83%; P=.013). Treatment was successful in patients for whom initial treatment was with a carbapenem, regardless of the ESBL status of the pathogen. CONCLUSION: The cost of non-urinary tract infections caused by ESBL-EK was 1.7 times the cost of non-urinary tract infections caused by non-ESBL producers. Prompt recognition and appropriate antimicrobial selection may minimize this ESBL-related impact on hospital costs.

Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients.

The objectives of this study were to develop a meropenem population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria. We gathered concentration data from 79 patients (ages 18-93 years) who received meropenem 0.5, 1, or 2 g over 0.5- or 3-hour infusion every 8 hours. Meropenem population pharmacokinetic analysis was performed using the NONMEM program. A 2-compartment model fit the data best. Creatinine clearance, age, and body weight were the most significant covariates to affect meropenem pharmacokinetics. Monte Carlo simulation was applied to mimic the concentration-time profiles while 1 g meropenem was administrated via infusion over 0.5, 1, 2, and 3 hours. The 3-hour prolonged infusion improved the likelihood of obtaining both bacteriostatic and bactericidal exposures most notably at the current susceptibility breakpoints.

Population pharmacokinetics and pharmacodynamics of meropenem in pediatric patients.

Meropenem is a highly potent carbapenem antibiotic against gram-positive and gram-negative bacteria. Meropenem plasma concentration data from 99 pediatric patients (aged 0.08-17.3 years) were used to develop a population pharmacokinetic model. Pharmacokinetic analysis was performed using NONMEM with exponential interindividual variability and combinational residual error model. A 2-compartment model was found to fit the data best. Creatinine clearance and body weight were the most significant covariates explaining variabilities in meropenem pharmacokinetics among pediatric patients. The validated final model was used to predict meropenem plasma concentrations in 37 pediatric meningitis patients, receiving 40 mg/kg meropenem, who had minimum inhibitory concentration values of the causative pathogens and outcome available. Since the causative pathogens in all patients were eradicated, no break points for required exposure could be found. The microbiological outcomes indicate that the current clinical dosage regimen provides sufficient drug exposure to eradicate the pathogens commonly involved in pediatric meningitis.

Assessment of the efficacy of telithromycin simulating human exposures against S. pneumoniae with ribosomal mutations in a murine pneumonia model.

Telithromycin (TEL) is a ketolide antimicrobial agent with in vitro activity against Streptococcus pneumoniae (SPN), including macrolide resistant strains. The purpose of this study was to assess the efficacy of TEL against clinical SPN isolates with various genotypic mutations including the newly recognized ribosomal mutations. Pneumonia was induced in either immunocompetent and immunosuppressed mice. Six isolates were included in the study and all were resistant to azithromycin (AZI) by MIC testing. Three oral regimens of TEL were chosen to simulate the human pharmacokinetic (PK) exposures observed in young healthy, healthy elderly (> or =65 years), and infected subjects. An additional group was given AZI in human simulated doses. Bacterial density in lung was determined after each treatment. Telithromycin administered simulating infected patients showed greater efficacy (i.e., change in logCFU) than the azithromycin treated group for all isolates except P1660008. The immune system was responsible for increased efficacy (ranging from 45-146%) for all but one of the telithromycin treatment regimens. Unlike other isolates studied in this in vivo model, P1660008 displayed a highly variable response to therapy, such that the reductions in CFU were not consistent with the microbiological and PK profiles of either compound. For all other isolates, the activity of AZI was comparable with untreated controls. Human simulated exposures of TEL displayed 0.5-3.4 log kill in vivo despite the ribosomal mutations studied. These data support the in vivo efficacy of TEL against a variety of genotypic resistance profiles observed in pneumococci, however, additional studies are required to fully characterize the killing profile of the compound against these recently determined ribosomal mutations.

Evaluation of telithromycin against Streptococcus pneumoniae with ribosomal mutations utilizing in vitro time-kill methodology.

In a recent study, our in vivo data suggested that clinically achievable levels of telithromycin are more effective than azithromycin against selected Streptococcus pneumoniae isolates with ribosomal mutations in 23S rRNA gene alleles and L22 region mutations. In the current study, we attempt to investigate further the antibacterial activity of telithromycin against these isolates to better delineate the disparity between isolates based on allelic differences. Four isolates of S. pneumoniae with ribosomal mutations were tested using in vitro time-kill methodology. Isolates were exposed to telithromycin at concentrations of 0.5-8 x the minimum inhibitory concentration (MIC). At these exposures, telithromycin demonstrated concentration-dependent killing for three of the four isolates. Against the fourth isolate, telithromycin affected only a 1 log decrease in colony-forming units/mL despite exposures of 8 x MIC. These data demonstrate the in vitro killing profile of telithromycin against S. pneumoniae isolates with ribosomal and L22 mutations. Whilst telithromycin did not demonstrate bactericidal activity against all isolates in these time-kill studies, the in vivo human-simulated exposures did result in a high degree of bacterial kill. Full evaluation of the potential utility of new antimicrobial agents against these emerging genotypic profiles requires both in vitro and in vivo assessments.

Future in vitro and animal studies: development of pharmacokinetic and pharmacodynamic efficacy predictors for tissue-based antibiotics.

For antibiotics to exert their action on bacteria, both the bacteria and the drug need to be in the same place at the same time. The pharmacodynamics of antibiotics, measured as the ratio of area under the concentration-time curve:minimum inhibitory concentration (AUC:MIC), the ratio of plasma concentration:MIC, or time above MIC, indexes the pharmacokinetic properties of an antibiotic (in vivo) to a measure of microbiologic (antimicrobial) activity. Antimicrobial activity is measured as the MIC, and the pharmacokinetics generally used are those in the blood. However, if the infection is not in the blood but in some peripheral tissue such as the lung, it is the concentration of the drug in the lung that the pathogen sees, and thus the concentration in the blood (serum or plasma) is not important. Both in vitro and in vivo studies can aid in the development of pharmacodynamic parameters that characterize the drug-pathogen interaction, resulting in the determination of a dose or dosage regimen capable of curing an infection clinically.

Comparison of pharmacodynamic target attainment between healthy subjects and patients for ceftazidime and meropenem.

STUDY OBJECTIVE: To compare the pharmacodynamics of two beta-lactams--ceftazidime and meropenem--in healthy subjects versus patients. DESIGN: Monte Carlo simulation based on published pharmacokinetic studies. SUBJECTS: One hundred and ninety-seven participants (75 healthy volunteers and 122 patients) from published pharmacokinetic studies of ceftazidime or meropenem. MEASUREMENTS AND MAIN RESULTS: Data on total body clearance and volume of distribution for ceftazidime and meropenem in healthy subjects and patients were obtained from published studies. Monte Carlo simulations were performed based on the pharmacokinetics from each study for ceftazidime 1000 mg every 8 hours and meropenem 1000 mg every 8 hours against isolates of Escherichia coli , Klebsiella pneumoniae , Acinetobacter baumannii , and Pseudomonas aeruginosa collected from North and South America. We calculated the likelihood of obtaining bactericidal exposures (50% time above the minimum inhibitory concentration [MIC] for ceftazidime and 40% time above the MIC for meropenem) for each combination of pharmacokinetic study data and MIC distribution. Linear regression was used to compare target attainments for healthy subjects versus patients. Only three drug-pathogen combinations differed in target attainment between healthy subjects and patients: ceftazidime against P. aeruginosa in North America and meropenem against E. coli and P. aeruginosa in South America. The regression line of target attainment for patients versus healthy subjects had a slope of 1.04 (95% confidence interval [CI] 0.983-1.093) and a y intercept of -3.73 (95% CI -8.265-0.827, r2 = 0.992). The beta values for slope and intercept did not differ to a statistically significant extent between the regression line and the line of identity (p=0.264). CONCLUSION: The pharmacodynamic target attainment calculated with healthy subject pharmacokinetic data was predictive of patient target target attainment for ceftazidime and meropenem.

A sensitive assay of amoxicillin in mouse serum and broncho-alveolar lavage fluid by liquid-liquid extraction and reversed-phase HPLC.

A sensitive and simple high-performance liquid chromatography (HPLC) method was developed and validated for the analysis of amoxicillin in mouse serum and broncho-alveolar lavage (BAL) fluid. One hundred microlitres of sample were needed for the assay. Sample processing was carried out with liquid-liquid extraction. Cefadroxil was used as an internal standard. The chromatographic separation was achieved on a C18 reversed-phase column with a mobile phase consisting of phosphate buffer, 1-octanesulphonic acid sodium salt and acetonitrile. The detection was conducted at 210 nm. The ranges of the standard curves were 0.2-20 and 0.05-5 microg/ml for serum and BAL samples, respectively. The recoveries of amoxicillin from serum and normal saline were 87 and 88%, respectively. The coefficients of variation were 1.78-6.13% for intra-day and 0.82-6.42% for inter-day analyses. The accuracy was within 100+/-6%. This method was successfully applied to analyze amoxicillin in mouse serum and BAL samples from a pharmacokinetic study.

The clinical and economic benefits of administering piperacillin-tazobactam by continuous infusion.

Beta-lactam antibiotics, such as piperacillin-tazobactam, are commonly administered frequently throughout the day as intermittent infusions over a period of 30-60 min. However, increasing knowledge of how these antibiotics kill bacteria has made continuous infusion a valuable option to achieve maximal clinical outcomes while consuming the least amount of institutional resources. Continuous infusion of piperacillin-tazobactam is currently used at our hospital because of its clinical and economic benefits when compared with intermittent infusion. This article will review our experience with the administration of piperacillin-tazobactam by continuous infusion and the numerous advantages we have documented. Additionally, advantages related to a reduction in nursing resource consumption will be a focus of discussion.

Cost effect of managing methicillin-resistant Staphylococcus aureus in a long-term care facility.

OBJECTIVES: The purpose of this study was to measure the total consumption of resources involved in the care of a long-term care facility (LTCF) resident infected with methicillin-resistant Staphylococcus aureus (MRSA). DESIGN: A retrospective cohort study. SETTING: A 375-bed LTCF that provides two levels of care. PARTICIPANTS: Ninety LTCF residents infected with Staphylococcus aureus (mean age +/- standard deviation for methicillin-sensitive Staphylococcus aureus (MSSA) patients = 85 +/- 8.8, for MRSA patients = 82 +/- 9.5, P =.127; 49 MSSA and 41 MRSA patients). Inclusion criteria consisted of identification of a positive S. aureus culture in addition to symptoms/signs consistent with infection. Patients colonized with S. aureus were excluded. MEASUREMENTS: A standardized data collection tool was used to conduct chart and database review throughout the defined infection period. The type of information collected included demographic, infection characterization, antibiotic regimen, resource assessment, and cost data. The cost data were further categorized into total pharmaceutical, infection management, physician care, nursing care, and total infection cost. RESULTS: One hundred eleven cases were identified, with 90 cases eligible for evaluation. No difference in population demographics was noted between groups. A significantly higher number of patients in the MRSA group had an indwelling device (P <.001), pressure ulcer(s) (P =.028), or diabetes mellitus (P =.007). There was a significantly higher number of patients with congestive heart failure in the MSSA group (P =.047), but no difference existed in the primary infection site (P =.297) or the incidence of patients with more than two comorbidities (P =.509). The infection characterization variables included were also similar between groups. The most prevalent infection site was the urinary tract (48%) followed by skin/skin structure (38%). Because the majority of patients (82%) developed infection at least 30 days after their LTCF admission, the infections may be considered to have been largely LTCF acquired. The median infection management cost of an MRSA infection was six times greater than that of a MSSA infection (P <.001), whereas the median associated nursing care cost was two times greater (P =.001). The median overall infection cost associated with MRSA was 1.95 times greater than that of MSSA (median (range): MSSA 1,332 US dollars (268-7,265 US dollars) vs MRSA 2,607 US dollars (849-8,895 US dollars), P <.001). Nursing care cost constituted the major portion of the overall infection cost in both groups (MSSA 51%, MRSA 48%). Evaluation of antimicrobial management revealed that infected residents were treated with a wide array of combination therapies (65% of patients received combination therapy). CONCLUSIONS: The management of a resident infected with MRSA was much more costly to the LTCF than that of an MSSA-infected patient. The general care of the patient and not the specific antibiotic regimen influenced the large difference in cost between groups. The approach to the antibiotic management of these patients was variable. A more streamlined approach to infection management that facilitates a faster cure rate may dramatically lower resource consumption and improve patient outcomes.

Impact of pharmacodynamics on dosing of macrolides, azalides, and ketolides.

The study of pharmacodynamics characterizes the relationship between changing drug concentrations over time and antimicrobial and toxicologic effects and thereby offers a targeted approach to the design of dosing regimens for many antimicrobials. Distinct patterns of antimicrobial dynamics have been elucidated from these relationships and pharmacodynamic parameters (peak-MIC, AUC-MIC, T > MIC) have been used to quantify antimicrobial effects in relation to drug exposure. These relationships can be used to predict efficacy of a given dosing regimen. The accuracy of these predictions is influenced, in part, by the completeness of the model in which they are studied. This article discusses various in vitro and in vivo studies and clinical data that have contributed to the understanding of pharmacodynamics of the macrolides, azalides, and ketolides.

Review of the pharmacodynamics of antibiotic use in animal food production.

Much attention has been focused on food-producing animals as a potential source of antimicrobial-resistant bacteria in humans. These efforts, however, have been met with continued debate and disagreement within the medical, veterinary, and regulatory communities as to whether the veterinary use of antimicrobials is a significant risk factor for the development of antimicrobial-resistant pathogens. As such, it is the purpose of our paper to assess factors involved in the pharmacokinetics and pharmacodynamics of antibiotic use in animal food production. We conclude that, based on the number of variables involved and the lack of definitive studies, it is difficult to determine the AUC:MIC for antimicrobials. Unfortunately, we are left only with general principles that indicate that low doses of antibiotic tend to select for bacterial resistance, and high doses tend to kill the microorganism. In the case where animal-associated pathogens cause human disease, those practices that target adequate exposures (AUC:MIC) of antimicrobials should continue, whereas those practices producing low exposures should be modified or halted to prevent the emergence and spread of resistant organisms.

Pharmacodynamic profiling of continuously infused piperacillin/tazobactam against Pseudomonas aeruginosa using Monte Carlo analysis.

Standard doses of piperacillin/tazobactam (9-13.5 g over 24 h) administered by continuous infusion (CI) routinely provide serum concentrations in excess of the susceptibility breakpoint (< or =16/4 micro g/ml) for most Enterobacteriaceae. Since the breakpoint of this agent for Pseudomonas aeruginosa is considerably higher (< or=64/4 micro g/ml), the likelihood of obtaining adequate drug exposures with these doses against this bacterium is currently unknown. Monte Carlo simulation was utilized to determine the probability of obtaining adequate piperacillin concentrations above its MICs for P. aeruginosa in patients receiving CI. MICs of 557 P. aeruginosa isolates were determined by E-test and a distribution was constructed for the 496 susceptible isolates. Using a previously validated population pharmacokinetic equation, steady-state serum concentrations were estimated for 210 patients who received piperacillin/tazobactam via CI. A Monte Carlo simulation was performed to predict the probability of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for patients infected with susceptible P. aeruginosa isolates. MICs ranged from 0.09 to 64 micro g/ml with modal and median values of 3 and 4 micro g/ml, respectively. Steady-state concentrations of 51.14 +/- 17.52 micro g/ml were estimated in our patient population. The simulation resulted in a median level of exposure 12.62 times the MIC. The level of certainty of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for piperacillin administered by CI was 97, 93, 85, 81, and 77%, respectively. Despite concern for the place of CI piperacillin/tazobactam in the management of P. aeruginosa infections due to the higher established breakpoint, these data suggest a high probability of achieving adequate drug exposure against susceptible isolates with this dosing regimen.

Prevalence of extended spectrum beta-lactamase producing Escherichia coli and Klebsiella isolates in a large community teaching hospital in Connecticut.

The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESC) and Klebsiella (KS) among consecutive non-urine isolates were evaluated. Twenty-four of 392 isolates produced ESBLs. Among these half were from respiratory sites and all were susceptible to meropenem. Pulse field-gel electrophoresis (PFGE) showed 12 clonally distinct ESBLs and iso-electric focusing (IEF) revealed that most (83%) produced multiple enzymes.

Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem.

Prolonging the infusion of meropenem over 3 hours increases the percentage of the dosing interval that drug concentrations remain above the minimum inhibitory concentration (MIC), thereby maximizing the pharmacodynamics of this agent and adhering to drug stability constraints. Monte Carlo simulation was employed to determine pharmacodynamic target attainment rates for several prolonged infusion (PI) meropenem dosage regimens as compared with the traditional 30-minute infusion (TI) against Enterobacteriaceae, Acinetobacter species, and Pseudomonas aeruginosa populations. Percent time above the MIC (%T>MIC) exposures for 1000 mg TI q8h, 2000 mg TI q8h, 500 mg PI q8h, 1000 mg PI q12h, 1000 mg PI q8h, 2000 mg PI q12h, and 2000 mg PI q8h were simulated for 10,000 subjects. Variability in pharmacokinetic parameters and MIC distributions were derived from studies in healthy volunteers and the MYSTIC surveillance program, respectively. The probabilities of attaining bacteriostatic (30% T>MIC) and bactericidal (50% T>MIC) exposures were high for all dosage regimens against populations of Enterobacteriaceae. Against Acinetobacter species and Pseudomonas aeruginosa, the 2000-mg PI q8h dosage regimen provided the highest target attainment rates. For mild to moderate infections caused by Enterobacteriaceae, prolonged infusion regimens of 500 mg PI q8h and 1000 mg PI q12h would provide equivalent target attainment rates to the traditional 30-minute infusion while requiring less drug over 24 hours. For more serious infections presumably caused by Acinetobacter species or Pseudomonas aeruginosa, a dose of 2000 mg PI q8h is recommended because of its high bactericidal target attainment rate against these pathogens. Further study of these dosage recommendations in clinical trials is suggested.

Pharmacokinetic properties and stability of continuous-infusion meropenem in adults with cystic fibrosis.

BACKGROUND: Meropenem is commonly used to treat lung infections in adults with cystic fibrosis (CF). Although continuous infusion is the ideal method to maximize the pharmacodynamic properties of this betalactam antibiotic, meropenem is stable for only approximately 4 to 6 hours at room temperature, and its pharmacokinetic (PK) properties, when administered by continuous infusion to patients with CF, are largely unknown. OBJECTIVE: This study was undertaken to determine the PK properties and stability of meropenem when administered to adults with CF by a continuous ambulatory drug-delivery infusion pump stored in a cold pouch between 2 freezer packs. METHODS: This open-label, multidose, randomized, crossover PK study was conducted at the Clinical Research Center at Hartford Hospital (Hartford, Connecticut). Adults aged > or = 18 years with CF were eligible. Study participants were randomized to receive meropenem 125 mg/h or 250 mg/h (equivalent to 3 g and 6 g, respectively, over 24 hours) by continuous IV infusion for 12 hours. Serum samples were collected throughout the infusion and then for 6 hours after infusion to determine the PK properties (volume of distribution [V(d)], elimination rate constant, total body clearance [CL], terminal half-life [t 1/2], and steady-state concentration [C(ss)]). Serum meropenem concentrations were assayed using high-performance liquid chromatography, and PK profiles were determined using compartmental analysis. Meropenem stability was ascertained by sampling the drug directly from the infusion pump at prespecified time points. Meropenem tolerability was assessed throughout the study by questioning subjects on how they felt. In addition, laboratory values of serum chemistries and liver enzymes were compared with baseline values. RESULTS: Seven adult volunteers with CF (4 women, 3 men; mean [SD] age, 27 [10] years [range, 19-46 years]) participated in the study. Mean (SD) C(ss) values were 8.31 (0.68) mg/L and 18.50 (3.31) mg/L for the 125-mg/h and 250-mg/h infusion rates, respectively. V(d), CL, and t 1/2 were dose independent and similar between the 2 infusion rates. Meropenem stability was maintained over 12 and 24 hours. Meropenem by continuous infusion was well tolerated. One patient complained of a headache during the study. CONCLUSIONS: In this study of adults with CF, meropenem infusion rates of 125 mg/h and 250 mg/h provided serum drug concentrations greater than the minimum inhibitory concentration for pathogens considered meropenem susceptible (< or =4 microg/mL) and intermediately resistant (8 microg/mL), respectively.

Production and resolution of cantharidin-induced inflammatory blisters.

While inflammatory blisters have long been utilized as a means of evaluating antimicrobial disposition to aid in the development of new treatments for skin and skin structure infections, sparse data are available regarding the healing of the blisters once the experiment has been completed. We report the blister induction technique and resolution time in ten volunteers enrolled in a pharmacokinetic study using the cantharidin-induced inflammatory blister technique.

Population pharmacokinetics of gentamicin in hospitalized patients receiving once-daily dosing.

The purpose of this study was to describe the population pharmacokinetics of gentamicin in a group of 939 adult hospitalized patients receiving once-daily administration of gentamicin and to evaluate the potential influence of patient covariates on gentamicin disposition. Data comprising 1294 serum concentrations from 939 patients, were analyzed using a nonlinear mixed-effect model (NONMEM). The patients had an average age of 55 and an average weight of 70 kg, 431 of the patients were female. The patient covariates including body weight, gender, age, and creatinine clearance (CL(CR)) were analyzed in a stepwise fashion to identify their potential influences on gentamicin pharmacokinetics. The data were best described with a two-compartment model. NONMEM analyses showed that gentamicin clearance (CL, l/h) was linearly correlated with CLcR with proportionality constant: 0.047 (S.E.: 0.0035) x CL(CR) (ml/min). Volume of the central compartment (V1, 1) was linearly related to body weight with proportionality constant: 0.28 (S.E.: 0.021) x body weight (kg). The mean population estimates of CL and V1 were 4.32 l/h and 19.61. respectively. The inter-individual variability in CL and V1 were 29.6 and 5.8%, respectively. Residual errors were 0.23 mg/l and 23.7%. The mean population values of CL and V1 of gentamicin dosed once daily are in agreement with those described by others. This analysis indicates that once-daily dosing (7 mg/kg) of gentamicin should achieve satisfactory concentration in patients with normal renal function although serum concentration monitoring is required to confirm the optimal dosing interval in patients with impaired renal function.

Extended interval aminoglycoside dosing: from concept to clinic.

Extended-interval aminoglycoside dosing (EIAD), while a relatively recent concept in mainstream clinical practice, actually has its roots in the mid 1970s. Early trial and error approaches of manipulating the dosage regimen to avoid toxicity and improve efficacy have helped to characterize the pharmacodynamic properties of these drugs. The increasing successful use of EIAD and improved understanding of pharmacodynamics has helped this dosing regimen gain acceptance into routine clinical practice. A 1998 United States survey demonstrated that approximately 75% of hospitals have adopted EIAD into routine patient care. However, controversy still exists regarding some aspects of infrequent aminoglycoside administration, such as length of the drug-free interval and patient exclusion criteria. After more than 50 years of experience with the aminoglycosides we continue to learn how to most appropriately use these drugs.