Search

A novel Bayesian method was developed to interpret serum vancomycin concentrations (SVCs) following the administration of one or more vancomycin doses with potential varying doses and intervals based on superposition principles. The method was evaluated using retrospective data from 442 subjects from three hospitals.

The effect of protein binding on the antimicrobial activity of ertapenem was evaluated using the bacterial kill rate and concentration-response studies. Various proportions of human serum were utilized to determine the total and free-drug concentrations using a validated high-performance liquid chromatography assay. The MICs and kill curves were determined for test isolates of Enterobacter cloacae and Staphylococcus aureus at various percentages of human serum. The killing of bacteria was analyzed in relation to the free and total concentrations of ertapenem at various proportions of human serum. It was determined that unbound ertapenem was responsible for the antimicrobial activity against the test isolates.

This study was conducted in order to (i) determine the effect of food, orange juice, or antacids on the absorption of a single oral 500-mg dose of ethionamide (ETA) in healthy volunteers, including an assessment of bioequivalence, and (ii) determine ETA population pharmacokinetic (PK) parameters. The pharmacokinetics of ETA in serum was determined for 12 healthy males and females in a randomized, four-period crossover study. Volunteers received single 500-mg doses of ETA either on an empty stomach (reference) or with food, orange juice, or antacids. Serum samples were collected for 48 h and assayed by high-performance liquid chromatography. Data were analyzed by noncompartmental and population methods. Mean test/reference ratios and 90% confidence intervals were determined. No statistically significant differences were seen in the maximum concentration of ETA ( C max ), time to maximum concentration ( T max ), or area under the concentration-time curve from 0 h to infinity (AUC 0–∞ ) between the four treatments ( P > 0.05 by analysis of variance). The least-squares mean ratios (with confidence intervals in parentheses) for C max were 105% (81.2 to 135%) after orange juice, 94% (72.8 to 121%) after food, and 88% (68.4 to 114%) after antacids. The least-squares mean ratios (with confidence intervals is in parentheses) for AUC 0–∞ were 91% (72.7 to 115%) after orange juice, 96% (76.4 to 121%) after food, and 95% (75.5 to 120%) after antacids. The mean T max was slightly prolonged following antacid or food administration (2.3 to 2.6 h) compared to administration on an empty stomach or with juice (1.7 to 1.9 h). The median population PK parameters were as follows: K a = 0.37 to 0.48 h −1 , V/F = 2.0 to 2.8 liters/kg, CL/ F = 56.5 to 72.2 liters/h, and terminal half-life = 1.7 to 2.1 h, where K a is the absorption rate constant, V is the volume of distribution, and CL is clearance. The PK behavior of ETA was not significantly modified by the different conditions studied. Mean ratios for AUC ranged from 0.91 to 0.96 for the orange juice, food, and antacid treatments, indicating a minimal effect on relative bioavailability. ETA can, therefore, be administered with food if tolerance is an issue.

The serum bactericidal activity of ciprofloxacin against strains of Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa for which MICs are similar (0.4 microgram/ml) was assessed with serum ultrafiltrates from five healthy volunteers receiving ciprofloxacin at 400 mg intravenously every 8 h. In addition, human serum was supplemented with ciprofloxacin to achieve a mean steady-state concentration (Css) that might be achieved in patients with renal failure, with total clearances of 3 to 4 liters/h (elimination rate constant, 0.08 h-1). The area under the inhibitory titer curve from 0 to 24 h (AUIC24) and the area under the bactericidal titer curve from 0 to 24 h (AUBC24) were both measured and predicted as the area under the concentration-time curve from 0 to 24 h (AUC24)/MIC and AUC24/MBC, respectively. We previously demonstrated that a breakpoint AUC24/MIC of 125 for ciprofloxacin had a significantly higher probability of treatment success than lower values, with 250 to 500 being optimal. Volunteer sera (mean Css, 1.55 to 2.48 micrograms/ml) achieved AUC24/MICs of 90 to 145. Supplemented serum (mean Css, 6.00 to 7.42 micrograms/ml) achieved AUC24/MICs of 350 to 450. Correlation coefficients for measured and predicted values of AUC24/MIC and AUC24/MBC were 0.826 and 0.941, respectively. The mean percent errors were not significantly different from zero for either AUIC24 or AUBC24 values (P > 0.1, P > 0.4). Time-kill curve studies were performed with low (1.55 to 2.48 micrograms/ml), intermediate (6.00 to 7.42 micrograms/ml), and high (15 to 25 micrograms/ml) concentrations of ciprofloxacin for the three organisms. At low concentrations (3 to 6 times the MIC) AUC24/MICs were

The checkerboard technique leading to the fractional inhibitory concentration indexes and the killing curve method are currently the most widely used methods to study antibiotic combinations. For both methods, experimental conditions and interpretation criteria are somewhat arbitrary. The relevance of the fractional inhibitory concentration index computation, in the classic case of additivity [P = d1/(D1)p + d2/(D2)p, where d1 and d2 are the doses of drugs 1 and 2 in combination to produce an effect at a percent level (P) and (D1)p and (D2)p are the doses required for the two respective drugs alone to produce the same effect] relies on the assumption of a linear relationship between the MIC and the concentration of the test antibiotics. In addition, there is no consensus as to the definition of synergy in killing curve interpretation. The fractional maximal effect (FME) method is a new approach which was developed to handle the nonlinear pharmacodynamics exhibited by antibiotics and other drugs. This method relies on the mathematical linearization of the nonlinear concentration-effect scales and eventual construction of an isobologram-type data plot. The FME method was applied to study interactions between several antibiotic combinations: amoxicillin and tetracycline, ciprofloxacin and erythromycin, and ticarcillin and tobramycin. These combinations were selected because the pharmacologic basis for their interactions has been previously described. The FME method correctly identified antagonism for the first two combinations and synergism for the last combination. Conclusions were reproducible across the range of concentrations studied. Besides providing information on the nature of the interaction, the method can rapidly explore the effect of changing concentration ratios of two antimicrobial agents on the degrees of interaction. The FME method may be applied to interactions between drugs or agents with either a linear or nonlinear endpoint measurement. Methods frequently used for drug combination testing are also discussed in the paper.

Nikkomycin Z is an antifungal drug that inhibits chitin synthase. This agent is under development as an orphan product for treatment of coccidioidomycosis. Safety and pharmacokinetics of nikkomycin Z were evaluated in healthy male subjects following single, rising oral doses ranging from 250 mg to 2,000 mg. A total of 12 subjects were recruited and divided into two groups. Group 1 ( n = 6) received two out of three doses of 250 mg, 1,000 mg, or 1,750 mg and a placebo randomly in place of one of the doses. Group 2 ( n = 6) received two out of three doses of 500 mg, 1,500 mg, or 2,000 mg and a placebo in place of one of the doses. Subjects were confined to the study unit overnight prior to dosing, and 12 blood samples were collected over 24 h postdosing while subjects were confined. Subjects returned for additional blood samples and safety evaluations at 48 h and 72 h after each dose. There was a 2-week washout period between doses. Plasma drug concentrations were determined using a validated high-performance liquid chromatography method. Nikkomycin Z was absorbed after oral administration, reaching a maximum concentration in serum of 2.21 μg/ml at 2 h postdose and an area under the concentration-time curve from 0 h to infinity of 11.3 μg·h/ml for the 250-mg dose. Pharmacokinetics appeared linear over the range of 250 to 500 mg; however, relative bioavailability was about 62 to 70% for the 1,000-mg dose and 42 to 47% for doses between 1,500 and 2,000 mg. The mean terminal half-life ranged from 2.1 to 2.5 h and was independent of dose. No serious or dose-related adverse events were observed. This study provides a basis for pharmacokinetic simulations and continued studies of nikkomycin Z administered in multiple doses.

Four strains of Helicobacter pylori were subjected to an in vitro serial passage technique to compare the propensity of the organisms to develop resistance to seven classes of antibacterial agents. The passages were made on serially doubling concentrations of antibacterial agents incorporated into agar starting at one-half the base-line MIC. The frequency of spontaneous resistance was also determined for each strain at four and eight times the MIC of each antibacterial agent. Strains resistant to ciprofloxacin, metronidazole, erythromycin, and tobramycin were isolated. The experiments failed to select organisms resistant to bismuth subsalicylate, furazolidone, or amoxicillin, although the MIC of amoxicillin was increased 4- to 16-fold. With the exception of erythromycin, organisms with the selected resistance were stable after at least three passages on antibacterial agent-free medium. Spontaneous resistance rates were generally of a low magnitude and were not predictive of the serial passage results.

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.

The effect of antacids on the systemic absorption of oral norfloxacin was evaluated in 12 healthy volunteers. Subjects were given each treatment in a balanced sequence at 7-day intervals. Treatments included 400 mg of norfloxacin alone, 400 mg of norfloxacin 5 min after aluminum-magnesium hydroxide (Maalox), Maalox 2 h after 400 mg of norfloxacin, and 400 mg of norfloxacin 5 min after calcium carbonate (Titralac). Blood and urine samples were collected at predetermined time intervals for 24 and 48 h, respectively. Norfloxacin concentrations in plasma and urine were determined by high-pressure liquid chromatography. The area under the plasma concentration-versus-time curve from time zero to infinity and urinary recovery were used to compare the relative bioavailability of norfloxacin with antacids with that of norfloxacin alone. Norfloxacin bioavailability was markedly reduced when subjects received antacid pretreatment. When norfloxacin was given 5 min after Maalox and Titralac, the bioavailabilities were 9.02 and 37.5%, respectively, relative to that for 400 mg of norfloxacin alone. When Maalox was given 2 h after norfloxacin, maximal concentrations of norfloxacin in plasma occurred between 1 and 1.5 h postdose, and absorption was reduced to a lesser extent, with a relative bioavailability of 81.31%. Norfloxacin concentrations in urine were also reduced as a result of antacid administration. Antacids containing aluminum and magnesium salts and calcium carbonate should be avoided by patients taking norfloxacin.

Ethambutol (EMB) is the most frequent “fourth drug” used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (6 standard deviation) EMB maximum concentration of drug in serum (Cmax )o f 4.56 1.0 mg/ml, time to maximum concentration of drug in serum (Tmax )o f 2.56 0.9 h, and area under the concentration-time curve fro m0ht oinfinity (AUC0‐‘) of 28.9 6 4.7 mg z h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 6 0.5 mg/ml, Tmax of 2.9 6 1.2 h, and AUC0‐‘ of 27.5 6 5.9 mg z h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 6 0.8 mg/ml, Tmax of 3.2 6 1.3 h, and AUC0‐‘ of 29.6 6 4.7 mg z h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0‐‘ can be avoided by giving EMB on an empty stomach whenever possible. Ethambutol (EMB) is the most frequently used “fourth drug” for the empiric treatment of tuberculosis (3). The standard short-course treatment of tuberculosis consists of isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA), plus either EMB or streptomycin until susceptibility data are available (3). Also, EMB is frequently used for the treatment of infections caused by Mycobacterium avium complex (2). Limited information exists regarding the pharmacokinetics of EMB in healthy or infected individuals or regarding the effect of food or antacids on the gastrointestinal absorption of the drug (1, 12‐15, 17‐19, 21, 22). We examined the pharmacokinetics of EMB in healthy volunteers under fasting conditions (two replicates), with food, and with an aluminum-magnesium hydroxide antacid. This study describes the concentrations in serum and the pharmacokinetic behavior under optimal conditions, and the results can be used as benchmarks for comparison with those for samples obtained in other clinical settings. (Part of this study was presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 28 September to 1 October 1997 [20].)

Ten patients with AIDS and cytomegalovirus (CMV) gastrointestinal infection were included in an open-label study to evaluate the safety, efficacy, and pharmacokinetics of 90 mg of intravenous foscarnet/kg of body weight twice daily accompanied by (pre)hydration of 500 to 750 ml. Efficacy was documented endoscopically, while safety was evaluated clinically by patient reports and physical and laboratory observation. The pharmacokinetics of foscarnet was evaluated after the first dose and following approximately 20 days of therapy. Nine patients (90%) responded histopathologically, nine (90%) responded endoscopically, and nine (90%) responded symptomatically to foscarnet therapy. Adverse events resulted in discontinuance of medication in the case of one patient. The mean maximal concentration was 621 microM following the first dose and 687 microM at steady state (P = 0.11). The apparent elimination rate constant and elimination half-life were not different between dose 1 and steady state. There were no significant changes in foscarnet excretion or renal clearance between dose 1 and steady state. The steady-state volume of distribution was 23.4 liters following the first dose and 19.0 liters at steady state (P < 0.002). Twice-daily foscarnet appeared to be safe and efficacious in the treatment of CMV gastrointestinal disease in this study, resulting in endoscopic or histologic improvement in 9 of the 10 (90%) patients. Minor changes in clearance and volume of distribution noted at steady state compared to single-dose administration are readily explained by study design, known information about foscarnet pharmacokinetics, and changes in body weight and creatinine clearance in the patients.

Mycobacterium avium is an intracellular pathogen that can invade and multiply within macrophages of the reticuloendothelial system. Current therapy is not highly effective. Particulate drug carriers that are targeted to the reticuloendothelial system may provide a means to deliver antibiotics more efficiently to M. avium-infected cells. We investigated the formulation of the antibiotics ciprofloxacin and azithromycin in liposomes and tested their antibacterial activities in vitro against M. avium residing within J774, a murine macrophage-like cell line. A conventional passive-entrapment method yielded an encapsulation efficiency of 9% for ciprofloxacin and because of aggregation mediated by the cationic drug, was useful only with liposomes containing < or = 50 mol% negatively charged phospholipid. In contrast, ciprofloxacin was encapsulated with > 90% efficiency, regardless of the content of negatively charged lipids, by a remote-loading technique that utilized both pH and potential gradients to drive drug into preformed liposomes. Both the cellular accumulation and the antimycobacterial activity of ciprofloxacin increased in proportion to the liposome negative charge; the maximal enhancement of potency was 43-fold in liposomes of distearoylphosphatidylglycerol-cholesterol (DSPG-Chol) (10:5). Azithromycin liposomes were prepared as a freeze-dried preparation to avoid chemical instability during storage, and drug could be incorporated at 33 mol% (with respect to phospholipid). Azithromycin also showed enhanced antimycobacterial effect in liposomes, and the potency increased in parallel to the moles percent of negatively charged lipids; azithromycin in DSPG-Chol (10:5) liposomes inhibited intracellular M. avium growth 41-fold more effectively than did free azithromycin. Thus, ciprofloxacin or azithromycin encapsulated in stable liposomes having substantial negative surface charge is superior to nonencapsulated drug in inhibition of M.avium growth within cultured macrophages and may provide more effective therapy of M.avium infections.

The pharmacodynamic effects of metronidazole on Trichomonas vaginalis have been poorly characterized. The present in vitro study was performed to characterize the relationship between killing of trichomonads and metronidazole exposure (metronidazole concentration and time of exposure). Five laboratory strains and five recent clinical isolates of T. vaginalis were studied. The minimum lethal concentrations (MLCs) of metronidazole for the strains ranged from 0.8 to 25 micrograms/ml under anaerobic conditions. Metronidazole exhibited concentration-dependent killing against T. vaginalis at concentrations ranging from 0.1 to > 10 times the MLC. The endpoint measurement, the kill rate constant, which was derived from the reduction in the logarithm of the colony count divided by exposure time, compared with the kill rate constant for the growth control was not affected by the time of assessment between 2 and 24 h. The kill rate constant-versus-metronidazole exposure curves were similar when concentration was expressed as a multiple of the MLC. There were no apparent differences between the clinical isolates and laboratory strains. These data suggest that peak metronidazole concentration and/or area under the plasma concentration-versus-time curve are the important pharmacodynamic parameters to be optimized.

Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two-compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-1.h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent probabilities of clinical and microbiologic cures were 42 and 26%, respectively. At an AUIC above 125 (45 patients), the probabilities were 80% (P < 0.005) and 82% (P < 0.001), respectively. There were two significant breakpoints in the time-to-bacterial-eradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication was 6.6 days: and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.

A turbidimetric assay was developed and validated against Escherichia coli for the quantitation of viable bacterial densities. The Abbott MS-2 research system was employed for continuous 5-min measurements of optical density. A linear standard curve was obtained by regressing the initial bacterial density (log CFU per milliliter) against the time required for bacterial growth causing a 5% decrease in optical transmittance. Slope and intercept values obtained from eight standard curves showed excellent assay reproducibility. Results obtained by the turbidimetric assay compared favorably to those obtained by the conventional pour plate assay. Prior to the application of the new assay, possible interferences of postantibiotic effect induced by the test antibiotics were excluded. The turbidimetric assay, which is presumably more efficient and less expensive, was implemented for the time-kill studies of three different beta-lactams against E. coli.

The postantibiotic effect (PAE) for 10 isolates of Escherichia coli was measured by two methods after 1 h of exposure to ampicillin, ciprofloxacin, or tobramycin. The reference method involved serial colony counting to determine growth after antibiotic exposure in relation to control growth. A spectrophotometric procedure was developed with the Abbott MS-2 research system. This method measured the time to detection of growth after exposure and compared this with the time for growth detection in control chambers having the same initial colony count. A reference curve of time to growth versus log initial CFU per milliliter was used to standardize control growth. PAE was determined after exposure to antibiotic at two and six times the MIC and with inocula ranging from 10(3) to 10(9) CFU/ml. There was a statistically significant correlation between PAE measured by the spectrophotometric and the reference methods, and the residuals about the regression line were normally distributed. The mean PAE determined by both methods was statistically different for tobramycin-exposed, but not for ampicillin- or ciprofloxacin-exposed, organisms. There was a concentration-dependent PAE for ciprofloxacin and tobramycin. The PAEs for ciprofloxacin (151 min) and tobramycin (108 min) at concentrations six times the MIC were prolonged compared with those measured at two times the MIC (69 and 66 min, respectively). PAE was inversely related to the exposed inoculum for ciprofloxacin and tobramycin. The PAE for E. coli exposed to ampicillin was minimal and was not affected by either concentration or inoculum. The MS-2 method for determining PAE yields similar results, but is less laborious than the reference method.

The effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline was studied. In a randomized crossover design, six healthy male volunteers received an infusion of 200 mg of doxycycline hyclate on two occasions separated by 7 days. On one occasion, subjects were given 30 ml of aluminum hydroxide orally four times a day for 4 days, beginning 2 days prior to doxycycline dosing. Blood and urine samples were collected up to 48 and 96 h after the infusion, respectively, and were analyzed by a microbial assay. Values for volume of distribution at steady state, nonrenal clearance, urine recovery, and urine pH were not statistically different among treatment groups. With concomitant antacid therapy, the half-life of intravenous doxycycline was shortened from 16.2 +/- 2.6 to 11.2 +/- 1.2 h (P = 0.003), and total body clearance increased from 37.4 +/- 6.5 to 54.1 +/- 12.3 ml/min (P = 0.008). Area under the concentration-time curve for serum was decreased by 18 to 44%, with a 22 to 41% increase in renal clearance. Although the increase in nonrenal clearance ranged from 11 to 128%, the high variability led to a nonsignificant difference (P = 0.07). Concomitant oral antacid therapy may significantly enhance the clearance of intravenous doxycycline.

A study involving 25 health male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 +/- 3.0 years, and the mean weight was 77.3 +/- 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophylline dose. Theophylline concentrations in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 +/- 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 +/- 1.63 to 7.02 +/- 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.