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Biomedical subjects

J J Schentag

Publications and source records attributed to J J Schentag.

At least 55 records · Page 3Linked to original sources
PubMed1998

Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy.

The selection of bacterial resistance was examined in relationship to antibiotic pharmacokinetics (PK) and organism MICs in the patients from four nosocomial lower respiratory tract infection clinical trials. The evaluable database included 107 acutely ill patients, 128 pathogens, and five antimicrobial regimens. Antimicrobial pharmacokinetics were characterized by using serum concentrations, and culture and sensitivity tests were performed daily on tracheal aspirates to examine resistance. Pharmacodynamic (PD) models were developed to identify factors associated with the probability of developing bacterial resistance. Overall, in 32 of 128 (25%) initially susceptible cases resistance developed during therapy. An initial univariate screen and a classification and regression tree analysis identified the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC[0-24]/MIC) as a significant predictor of the development of resistance (P < 0.001). The final PK/PD model, a variant of the Hill equation, demonstrated that the probability of developing resistance during therapy increased significantly when antimicrobial exposure was at an AUC[0-24]/MIC ratio of less than 100. This relationship was observed across all treatments and within all organism groupings, with the exception of beta-lactamase-producing gram-negative organisms (consistent with type I beta-lactamase producers) treated with beta-lactam monotherapy. Combination therapy resulted in much lower rates of resistance than monotherapy, probably because all of the combination regimens examined had an AUC[0-24]/MIC ratio in excess of 100. In summary, the selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUC[0-24]MIC ratio of less than 100.

Acute Disease↗
PubMed1998

Pharmacodynamic interactions of ciprofloxacin, piperacillin, and piperacillin/tazobactam in healthy volunteers.

Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four-period crossover design. Serum drug concentrations were analyzed by means of high-performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill-type model where Emax was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.

Adolescent↗
PubMed1997

Comparative in vitro assessment of sparfloxacin activity and spectrum using results from over 14,000 pathogens isolated at 190 medical centers in the USA. SPAR Study Group.

Sparfloxacin, a new orally administered fluoroquinolone, was tested against 14,182 clinical strains isolated (generally blood stream and respiratory tract cultures) at nearly 200 hospitals in the United States (USA) and Canada. Sparfloxacin activity was compared with 13 other compounds by Etest (AB BIODISK, Solna, Sweden), broth microdilution, or a standardized disk diffusion method. Using the Food and Drug Administration/product package insert MIC breakpoint for sparfloxacin susceptibility (< or = 0.5 microgram/ml), 94% of Streptococcus pneumoniae (2666 isolates) and 89% of the other streptococci (554 isolates) were susceptible. However, at < or = 1 microgram/ml (the breakpoint for all nonstreptococcal species) sparfloxacin susceptibility rates increased to 100% and 98%, respectively, for the two groups of streptococci. Only 50% and 65% of pneumococci were susceptible to ciprofloxacin (MIC90, 3 micrograms/ml) and penicillin (MIC90, 1.5 micrograms/ml), respectively. Although there were significant differences between regions in the USA in the frequency of penicillin-resistant pneumococcal strains, results indicate that the overall sparfloxacin MIC90 was uniformly at 0.5 microgram/ml. Nearly all (> or = 99%) Haemophilus species and Moraxella catarrhalis, including those harboring beta-lactamases, were susceptible to sparfloxacin, ciprofloxacin, and amoxicillin/clavulanic acid. Only cefprozil and macrolides demonstrated lower potency and spectrum against these two species. Sparfloxacin was active against oxacillin-susceptible Staphylococcus aureus (96 to 97%), Klebsiella spp. (95%), and other tested enteric bacilli (93%). Comparison between broth microdilution MIC and disk diffusion interpretive results for M. catarrhalis, Staphylococcus aureus, and the Enterobacteriaceae showed an absolute intermethod categorical agreement of > 95% using current sparfloxacin breakpoints, in contrast to those of cefpodoxime for S. aureus where a conspicuous discord (98% versus 59%) between methods was discovered. These results demonstrate that sparfloxacin possesses sufficient in vitro activity and spectrum versus pathogens that cause respiratory tract infections (indications), especially strains resistant to other drug classes such as the earlier fluoroquinolones, oral cephalosporins, macrolides, and amoxicillin/clavulanic acid. The sparfloxacin susceptibility breakpoint for streptococci may require modification (< or = 1 microgram/ml) based on the MIC population analysis presented here. A modal MIC (0.38 to 0.5 microgram/ml) was observed at the current breakpoint. Regardless, sparfloxacin inhibited 89% (nonpneumococcal Streptococcus spp.) to 100% (Haemophilus spp., M. catarrhalis) of the isolates tested with a median activity of 97% against indicated species.

Anti-Bacterial Agents↗
PubMed1997

Changing the infection control paradigm from off-line to real time: the experience at Millard Fillmore Health System.

In 1993, several departments at Millard Fillmore Health System joined efforts to initiate a new approach to infection control. The main emphasis of this program is to move infection control to a real-time mode to manage patient outcomes daily. The principal objective was to decrease the number of nosocomial infections by 10%, with a particular emphasis on surgical-site infections. Besides real-time surveillance, we are critically evaluating several aspects of the management of nosocomial infections. High-level computer support has been the frame-work upon which this program was built. We have microcomputers that are linked directly to microbiology, pharmacy, billing, and admissions, downloading data several times daily. An expert software system merges all of the data, and from this we can target patients for real-time interventions. The computer system allows all inpatients to be screened for either infection control or antibiotic management interventions on a daily basis, with minimal time being spent on data collection and maximal efforts devoted to interventions at the bedside. Additionally, the infection management program will assist in maintaining the extraordinarily low expenditures on antimicrobial agents. During 1993, the Millard Fillmore Health System spent $924,884 on antibiotics, an amount approximately 50% that of comparably sized hospitals.

Anti-Bacterial Agents↗
PubMed1997

Pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis.

This analysis was designed to characterize the population pharmacokinetics and pharmacodynamics of oral grepafloxacin (OPC-17,116) in patients with acute bacterial exacerbations of chronic bronchitis (ABECB). The study group included 76 patients (43 male, 33 female) between 23 and 81 years of age, who were part of a multicentre, randomized, double-blind, dose-response study. Patients were randomly assigned to receive oral regimens of grepafloxacin, 200, 400 or 600 mg, each administered once daily for 14 days. Plasma samples for drug assay (typically eight per subject; four samples on either day 3, 4 or 5, plus troughs on other clinic visit days), were obtained during treatment. Population pharmacokinetic analysis was accomplished using iterative two-stage analysis. Cultures and quantitative Gram stains from serial 24 h collections of sputum were used to determine the time (in days) taken to eradicate each bacterial strain. Population pharmacodynamic analysis was performed for three measures of antibacterial response: probability of bacteriological cure, probability of clinical cure, and time to eradication. Grepafloxacin plasma concentration profiles were best fitted by a pharmacokinetic model with first-order absorption following a lag time between administration of the dose and onset of systemic absorption. All three measures of response were strongly related to the 24 h AUIC (AUC/MIC). At an AUIC of <75, the percent probability of clinical cure was 71%; at an AUIC of 75-175, it was 80% (P < 0.05) and at an AUIC of >175, it was 98% (P < 0.01). In conclusion, antibacterial response for grepafloxacin in ABECB patients was highly related to AUIC; values of <75 appear inadequate and values of >175 were optimal.

Administration, Oral↗
PubMed1997

Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers.

The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period randomized crossover study involving 12 healthy adults. The PK of cefotaxime and ofloxacin were modeled. PD was assessed from the predicted concentrations in serum and serum untrafiltrate inhibitory titers for 10 test organisms. An inhibitory sigmoid Emax model based on the probability of bacterial growth was used, where Emax = 1 and EC50 is the concentration resulting in a 50% probability of growth. The total body clearance (CL(T)) and volume of distribution at steady state (V(SS)) for cefotaxime were 0.236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liters/kg for the combination therapy. Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CL(T) and 1.20 liters/kg for V(SS) following the monotherapy and of 0.141 liters/kg/h for CL(T) and 1.16 liters/kg for V(SS) following combination therapy. For the combination therapy, an interaction term, theta, defined the type and relative extent of interaction. The range of observed theta values (-0.033 to 0.067) is consistent with an additive PD interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.

Adult↗
PubMed1997

Modeling the response of pneumonia to antimicrobial therapy.

The response to antimicrobial therapy in patients with pneumonia was assessed by using a previously developed pneumonia scoring system. Patients from two different clinical trials were evaluated. The first group (n = 22) was treated with cefmenoxime. For these patients, doses were adjusted to achieve an area under the plasma concentration-versus-time curve (AUC) above the MIC of 140 microg x h/ml and pneumonia response scores were evaluated retrospectively. The second group (n = 21) were treated with either ciprofloxacin (CIP) or ceftazidime (TAZ) in a randomized clinical trial. Here, doses were adjusted to achieve AUC from 0 to 24 h/MIC values that were > 250 SIT(-1) x h (estimate of the area under the curve of inverse serum inhibitory titer versus time) and pneumonia response scoring was concurrent. In both studies eradication of the pathogen was determined by serial endotracheal cultures and clinical parameters were scored daily. A decrease in total score was indicative of an improving clinical condition. The percent change in clinical daily score was determined for each day of treatment. The rate of clinical response was determined by linear regression of the percent change in daily clinical score versus time during the course of antimicrobial therapy. Factors predictive of time to eradication were explored by interval analysis. Logistic regression was used to determine the earliest time point in therapy at which treatment scores predicted outcome. Kruskal-Wallis analysis of variance was used for statistical analysis, and significance was accepted at P < 0.05. There were no differences in baseline scores at day one for the patients treated with different antibiotics (P = 0.58). For patients with pathogen eradication, a significant difference between the two studies in time to eradication was found: 4.8 days for cefmenoxime-treated patients and 1.4 days for CIP- or TAZ-treated patients (P < 0.001). For patients experiencing bacterial eradication, the rates of clinical change for cefmenoxime and CIP or TAZ treatment were similar (P = 0.77). For patients with organisms that were not eradicated, the rates of change were similar (P = 0.14). There was a significant difference in the rate of change for patients experiencing eradication compared with that for patients in which the organism persisted (P << 0.01). Both treatment group and rate were found to be predictive of days to eradication. There was a significant difference in the percent change in clinical score on day 3 of therapy for patients with bacteria that were eradicated versus those with persistent organisms (P < 0.01). The percent change was more predictive of outcome with each subsequent day. Patients who demonstrated a > or = 10% reduction in clinical score after 72 h of treatment had an 88% probability of bacterial eradication. The clinical scoring system is a useful tool for modeling the response of pneumonia to antimicrobial therapy. The ability to predict outcome relatively early in therapy, by using a scoring system of clinical parameters which can be routinely monitored, will aid in assessing the response to antimicrobial therapy in clinical as well as in research settings.

Anti-Infective Agents↗
PubMed1997

Assessment of the enzymuria resulting from gentamicin alone and combinations of gentamicin with various beta-lactam antibiotics.

OBJECTIVE: To determine the propensity of beta-lactam antimicrobials to ameliorate or potentiate aminoglycoside-induced renal enzymuria. DESIGN: Two open, randomized, double-blind, parallel-group studies were conducted in young, healthy, male volunteer subjects. Using a common protocol, 24-hour urine collections were analyzed for the renal tubular enzymes alanine aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase (NAG), as well as for creatinine. Antimicrobial combinations studied included gentamicin plus placebo and gentamicin plus ticarcillin/clavulanate (protocol 1); and gentamicin plus placebo, gentamicin plus piperacillin, and gentamicin plus ceftazidime (protocol 2). The antimicrobial regimens were administered for 7 days. Eight subjects completed each treatment group. RESULTS: There were no significant differences between treatment groups with regard to urine creatinine excretion or serum gentamicin concentrations in either protocol. Enzymuria (AAP [p = 0.039] and NAG [p = 0.337]) was decreased in the gentamicin plus ticarcillin/clavulanate treatment compared with that in the gentamicin plus placebo treatment. Increased enzymuria, as indicated by increased urine concentrations of AAP and NAG, was observed in the gentamicin plus ceftazidime treatment (p < 0.05) compared with the other two treatments. CONCLUSIONS: Based on relative enzymuria, ticarcillin/clavulanate may be renal protective. Piperacillin neither potentiated nor ameliorated aminoglycoside-induced enzymuria. Since acute elevations in AAP and NAG reflect insults to the kidney, these studies suggest that ceftazidime may enhance aminoglycoside-induced renal injury. Piperacillin had no effect on enzymuria and would appear not to enhance or protect against aminoglycoside-induced renal injury.

Acetylglucosaminidase↗
PubMed1997

Assessing antibacterial pharmacoeconomics in the intensive care unit.

Intensive care units (ICUs) represent areas of high use of antibacterials and other pharmacy goods and services. Many institutions view their ICUs as a target for drug-use surveillance and cost-containment programmes. Economic assessment of antibacterial interventions in the ICU should include all direct costs and patient outcomes. Nonetheless, many of these institutions focus their efforts at reducing antibacterial costs without considering the consequences of these actions. It is possible that devoting more resources to antibacterials can have an overall positive economic impact if more appropriate antibacterial use reduces length of stay, decreases bacterial resistance or lowers frequency of adverse complications. Two consequences of antibacterial use which can result in substantial economic burdens to institutions are drug-induced complications (toxicities and adverse events) and the development of antibacterial-resistant organisms. These events are logical targets for performing pharmacoeconomic studies to evaluate appropriate and inappropriate antibacterial use. Either of these problems can increase length of stay, which is the single most important variable influencing the overall cost of patient care. The primary goal of patient care is to hasten patients' clinical improvement. This will result in decreased antibacterial acquisition costs, decreased lengths of ICU and hospital stays, and ultimately decreased consumption of hospital resources. These can be accomplished by using strategies to guide antibacterial use in order to reduce failures, adverse events, toxicity and antimicrobial resistance.

Anti-Infective Agents↗
PubMed1997

In nosocomial pneumonia, optimizing antibiotics other than aminoglycosides is a more important determinant of successful clinical outcome, and a better means of avoiding resistance.

In in vitro and animal models, antibiotics show good relationships between concentration and response, when response is quantified as the rate of bacterial eradication. The strength of these in vitro relationships promises their utility for dosage regimen design and predictable cure of infections such as nosocomial pneumonia. In spite of their intuitive logic, close relationships between dosage and bacterial eradication have not been easy to show in clinical studies of nosocomial pneumonia. Presumably, a variety of patient, disease, bacterial, and pharmacokinetic variables cloud these relationships in patients, and delay their elucidation in patient trials. Patients with serious infections like nosocomial pneumonia require bactericidal antimicrobial activity. Studies in our laboratory show that the minimum effective antimicrobial action is an area under the inhibitory titer (AUIC) of 125, in which AUIC is calculated as the 24 hour serum area under the curve (AUC) divided by the minimum inhibitory concentration (MIC) of the pathogen. This target AUIC may be achieved with either a single antibiotic or it can be the sum of AUIC values of two or more antibiotics. There is considerable variability in the actual AUIC value for patients when antibiotics are administered in their usual recommended dosages. Examples of this variance will be provided using aminoglycosides, fluoroquinolones, and beta-lactams. The achievement of minimally effective antibiotic action, consisting of an AUIC of at least 125, is associated with bacterial eradication in about 7 days for beta-lactams and quinolones. Adding an aminoglycoside to beta-lactams may produce a slight increase in their rate of bacterial killing in vivo, but because of their narrow therapeutic window, and the associated low doses in relation to MIC, there are situations in which the aminoglycosides may be unable to add sufficient additional AUIC. Antibiotic activity indices allow clinicians to evaluate individualized patient regimens. Furthermore, antibiotic activity is a predictable clinical endpoint with predictable clinical outcome. This value also is highly predictive of the development of bacterial resistance. Antimicrobial regimens that do not achieve an AUIC of at least 125 cannot prevent the selective pressure that leads to overgrowth of resistant bacterial subpopulations. The methods based on the determination of AUIC have clinical applicability in routine practice, through software developed for this purpose. These indices can assist with patient management strategies in a prospective manner because they can identify patients at high risk of therapeutic failure or acquired resistance early in therapy before therapy fails. Our studies show that calculations of AUIC can be used to prospectively target regimens to improve the chances of cure with nosocomial pneumonia and other serious infections. A clinical intervention team has been organized to optimize antimicrobial regimens as early in therapy as possible, to lower the high cost events such as failure and acquired bacterial resistance.

Aminoglycosides↗
PubMed1996

Benchmark analysis of strategies hospitals use to control antimicrobial expenditures.

Hospital expenditures on antimicrobial drugs, antimicrobial management practices, and the effects of these practices were studied. A survey on institutional budget, size, and staffing; intensive care unit drug costs and use evaluations; and pharmacy expenditures, including antimicrobial costs, for 1993 and 1994 was sent to 122 hospitals. The written survey was followed by telephoned questions regarding each institution's antimicrobial management and expenditures, and any perceived link between the two. Hospitals were grouped by size and type, data were normalized to costs per occupied bed and costs per occupied bed per case mix index, and averages for each size category were calculated for general institutional information and expenses per antimicrobial. Eighty-eight institutions (72%) responded. Although 61% to 74% of the respondents used an antimicrobial formulary to restrict drug choices and control costs, average total antimicrobial expenses increased by more than $300 per occupied bed between 1993 and 1994. Only 7% of the institutions saw decreased costs of $500 or more per occupied bed. The most common reasons for these decreases were restructuring of pricing contracts and implementation of educational programs. The replacement of one formulary alternative with another led to increases in the use of antimicrobials other than the replacement drug and often did not produce savings. The replacement of one formulary antimicrobial with another led more to costshifting than to overall savings.

Anti-Bacterial Agents↗
PubMed1996

Performance of the fractional maximal effect method: comparative interaction studies of ciprofloxacin and protein synthesis inhibitors.

The performance of the recently developed Fractional Maximal Effect (FME) method was evaluated along with the conventional checkerboard technique and time-kill method. Ciprofloxacin in combination with tobramycin was tested against Escherichia coli and Pseudomonas aeruginosa and in combination with tetracycline, chloramphenicol, erythromycin against Escherichia coli. Two combinations, amoxicillin-tetracycline (antagonistic) and tobramycin-ticarcillin (synergistic), were included as reference interactions. The FME method unequivocally showed an antagonistic interaction between ciprofloxacin and all the protein synthesis inhibitors (PSIs) tested, while the other two methods yielded variable results. At a total FME (TFME) level of 1, the FME method demonstrated a similar degree of antagonism against ciprofloxacin by tetracycline, chloramphenicol, and erythromycin, and much lower by tobramycin. Internal consistency of the FME operation was demonstrated by the identical conclusions obtained at both TFME levels of 0.5 and 1. The FME method appears to be a practical alternative for resolving the inconsistencies observed in conventional methods of antibiotic combination testing.

Anti-Infective Agents↗
PubMed1996

The economic potential of dual individualisation methodologies.

Cost-effective treatment of patients with bacterial infections can best be accomplished by facilitating a rapid response. Achieving a more rapid cure of the infection should result in reduced utilisation of healthcare resources. An innovative means of achieving a more rapid response to antibacterial therapy has been termed dual individualisation. Dual individualisation allows for the simultaneous consideration of the pharmacokinetic interaction between an antibacterial agent and a patient, with the pharmacodynamic interaction between the antibacterial agent and the bacterial pathogen. Integrating the pharmacokinetic parameter of area under the curve (AUC), with the pharmacodynamic measure of minimum inhibitory concentration (MIC) yields a ratio called the area under the inhibitory curve (AUIC). Clinical studies using dual individualisation to achieve a target AUIC24h of 125-250 have been performed with cephalosporins and fluoroquinalones. Economic evaluation of the results demonstrate that dual individualisation is cost-effective. Dual individualisation can be implemented in most practice setting using existing clinical data. Use of a computer model allows for cost-effective calculation of AUIC24h without having to measure serum drug concentrations of bacterial MIC. By adjusting antibacterial regimens to achieve a target AUIC, optimisation of antibacterial therapy can be achieved with resultant economic benefits.

Anti-Infective Agents↗
PubMed1995

Understanding and managing microbial resistance in institutional settings.

Patient factors that contribute to resistance are identified, the concept of the "genesis patient" is explained, and strategies for preventing or overcoming resistance are described. Technology makes it possible to support medically compromised patients. These patients, called genesis patients, cannot clear mutant organisms that develop resistance, and they become focal points for the emergence and spread of resistant organisms. Strategies to control the emergence of resistance in institutional settings must take into consideration the unique role of genesis patients. A wide range of patient- and antibiotic-related factors must be considered. Suboptimal dosing clearly plays a role in the development of resistance. A formulary that seeks to curtail expenses by severely limiting antimicrobial choices may actually drive costs up because it contributes to the emergence of resistance. The best formulary strategy may be to include a wide variety of antimicrobials from all available classes. Particularly in genesis patients, real-time surveillance to ensure timely, effective antimicrobial therapy is essential.

Anti-Bacterial Agents↗
PubMed1995

Effect of food on the oral bioavailability of isosorbide-5-mononitrate administered as an extended-release tablet.

We evaluated the effect of a high-fat breakfast and gastric emptying rate on the oral bioavailability of a isosoribide-5-mononitrate (5-ISMN) controlled-release tablet formulation (IMDUR 60-mg tablets, Astra Hässle AB, Mölndal, Sweden) relative to an oral solution in 18 healthy men. Gastric emptying was monitored by radiotelemetry using the Heidelberg capsule technique. After administration of the 5-ISMN 60-mg solution, absorption was rapid with mean peak plasma 5-ISMN concentrations of 1533 ng/mL achieved in less than 1 hour. In contrast, after administration of IMDUR 60-mg tablets, the drug was more slowly absorbed, reaching mean peak plasma concentrations of 541 ng/mL in 3 to 4 hours. The bioavailability of 5-ISMN from IMDUR tablets under fasted conditions was approximately 78% relative to the solution; and, in the presence of food, the bioavailability was slightly increased to 86% (P = .057). The mean gastric residence time of IMDUR tablets under fasted conditions was 68 minutes, and in the presence of food was increased to 478 minutes, with 9 of the 18 subjects having gastric emptying delayed for at least 600 minutes. We conclude that in the presence of food, gastric emptying time is considerably increased causing a delay in drug absorption and a slight increase in the bioavailability of 5-ISMN from this controlled-release tablet formulation, however this effect is not clinically relevant.

Administration, Oral↗
PubMed1995

The effect of verapamil on the nephrotoxic potential of gentamicin as measured by urinary enzyme excretion in healthy volunteers.

The effects of verapamil on the nephrotoxic potential of multiple-dose gentamicin were studied in healthy adult male volunteers. Subjects received a gentamicin infusion every 8 hours for 19 doses. Gentamicin dosage was adjusted to maintain peak concentrations of 5.5 mg/L and trough concentrations of 0.5 mg/L. Verapamil was given as a sustained release preparation of 180 mg twice daily starting 2 days before the aminoglycoside, and continued for 4 days post-gentamicin therapy. Nephrotoxicity was assessed by measuring 24-hour urinary alanine aminopeptidase excretion (AAP). The urinary AAP results of six subjects given gentamicin with verapamil were compared with urinary AAP from nine subjects treated with gentamicin alone. These nine subjects were matched with the verapamil-treated subjects on the basis of gentamicin area-under-the-curve (AUC). After matching AUC, gentamicin exposure was virtually identical between the two groups with an average gentamicin AUC of 26.61 +/- 1.49 and 27.51 +/- 1.25 mg.hr/L for the gentamicin/ve-rapamil and gentamicin only groups respectively. Verapamil retarded the rise in mean daily AAP excretion on days 1 to 6 of gentamicin therapy, with a significant difference with respect to AAP urinary excretion (P < .05) observed on day 2. There was no significant difference in total cumulative AAP excretion or in the time to return to baseline AAP excretion. Therefore, verapamil was effective in reducing AAP excretion associated with gentamicin therapy.

Adolescent↗