Pefloxacin as a surrogate marker for quinolone susceptibility in Salmonella enterica serovars Typhi & Paratyphi A in India.

BACKGROUND & OBJECTIVES: The emergence of resistance to fluoroquinolones in enteric fever despite the pathogen being susceptible by in vitro laboratory results, led to repeated changes in Clinical and Laboratory Standard Institute (CLSI) guidelines for this class of antibiotics to have specific and sensitive interpretative criteria. In 2015, CLSI added pefloxacin disk diffusion criteria as a surrogate marker for fluoroquinolone susceptibility. This study was carried out to evaluate the use of pefloxacin as a surrogate marker for ciprofloxacin, ofloxacin and levofloxacin susceptibility in clinical isolates of Salmonella Typhi and S. Paratyphi A. METHODS: A total of 412 strains of S. Typhi and S. Paratyphi A were studied for pefloxacin disk diffusion test as a surrogate marker for susceptibility to ciprofloxacin, ofloxacin and levofloxacin as per CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Molecular mechanisms of resistance to fluoroquinolones were also determined and correlated with pefloxacin susceptibility breakpoints. RESULTS: Of the total 412 strains, 34 were susceptible to ciprofloxacin and 33 each to levofloxacin and ofloxacin using CLSI minimum inhibitory concentration (MIC) breakpoints. There was a positive correlation between MICs with correlation coefficients 0.917, 0.896 and 0.958 for the association between ciprofloxacin and ofloxacin, ciprofloxacin and levofloxacin and ofloxacin and levofloxacin, respectively (P <0.001). The sensitivity, specificity and positive predictive value of pefloxacin as a surrogate marker using ciprofloxacin MIC as a gold standard were 100, 99.5 and 94.4 per cent, while 100, 99.2 and 91.7 per cent taking ofloxacin and levofloxacin MIC as gold standard. Mutations in target genes correlated with the pefloxacin susceptibility results. INTERPRETATION & CONCLUSIONS: Our results showed that pefloxacin served as a good surrogate marker for the detection of susceptibility to ciprofloxacin, ofloxacin and levofloxacin in S. Typhi and S. Paratyphi A. Further studies are required to confirm these findings.

dOFV distributions: a new diagnostic for the adequacy of parameter uncertainty in nonlinear mixed-effects models applied to the bootstrap.

Knowledge of the uncertainty in model parameters is essential for decision-making in drug development. Contrarily to other aspects of nonlinear mixed effects models (NLMEM), scrutiny towards assumptions around parameter uncertainty is low, and no diagnostic exists to judge whether the estimated uncertainty is appropriate. This work aims at introducing a diagnostic capable of assessing the appropriateness of a given parameter uncertainty distribution. The new diagnostic was applied to case bootstrap examples in order to investigate for which dataset sizes case bootstrap is appropriate for NLMEM. The proposed diagnostic is a plot comparing the distribution of differences in objective function values (dOFV) of the proposed uncertainty distribution to a theoretical Chi square distribution with degrees of freedom equal to the number of estimated model parameters. The uncertainty distribution was deemed appropriate if its dOFV distribution was overlaid with or below the theoretical distribution. The diagnostic was applied to the bootstrap of two real data and two simulated data examples, featuring pharmacokinetic and pharmacodynamic models and datasets of 20-200 individuals with between 2 and 5 observations on average per individual. In the real data examples, the diagnostic indicated that case bootstrap was unsuitable for NLMEM analyses with around 70 individuals. A measure of parameter-specific "effective" sample size was proposed as a potentially better indicator of bootstrap adequacy than overall sample size. In the simulation examples, bootstrap confidence intervals were shown to underestimate inter-individual variability at low sample sizes. The proposed diagnostic proved a relevant tool for assessing the appropriateness of a given parameter uncertainty distribution and as such it should be routinely used.

Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling.

Taking parameter uncertainty into account is key to make drug development decisions such as testing whether trial endpoints meet defined criteria. Currently used methods for assessing parameter uncertainty in NLMEM have limitations, and there is a lack of diagnostics for when these limitations occur. In this work, a method based on sampling importance resampling (SIR) is proposed, which has the advantage of being free of distributional assumptions and does not require repeated parameter estimation. To perform SIR, a high number of parameter vectors are simulated from a given proposal uncertainty distribution. Their likelihood given the true uncertainty is then approximated by the ratio between the likelihood of the data given each vector and the likelihood of each vector given the proposal distribution, called the importance ratio. Non-parametric uncertainty distributions are obtained by resampling parameter vectors according to probabilities proportional to their importance ratios. Two simulation examples and three real data examples were used to define how SIR should be performed with NLMEM and to investigate the performance of the method. The simulation examples showed that SIR was able to recover the true parameter uncertainty. The real data examples showed that parameter 95 % confidence intervals (CI) obtained with SIR, the covariance matrix, bootstrap and log-likelihood profiling were generally in agreement when 95 % CI were symmetric. For parameters showing asymmetric 95 % CI, SIR 95 % CI provided a close agreement with log-likelihood profiling but often differed from bootstrap 95 % CI which had been shown to be suboptimal for the chosen examples. This work also provides guidance towards the SIR workflow, i.e.,which proposal distribution to choose and how many parameter vectors to sample when performing SIR, using diagnostics developed for this purpose. SIR is a promising approach for assessing parameter uncertainty as it is applicable in many situations where other methods for assessing parameter uncertainty fail, such as in the presence of small datasets, highly nonlinear models or meta-analysis.

Tissue dyslipidemia in Salmonella-infected rats treated with amoxillin and pefloxacin.

BACKGROUND: This study investigated the effects of salmonella infection and its chemotherapy on lipid metabolism in tissues of rats infected orally with Salmonella typhimurium and treated intraperitoneally with pefloxacin and amoxillin. METHODS: Animals were infected with Salmonella enterica serovar Typhimurium strain TA 98. After salmonellosis was confirmed, they were divided into 7 groups of 5 animals each. While one group served as infected control group, three groups were treated with amoxillin (7.14 mg/kg body weight, 8 hourly) and the remaining three groups with pefloxacin (5.71 mg/kg body weight, 12 hourly) for 5 and 10 days respectively. Uninfected control animals received 0.1 ml of vehicle. Rats were sacrificed 24h after 5 and 10 days of antibiotic treatment and 5 days after discontinuation of antibiotic treatment. Their corresponding controls were also sacrificed at the same time point. Blood and tissue lipids were then evaluated. RESULTS: Salmonella infection resulted in dyslipidemia characterised by increased concentrations of free fatty acids (FFA) in plasma and erythrocyte, as well as enhanced cholesterogenesis, hypertriglyceridemia and phospholipidosis in plasma, low density lipoprotein-very low density lipoprotein (LDL-VLDL), erythrocytes, erythrocyte ghost and the organs. The antibiotics reversed the dyslipidemia but not totally. A significant correlation was observed between fecal bacterial load and plasma cholesterol (r=0.456, p<0.01), plasma triacyglycerols (r=0.485, p<0.01), plasma phospholipid (r=0.414, p<0.05), plasma free fatty acids (r=0.485, p<0.01), liver phospholipid (r=0.459, p<0.01) and brain phospholipid (r=0.343, p<0.05). CONCLUSION: The findings of this study suggest that salmonella infection in rats and its therapy with pefloxacin and amoxillin perturb lipid metabolism and this perturbation is characterised by cholesterogenesis.

Effects of systemic ornidazole, systemic and local compound ornidazole and pefloxacin mesylate on experimental periodontitis in rats.

BACKGROUND: The purpose of the current study is to evaluate the effects of systemic ornidazole (SO) and systemic and local compound ornidazole and pefloxacin mesylate (SCOPM/LCOMP) on the inflammatory response associated with rat experimental chronic periodontitis (ECP) in sites with subgingival debridement. MATERIAL/METHODS: Periodontitis was induced in male Sprague-Dawley rats by placing a thin steel ligature around the upper first molars and inoculating them with Porphyromonas gingivalis 381. After the successful induction of the rat ECP, the periodontitis rats were randomly divided into 3 different combined treatment groups: (A) SO with scaling and root planing (SRP); (B) SCOMP with SRP; and (C) LCOMP with SRP. After 2 weeks the effects of the treatments were evaluated based on gingivitis, plaque index, probing pocket depth, aspartate aminotransferase, alveolar bone loss, and hematoxylin-eosin staining of the region around the first molars. RESULTS: After treatment, comparison with ECP was performed. The mean percentage reductions of SBI in SO, SCOPM, and LCOPM were 27.73%, 33.61%, and 58.82%, respectively. Those of PI were 33.20%, 42.80%, and 60.00%; those of PPD were 48.66%, 55.70%, and 72.48%; those of GCF-AST were 41.64%, 49.03%, and 66.42%; and those of ABL were 41.19%, 43.63%, and 54.47%, respectively. The inflammatory score of H&E showed median scores of 2.5, 1.75, 1.63, and 0.95 for ECP, SO, SCOMP, and LCOMP, respectively. All 3 treatment groups exhibited significantly reduced inflammation indicators (P<0.05). Of the 3, group C was the most effective (P<0.05). CONCLUSIONS: Although all the combined treatment groups responded to therapy with significant resolution of the infection, adjunctive LCOMP therapy is more effective for periodontitis.

Validation of UV Spectrophotometric Method of Analysis of some Marketed Perfloxacin in Nigeria

Background: Acquiring sophisticated LC instruments by most third world laboratories is capital intensive.Literatures on simple spectrophotometric analytical methods for pefloxacin are scarce. Objectives: The present study was undertaken to develop and validate a simple and economic UV spectrophotometric method for estimating pefloxacin mesylate (PFM) in dosage preparations.Methods: Using a JENWAY spectrophotometer at predetermined emax of 277nm with 1 v/v aqueous glacialacetic acid as blank; the method was validated for linearity; accuracy; precision; reproducibility; and specificity asper International Conference on Harmonization (ICH) guidelines and used to determine the content of pefloxacinin seven marketed brands in Nigeria. Results: The method exhibited good linearity over a range of 0.40-12.0 ?g/ml (regression equation: y = 0.0859x+0.0211 ; r=0.999). Mean recovery accuracy (99.183 ) and assay result in the range of 100.5- 110.17 for these lected brands were not significantly different at p=0.05. The coefficient of variation (CV) for both intra andinter-day were below 7 . The method was specific for pefloxacin in the presence of common excipients Conclusion: The method gave good validation results and could be employed for routine analysis of PFM incommercial formulations

Modification of innervation pattern by fluoroquinolone treatment in the rat salivary glands.

Fluoroquinolone antibiotics (FQAs) are widely used in dental and medical therapy. Despite their known severe adverse actions on the central and peripheral nervous system, little attention has been directed toward the potential toxic side effects of these compounds on the oral tissues. As the saliva secretion is controlled by the nervous system and neuropeptides, the neurotoxic effect of pefloxacin (PEF), a representative member of FQAs, was studied in rats in the present work. Previously, we demonstrated a significant weight loss of parotid gland tissue, a marked decrease in 3H-thymidine incorporation, a decreased volume of saliva and amylase activity of the glandular tissue in response to PEF. Animals received intraperitoneal injection of PEF (20 mg/100 g body weight daily) for 3 and 7 days. Normal histology, and neurofilament 200, substance P (SP) and calcitonin gene-related polypeptide (CGRP) containing nerve fibers were detected with immunohistochemical methods. A marked decrease of the weights in salivary glands and the acinar diameters were measured. Similarly, a strong and significant decrease of the number of SP and CGRP containing nerve fibers were detected. These findings suggest that the impaired morphology and innervation pattern of salivary glands is related to the neurotoxic adverse effect of FQA treatment.

Effect of trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats.

The pharmacokinetics of orally administered pefloxacin were studied to evaluate the bio-enhancing effect of the herbal bio-enhancer, trikatu, in mountain Gaddi goats (n = 6). The findings of the study revealed a decreased plasma concentration (p > 0.05) of pefloxacin following trikatu administration during the absorption phase (10, 15, 20 min post pefloxacin administration). In contrast, the plasma concentrations of pefloxacin were significantly higher at 4, 6, 8 and 12 h (during the elimination phase) of the pefloxacin administration. The findings of the investigation revealed higher values for the area under the curve, the area under the first moment of the plasma drug concentration time curve, the mean residential time, the total duration of pharmacological action and bioavailability. Trikatu treatment, however, significantly reduced the elimination half life (t 1/2 beta) and zero time intercept of the elimination phase. The apparent volume of distribution based on the total area under the plasma drug concentration curve [(Vd(area)] and the apparent volume of distribution based on the zero time plasma concentration intercept of the elimination phase [Vd(B)] were significantly higher in trikatu treated animals indicating a better penetration of the drug. Based on the MIC of 0.8 microg/ml of pefloxacin, a priming dose of 6.0 mg/kg and a maintenance dose of 2.21 mg/kg is required to be administered at 8 h intervals. For practical purposes in goats this would mean a priming dose of 6 mg/kg and a maintenance dose of 2 mg/kg given by the oral route, to be repeated at 8 h intervals.

Effect of trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats

The pharmacokinetics of orally administered pefloxacin were studied to evaluate the bio-enhancing effect of the herbal bio-enhancer, trikatu, in mountain Gaddi goats (n = 6). The findings of the study revealed a decreased plasma concentration (p > 0.05) of pefloxacin following trikatu administration during the absorption phase (10, 15, 20 min post pefloxacin administration). In contrast, the plasma concentrations of pefloxacin were significantly higher at 4, 6, 8 and 12 h (during the elimination phase) of the pefloxacin administration. The findings of the investigation revealed higher values for the area under the curve, the area under the first moment of the plasma drug concentration time curve, the mean residential time, the total duration of pharmacological action and bioavailability. Trikatu treatment, however, significantly reduced the elimination half life (t(1/2beta)) and zero time intercept of the elimination phase. The apparent volume of distribution based on the total area under the plasma drug concentration curve [(Vd((area))] and the apparent volume of distribution based on the zero time plasma concentration intercept of the elimination phase [Vd((B))] were significantly higher in trikatu treated animals indicating a better penetration of the drug. Based on the MIC of 0.8 microgram/ml of pefloxacin, a priming dose of 6.0 mg/kg and a maintenance dose of 2.21 mg/kg is required to be administered at 8 h intervals. For practical purposes in goats this would mean a priming dose of 6 mg/kg and a maintenance dose of 2 mg/kg given by the oral route, to be repeated at 8 h intervals.

Chronic urticaria and monoclonal IgM gammopathy (Schnitzler syndrome): report of 11 cases treated with pefloxacin.

BACKGROUND: Schnitzler syndrome is characterized by chronic urticarial rash and monoclonal IgM gammopathy and is sometimes associated with periodic fever, arthralgias, and bone pain. Current treatment is unsatisfactory. OBSERVATIONS: Eleven patients with Schnitzler syndrome were treated with oral pefloxacin mesylate (800 mg/d). In 10 patients, we observed a dramatic and sustained improvement of urticarial and systemic manifestations. Corticosteroid therapy could be stopped or reduced in 6 patients. In 9 patients, pefloxacin was administered for more than 6 months (

Meta-analysis of prophylactic parenteral antibiotic use in acute necrotizing pancreatitis.

BACKGROUND: Acute pancreatitis is a potentially serious condition. It carries an overall mortality rate of 10-15%. Infectious complications account for approximately 80% of deaths from acute pancreatitis, and the question arises whether or not prophylactic antibiotics are useful in the prevention of these complications. Therefore, we performed an evidence-based analysis to assess the effect of available prophylactic antimicrobial treatment on the development of infected necrosis and sepsis, need for surgery, and mortality. METHODS: A comprehensive PubMed search was performed evaluating the value of prophylactic administration of parenteral antibiotics in patients with acute necrotizing pancreatitis. Only articles published in English language between January 1990 and May 2006 were included. The search strategy initially generated 692 articles related to antibiotics in the treatment of acute pancreatitis. This number was reduced to 97 publications related to clinical trials on the same topic. Finally, 10 randomized clinical trials concerning prophylactic parenteral antibiotics in patients with acute necrotizing pancreatitis were identified. We have performed a meta-analysis using the random-effects model to assess the impact of prophylactic antibiotics on development of infected pancreatic necrosis and sepsis, need for surgery, and overall mortality. RESULTS: Patients with necrotizing acute pancreatitis should receive effective antibiotic prophylaxis (i.e., carbapenems intravenously) to decrease the risk of infected necrosis and sepsis and need of surgery. CONCLUSIONS: While providing new insights into key aspects of antibiotic prophylaxis, this evidence-based analysis highlights the need for further clinical trials regarding the indications for antibiotic prophylaxis.

Ion-activated, Gelrite-based in situ ophthalmic gels of pefloxacin mesylate: comparison with conventional eye drops.

The purpose of our work was to develop an ophthalmic delivery system of a flouroquinolone antibiotic, pefloxacin mesylate, based on the concept of ion-activated in situ gelation. Gelrite gellan gum, a novel ophthalmic vehicle, that gels in the presence of mono- or divalent-cations present in the lacrimal fluid, was used as the gelling agent. The developed formulation was compared with marketed eye drops in efficacy of treatment of bacterial conjunctivitis that was induced artificially in rabbits. The formulations were evaluated for rheological characteristics, in vitro release behavior, antimicrobial efficacy, and efficacy against bacterial conjunctivitis. We found that in situ gelling formulations passed the test for sterility. The formulations exhibited a first-order release pattern over 12 hr in in vitro release studies. The developed formulation was effective against selected micro-organisms in antimicrobial efficacy studies. The shelf lives of formulation was >2 years. The formulation demonstrated better therapeutic efficacy compared with standard eye drops because it improved the clinical parameters monitored for prolonged periods. The developed formulations can be considered as a viable alternative to conventional eye drops.

Pharmacokinetics and tissue residues of pefloxacin and its metabolite norfloxacin in broiler chickens.

1. The pharmacokinetics of pefloxacin and its active metabolite norfloxacin were investigated in chickens after a single oral administration of pefloxacin at a dosage of 10 mg/kg. To characterise the residue pattern, another group of chickens was given 10 mg of pefloxacin/kg body once daily for 4 d by oral route; the tissue concentrations of pefloxacin and norfloxacin were determined at 1, 5 and 10 d after the last administration of the drug. 2. The concentrations of pefloxacin and norfloxacin in plasma and tissues were determined by HPLC assay. The limit of detection for pefloxacin and norfloxacin was 0.03 microg/ml in plasma or microg/g in tissue. 3. The plasma concentration-time data for pefloxacin and norfloxacin were characteristic of a one-compartment open model. The elimination half-life, maximum plasma drug concentration, time to reach maximum plasma drug concentration and mean residence time of pefloxacin were 8.74 +/- 1.48 h, 3.78 +/- 0.23 microg/ml, 3.33 +/- 0.21 h and 14.32 +/- 1.94 h, respectively, whereas the respective values of these variables for norfloxacin were 5.66 +/- 0.81 h, 0.80 +/- 0.07 microg/ml, 3.67 +/- 0.21 h and 14.44 +/- 0.97 h. 4. Pefloxacin was metabolised to norfloxacin to the extent of 22%. 5. The concentrations of pefloxacin (microg/g) 24 h after the fourth dose of the drug declined in the following order: liver (3.20 +/- 0.40) > muscle (1.42 +/- 0.18) > kidney (0.69 +/- 0.04) > skin and fat (0.06 +/- 0.02). Norfloxacin was also detectable in all the tissues analysed except muscle. No drug and/or its metabolite was detectable in tissues except skin and fat 5 d after the last administration. The concentrations of pefloxacin and norfloxacin in skin and fat 10 d after the last dose of pefloxacin were 0.04 +/- 0.02 and 0.03 +/- 0.01 microg/g, respectively.

Ocular inserts for controlled delivery of pefloxacin mesylate: preparation and evaluation.

Pefloxacin mesylate is a flouroquinolone antibacterial drug effective in the treatment of bacterial conjunctivitis. The objective of the present work was to develop ocular inserts of pefloxacin mesylate and evaluate their potential for sustained ocular delivery. Reservoir-type ocular inserts were prepared by the film casting technique in teflon coated Petri dishes and characterized in vitro by drug release studies using a flow-through apparatus that simulated the eye conditions. Six formulations were developed, which differed in the ratio of polymers Eudragit RS 100 and Eudragit RL 100 used for the preparation of the rate controlling membrane. All formulations carried 0.72 mg pefloxacin mesylate, 2.69 mg polyvinyl pyrrolidone (PVP) K-30, plasticizers, propylene glycol (10% m/m) and dibutyl phthalate (15%, m/m). The optimized formulation was subjected to microbiological studies, in vivo studies, interaction studies, and stability studies to assess the effectiveness of the formulation. Cumulative drug released from the formulation ranged from 90-98% within 48 to 120 hours. On the basis of in vitro drug release studies, the formulation with Eudragit RS 100/Eudragit RL 100 (4:1) was found to be better than the other formulations and it was selected as an optimized formulation. On the basis of in vitro, microbiological, in vivo drug release, interaction and stability studies, it can be concluded that this ocular insert formulation provided the desired drug release in vitro for 5 days and remained stable and intact at ambient conditions.

A three-way comparative study on the efficacy of twin sol to gel systems and marketed eye drops of pefloxacin mesylate.

The authors compare the efficacy of sol to gel systems and marketed eye drops of Pefloxacin mesylate (PM) in the patients with bacterial conjunctivitis. It was an open, comparative, 3-treatment, randomized, parallel study. Formulations were tested on 15 patients with bacterial conjunctivitis. Each formulation was tested on 5 patients. Patients receiving marketed eye drops were instructed to use 2 drops, 4 times a day for 7 days. Patients receiving sol to gel were instructed to use 1 drop every 12 hours for 7 days. Pharmacodynamic parameters, based on a scale of rating, were used to assess the improvement in conjunctivitis on treatment with formulations. Conjunctival swabs were taken from eyes of patients, and viable counts were performed at days 0, 3, 5, and 7. Statistical analysis of the pharmacodynamic data indicated that both sol to gel systems used were more effective than marketed eye drops in the treatment of bacterial conjunctivitis. Results of the viable count revealed that a faster reduction in the number of colony-forming units (cfu) were obtained with both sol to gel systems, compared to marketed eye drops. It can be concluded that both sol to gel systems were superior to marketed eye drops in the treatment of bacterial conjunctivitis.

A clinical trial of pefloxacin and ofloxacin in lepromatous leprosy.

A 2-month clinical trial of pefloxacin and ofloxacin in previously untreated multibacillary patients was conducted at the Leonard Wood Memorial Leprosy Research Center, Cebu, the Philippines. Treatment with either pefloxacin or ofloxacin resulted in rapid clinical improvement, in this regard pefloxacin appearing somewhat superior. Reactions and side effects were minimal. Single doses of either agent did not result in significant killing of Mycobacterium leprae, but significant bactericidal activity was observed for all fluoroquinolone-treated patients by one week of daily therapy (n = 21), and either agent independently by 3 weeks of daily therapy. At the completion of therapy only two of 10 pefloxacin-treated patients and 0 of 11 ofloxacin-treated patients harboured any detectable viable M. leprae from active lesions, confirming previous work that these fluoroquinolones exhibit bactericidal activity in leprosy patients and more than that found previously for dapsone and clofazimine.

Activity of combinations of ceftazidime, imipenem and pefloxacin against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.

The chequerboard technique was used to look for synergistic combinations of ceftazidime, imipenem and pefloxacin. The synergistic combinations were used in vivo in mice experimentally infected with Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa. In vitro ceftazidime/imipenem, ceftazidime/pefloxacin and pefloxacin/imipenem combinations showed synergistic effects against Staphylococcus aureus and S. typhimurium and additive effects against P. aeruginosa. Only the ceftazidime/pefloxacin combination was synergistic against E. coli while the ceftazidime/imipenem and pefloxacin/imipenem combinations resulted in additive effects. In vivo, combination of ceftazidime/imipenem against E. coli infection and the pefloxacin/imipenem combination against S. typhimurium infection were protective.

Some pharmacokinetic parameters of pefloxacin in lactating goats.

The aim of this study was to elucidate some of the pharmacokinetic parameters of pefloxacin in lactating goats (n = 5) following intravenous (i.v.) or intramuscular (i.m.) injections of 10 mg/kg bw. Serially obtained serum, milk and urine samples were collected at precise time intervals, and the drug concentrations were assayed using a microbiological assay. A two-compartment open model best described the decrease of pefloxacin concentration in the serum after intravenous administration. The maximum serum concentration (C0(p)) was 8.4 +/- 0.48 microg/ml; elimination half-life (t 1/2 beta) was 1.6 +/- 0.3 h; total body clearance (Cl(tot) was 3.6 +/- 0.3 L/kg/h; steady-state volume of distribution (V(dss)) was 5.14 +/- 0.21 L/kg; and the area under the curve (AUC) was 2.78 +/- 0.22 microg.ml/h. Pefloxacin was absorbed rapidly after i.m. injection with an absorption half-life (t 1/2 ab) of 0.32 +/- 0.02 h. The peak serum concentration (Cmax) of 0.86 +/- 0.08 microg/ml was attained at 0.75 h (Tmax). The absolute bioavailability after i.m. administration was 70.63 +/- 1.13% and the serum protein-bound fraction ranged from 7.2% to 14.3%, with an average value of 9.8 +/- 1.6%. Penetration of pefloxacin from the blood into the milk was rapid and extensive, and the pefloxacin concentration in milk exceeded that in serum from 1 h after administration. The drug was detected in milk and urine for 10 and 72 h, respectively; no samples were taken after 72 h.