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DRUG INTERACTIONS |
From the Department of Veterans Affairs Medical Center, Boise, Idaho (Dr Madaras-Kelly, Ms Michas, Ms George); the College of Pharmacy, Idaho State University, Pocatello, Idaho (Dr Madaras-Kelly, Mr May); and Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania (Dr Adejare).
Address for reprints: Karl Madaras-Kelly, PharmD, ISU College of Pharmacy, c/o Boise VA Medical Center, 500 W. Fort Street (119A), Boise, ID 83702.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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, t1/2, or CL/F. tmax was significantly prolonged when cephalexin was administered with ranitidine or omeprazole. Suboptimal T > MIC90 was observed for cephalexin irrespective of acid suppression. Delay in absorption of cephalexin resulted in a decrease in the percentage of T > MIC90 for certain acid-suppressive regimens and pathogen combinations. With the exception of an increase in tmax, there were no significant pharmacokinetic interactions between cephalexin and ranitidine or omeprazole. Delayed tmax associated with acid suppression may result in a diminished T > MIC90.
Key Words: Cephalexin • ranitidine • omeprazole • drug interactions • pharmacokinetics
The popularity and clinical effectiveness of cephalexin appear somewhat contradictory to the agent's pharmacokinetic and antimicrobial activities. For example, the cephalexin minimal inhibitory concentrations for 90% of organisms tested (MIC90) for Staphylococcus aureus (methicillin sensitive) and Streptococcus pyogenes are 4.0 and 2.0 µg/mL, respectively.2,3 After a 500-mg oral dose, reported peak serum concentrations (Cmax) of cephalexin are approximately 15 to 18 µg/mL, with a half-life (t1/2) of approximately 1.2 hours.4,5 Based on these susceptibility and pharmacokinetic parameters, the percentage T > MIC90 for S aureus and S pyogenes is approximately 38% and 57%, respectively. T > MIC is an important pharmacodynamic predictor of beta-lactam antibiotic effect; however, the optimal T > MIC for cephalexin versus common cellulitis pathogens is unknown. In general, the critical T > MIC is considered to be approximately 50% against Streptococcus spp. and 25% to 35% for S aureus.6,7 A decrease in bioavailability or other pharmacokinetic variables due to drug interactions might influence the effectiveness of cephalexin.
Previously, we published a retrospective analysis of all outpatients treated for uncomplicated cellulitis at our institution to examine the relative efficacy of cephalexin versus other antibiotics.8 Results indicated that the odds ratio of clinical failure while being treated with cephalexin was 2.41 (95% confidence interval [CI] = 2.0-182.0) when compared to other oral antibiotic regimens. Further comparison of cephalexin clinical failures versus cures revealed that concurrent acid-suppressive therapy was present in 42% of cephalexin failures but in only 20% of cephalexin cures (P = .1). Acid-suppressive therapy consisted of a variety of histamine-2 blockers and proton pump inhibitors.
Only 1 published study has investigated the potential interaction between ranitidine and the absorption of cephalexin.9 Coadministration was associated with modest decreases in Cmax and tmax and essentially no change in area under curve (AUC). The authors' conclusions were that the pharmacokinetic differences were small and not clinically significant. We were not able to identify any pharmacokinetic studies conducted with proton pump inhibitor coadministration.
As a result of our prior observations and the lack of pharmacokinetic interaction data on these agents, we designed a study to determine if concurrent use of acid-suppressive therapy decreases the total AUC (AUC) of cephalexin by greater than 25% and whether the subsequent decrease in absorption results in a decrease in T > MIC90 to <50% and 30% of the 6-hour dosing interval for S pyogenes and S aureus, respectively.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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when cephalexin was administered with and without acid-suppressive therapy.9 Twenty-one healthy adult volunteers were recruited for the study from the surrounding community. Study inclusion criteria were as follows: subjects had to be 
18 years of age; be able to abstain from all drug intake, including over-the-counter medications and herbals, for 2 weeks prior to and during the study; and be able and willing to adhere to self-administration of the randomized acid-suppressive therapy as directed. Potential subjects were excluded from the study if they had abnormal liver function tests, serum chemistries, and hematological profiles, or if they were pregnant or breast-feeding. Potential subjects were also excluded if they had a history of allergy to penicillin, other beta-lactam antibiotics, ranitidine, or omeprazole. The University of Washington Investigational Review Board approved this protocol, and informed consent was obtained for all subjects prior to study initiation.
Data Collection Procedures
Subjects were provided a written set of instructions pertaining to the study chronology, medication administration schedule, and potential protocol violations. Subjects were instructed to not eat or drink anything after midnight the day of the study. An intravenous lock was placed in an antecubital vein and patency maintained with saline flushes. Baseline labs, including serum for cephalexin concentrations, were collected. A 500-mg capsule of cephalexin monohydrate (lot 59926; Teva Pharmaceuticals) was administered with 100 mL of water. Subjects were allowed to eat or drink liquids 2 hours after the dose was administered, but no caffeine-containing beverages were permitted until after all serum sampling was complete. Blood was obtained via intravenous lock predose and at 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after ingestion of cephalexin. Urine was collected at intervals of 0 to 2, 2 to 4, 4 to 6, and 6 to 24 hours. All blood samples for cephalexin concentration analysis were immediately centrifuged and stored at -70°C until assayed.
In phase 2 of the study, subjects were randomized to receive 1 of 3 regimens of oral acid suppression. Patients in group 1 received 150 mg ranitidine (lot 126511; Geneva) every 12 hours for 3 doses, group 2 received 20 mg omeprazole (lot 3580; Astra-Merck) orally every 24 hours for 5 days, and group 3 received 40 mg omeprazole every 24 hours for 5 days. Randomization was performed by instructing the subject to select 1 of 3 identical-looking envelopes containing prescriptions for the 3 acid-suppressive regimens. Acid-suppressive regimens were supplied in Medication Monitoring Event Systems (MEMS) (AARDEX Ltd, Basel, Switzerland) containers to facilitate verification of adherence to the prescribed acid-suppressive regimen. Adherence was defined as an opening of the pill container twice daily for the ranitidine arm and once daily for the omeprazole arms for the duration of the prescribed regimen; in addition, the last dose taken on the day prior to the pharmacokinetic study had to be taken within 2 hours of the recommended time. All groups took their last dosage of acid-suppressive therapy the morning of their return visit for the completion of the pharmacokinetic study. Subjects had an intravenous lock placed again and then ingested a 500-mg capsule of cephalexin with 100 mL of water. All subsequent procedures were performed in an identical manner as described in phase 1.
Quantitative Analysis
Analysis of cephalexin in human serum samples was done using solid-phase extraction (SPE) columns followed by high-performance liquid chromatography (HPLC) quantitation of the analyte in the extracts using UV detection.
The serum sample extraction procedure was performed using Strata-X SPE columns (Phenomonex, Torrance, Calif). Serum samples (250 µL) were diluted 1:1 with 0.1 M NaH2PO4 adjusted to pH 6.0. Cephadrine (lot 012K1174, Sigma, St. Louis, Mo) was used as the internal standard. Then, 10 µL to 1000 mg/L cephadrine in 100% methanol was added to each sample except the Method Blank. Samples (250 µL) were then loaded onto 30-mg/1-mL Strata-X 33-mm polymeric sorbent columns. Columns were first conditioned with 1 mL methanol followed by 1 mL de-ionized water and dried by forced air. The samples were then eluted using two 250-µL aliquots of methanol, which were then mixed to ensure homogeneity.
Analysis of extracts was conducted using a Hitachi HPLC system consisting of an L-6200A Intelligent Pump, AS-4000 Autosampler, and L-4000 UV Detector. The output from the detector was recorded using a Spectra Physics SP4290 Integrator. A Luna C18 (2) 5-µm 250 x 4.6-mm column (Phenomenex, Torrance, Calif) was used to achieve separation with the gradient elution. The gradient was 15/85 (acetonitrile/0.05 M NaH2PO4 adjusted pH 3.0) at time 0 to 55/45 at 7.5 minutes. A wash step using a gradient to 75/25 in 1 minute was held for 1 minute, then went back to 15/85 via a gradient for another minute, and finally held at 15/85 for 2 minutes to equilibrate the column. The detector was set to 254 nm, fast response, 0.2 AUFS. Injection volume was 20 µL. Cephalexin eluted at 6.25 ± 
0.5 minutes and cephadrine at 7.25 ± 0.5 minutes, respectively.
Calibration for serum samples was done using peak areas of standards containing 1, 2, 5, 10, and 20 mg/L cephalexin (Fluka lot 365570/1 20702, Switzerland) and cephadrine each. Calibration for urine samples was necessarily higher at 4, 20, 50, 100, and 400 mg/L for both cephalexin and cephadrine. The sample concentrations were calculated from the calibration curve, correcting for the internal standard recovery and dilution. The limits of quantitation and detection for the method were 1.5 mg/L and 0.5 mg/L cephalexin, respectively.
For the serum samples, average cephalexin spike recovery was 108.0% (SD = 9.7) and 99.3% (SD = 11.7) for cephadrine. Urine samples had recoveries of 92.3% (SD = 16.8) for cephalexin and 105.0% (SD = 8.7) for cephadrine. All calibration curves had r2 values of 0.99 or better.
Pharmacokinetic Analysis
The individual subject serum concentration data for each patient were analyzed using noncompartmental analysis (Microsoft Excel, Version 8.0). AUC was calculated using the log-trapezoidal rule. In situations in which serum concentrations were below the limit of quantitation, AUC parameters were estimated by dividing the last serum value in excess of the limit of quantitation by the elimination rate constant. The elimination rate constant was calculated by linear regression of the terminal portion of the serum time-concentration profile. t1/2 was calculated by dividing 0.693 by the elimination rate constant. Cmax and tmax were recorded based on the highest serum concentration observed in the serum time-concentration profile. Clearance divided by bioavailability (CL/F) was calculated by dividing dose by AUC. Renal clearance divided by F (CLR/F) was determined by an indirect method. First, the amount excreted (Ae) was calculated by multiplying urine concentration by urine volume for each interval. These were summed together to obtain the total Ae, which was divided by dose to yield the urinary fraction excreted (Fe). CLR/F was then estimated by multiplying CL/F by Fe.
Pharmacodynamic Analysis
T > MIC90 was estimated and compared for cephalexin with and without acid-suppressive therapy. MIC90 of 2 and 4 µg/mL was assumed for S pyogenes and Saureus, respectively.2-3 T<MIC prior to Cmax was defined as the time from cephalexin ingestion until the last reported sample of <2 or 4 µg/mL for S pyogenes and S aureus, respectively. T < MIC after Cmax was calculated using the following standard monoexponential pharmacokinetic equation: ln(C1/C2)/Ke = T, where C1 is 2 or 4 µg/mL for S pyogenes and Saureus, respectively; C2 is equal to Cmax; and Ke is the elimination rate constant. The values from these calculations were subtracted from tmax until 6 hours to obtain the T < MIC after Cmax. T<MIC prior to Cmax and T < MIC after Cmax were then summed and expressed as a percentage of the dosing interval. These calculations provided a conservative estimate of actual T > MIC90 for S pyogenes and S aureus.
Statistical Analysis
Patient characteristics such as weight, height, and creatinine were expressed as median values with interquartile ranges and compared using the Wilcoxon signed rank test. A P value of 
.05 was considered to indicate statistical significance.
Pharmacokinetic parameter data were analyzed in accordance with the two 1-sided test for bioequivalence.10 Analysis of variance (ANOVA) was performed on natural log-transformed pharmacokinetic parameters to determine least squares means (LSM) and standard error (SPSS, Version 10.0). Data were expressed as geometric means or least squares geometric mean ratios, with 90% confidence intervals (90% CI). The 90% CI was determined based on LSM from the cephalexin treatment alone. No significant difference (eg, drug interaction) was identified if 90% CIs were <80% or >125%.
Percentage T > MIC90 was expressed as median values with interquartile ranges and compared using the Wilcoxon signed-rank test. A P value of .05 was considered to indicate statistical significance.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Table II summarizes the cephalexin pharmacokinetic parameters with and without ranitidine coadministration. The coadministration of cephalexin with ranitidine resulted in relatively minor statistically insignificant changes in Cmax, AUC, t1/2, or CL/F parameters. tmax was significantly prolonged with ranitidine coadministration from 1.19 to 1.48 hours, and CLR/F was increased from 16.5 to 19.4 L/h. These parameters were considered not to be bioequivalent.
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Table III summarizes cephalexin pharmacokinetic parameters with and without omeprazole coadministration. The coadministration of cephalexin with omeprazole at either 20 or 40 mg daily resulted in significant prolongation of absorption. The tmax increased almost 2-fold from 0.76 to 1.38 hours when coadministered with 20 mg of omeprazole. The tmax was considered to be not bioequivalent when cephalexin was administered with either 20- or 40-mg doses. There were relatively few differences in other pharmacokinetic parameters, and none were considered significant.
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Table IV summarizes the T > MIC90 for cephalexin administered with and without acid suppression, and Figures 1, 2, 3 summarize the relationship between the serum concentration-time curve of cephalexin (geometric mean values) with and without acid suppression and the MIC90 for S pyogenes and S aureus. The T > MIC90 for cephalexin administered without acid suppression to the 3 subject groups ranged from 37% to 52% and from 30% to 34% for S pyogenes and Saureus, respectively. The T > MIC90 for cephalexin administered with the addition of acid suppression ranged from 33% to 54% and from 26% to 33% for S pyogenes and S aureus, respectively. Subjects who received 40 mg omeprazole had a significant T > MIC90 decline based on S pyogenes breakpoints and a trend toward significant declines for Saureus breakpoints. Based on S pyogenes breakpoints, 13/21 controls and 14/21 acid-suppressed subjects had a T > MIC90 of <50%. Based on S aureus breakpoints, 8/21 controls and 11/21 acid-suppressed subjects had a T > MIC90 of <30%. Furthermore, 3 cephalexin control subjects versus 5 acid-suppressed subjects had a T > MIC90 of <25% based on S aureus breakpoints.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In this study, cephalexin was administered as a single dose early in the morning, but antibiotics were administered intermittently throughout the day, and acid suppression with ranitidine or omeprazole was generally continuous. It is possible that the morning administration schedule underestimated the true effect of acid suppression on the pharmacokinetic and pharmacodynamic parameters of doses administered later in the day due to influences of circadian cortisol rhythm. Decreases in concentration-related pharmacokinetic parameters for doses of cephalosporins administered later in the day have been previously reported.11
The only other change in cephalexin pharmacokinetic parameters was a slight but statistically significant increase in CLR/F observed for subjects taking ranitidine. H2-receptor antagonists and cephalexin are actively cleared via renal tubular secretion by a similar active transport mechanism.12,13 Theoretically, a competitive interaction could exist. However, competitive inhibition of renal secretion would be expected to decrease renal clearance, which was increased in our study.13 Another possibility is that inherent error associated with subject urine collection or assay variability could be responsible for the observed differences.
The pharmacokinetic results involving cephalexin coadministration with ranitidine are consistent with those previously reported by Deppermann et al.9 In that study, administration of ranitidine 150 mg every 12 hours prior to cephalexin administration was associated with a 20% decrease in Cmax, a 25% increase in tmax, and essentially no change in AUC. The authors' conclusions were that the pharmacokinetic differences were small and not clinically significant. To our knowledge, the current study is the first published pharmacokinetics study of cephalexin administered with omeprazole. A possible explanation for the delay in tmax with acid suppression is related to the absorption mechanism associated with cephalexin. A proton-dependent, peptide-dependent transporter that is present on the brush-border membrane of the intestinal lumen cells has been shown to be responsible for the uptake of a number of cephalosporin antibiotics, including the zwitterionic cephalexin.14 The peptide transporter uses the natural proton gradient to concentrate substrates within the intestinal lumen cells prior to exit into the bloodstream. The activities of this transporter protein appear to be highly pH dependent, with cephalexin uptake significantly greater at a pH of 6 than at 7.5.15 Theoretically, small changes in luminal pH might result in significant changes in absorption or absorption rates of cephalexin. Although we cannot confirm that this is the reason for delayed absorption, further clinical study of the effects of localized pH on cephalosporin uptake via this process seems warranted.
The T > MIC90 data presented in this study illustrate several important points. First, the pharmacodynamic potency of cephalexin alone against gram-positive pathogens, particularly S aureus, is marginal. Of the subjects, two thirds and one third did not achieve a T > MIC90 considered minimal for an optimal pharmacodynamic effect against S pyogenes and S aureus, respectively. Second, although the total AUC was not changed appreciably by acid-suppressive regimens, the shape of the AUC curve was clearly different. Although not powered to detect a significant difference, the delay in tmax resulted in a decrease in the percentage of T > MIC90 for certain acid-suppressive regimens and pathogens. Finally, the dose of cephalexin used in this study was the normal maximal dose employed for serious skin and soft tissue infections. In our previous clinical analysis, although we could not identify a cephalexin dosing regimen associated with clinical failure, up to 25% of subjects received lesser doses or longer dosing intervals.8 The T > MIC90 data reinforce the concept that maximal doses of cephalexin should be used and that concurrent acid suppression may be problematic only in select patients.
One limitation of this study is that only the cephalexin monohydrate formulation was studied. Cephalexin is available in 2 formulations: cephalexin monohydrate and cephalexin hydrochloride. Both formulations are considered to be rapidly and completely absorbed from the gastrointestinal tract. The hydrochloride formulation appears to be absorbed more rapidly than the base, presumably because the base must be first converted to the ion prior to absorption.16 In healthy fasting adults, the extent of absorption appears similar, and the rate of absorption is considered to be clinically insignificant. It is possible that study of the different formulations may have resulted in different pharmacokinetic and pharmacodynamic results.
In conclusion, the coadministration of ranitidine or omeprazole did not result in major changes in cephalexin monohydrate pharmacokinetic parameters such as AUC, Cmax, t1/2, or CL/F. Both acid-suppressive agents resulted in significant changes in tmax. The optimal pharmacodynamic effect estimated by T > MIC90 against common cellulitis pathogens was frequently not achieved by cephalexin, irrespective of acid suppression. However, prolongation of tmax by acid suppression resulted in a further decrease in T > MIC90.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication November 25, 2003; Revised version accepted July 26, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Derrick CW, Reilly K. The role of cephalexin in the treatment of skin and soft-tissue infections. Postgrad Med J. 1981;59(suppl 5): 43-46.
2. Mallory SB. Azithromycin compared with cephalexin in the treatment of skin and skin structure infections. Am J Med. 1991;91(3A): 36S-39S.[CrossRef][Medline] [Order article via Infotrieve]
3. Tack KJ, Littlejohn TW, Mailloux G, Walf MM, Keyserking CH. Cefdinir versus cephalexin for the treatment of skin and skin structure infections. The Cefdinir Adult Skin Infection Study Group. Clin Ther. 1998;20: 244-256.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Karchmer AW. Cephalosporins. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingstone; 1995: 247-264.
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6. Craig WA, Ebert SC. Continuous infusion of beta-lactam antibiotics. Antimicrob Agents Chemother. 1992;36: 2577-2583.
7. McNabb JJ, Khanh QB. B-Lactam pharmacodynamics. In: Nightingale CH, Murkawa T, Ambrose PG, eds. Antimicrobial Pharmacodynamics in Theory and Clinical Practice. New York: Marcel Dekker; 2002: 99-123.
8. Madaras-Kelly K, Arbogast RA, Jue SG. Review of the failure rate of cephalexin versus other antibiotics used to treat uncomplicated outpatient cellulitis. Pharmacotherapy. 2000;20: 199-205.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Deppermann K, Lode H, Hoffken G, Tschink G, Kalz C, Koeppe P. Influence of ranitidine, pirenzepine, and aluminum magnesium hydroxide on the bioavailability of various antibiotics, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic acid. Antimicrob Agents Chemother. 1989;33: 1901-1907.
10. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15: 657-680.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Jonkman JH, Reinberg A, Oosterhuis B, et al. Dosing time and sex-related differences in the pharmacokinetics of cefodizime and in the circadian cortisol rhythm. Chronobiologia. Jan-Jun 1988;15: 89-102.[Web of Science][Medline] [Order article via Infotrieve]
12. Maiza A, Dale-Yates PT. Variability in the renal clearance of cephalexin in experimental renal failure. J Phamracokinet Biopharm. 1993;21: 19-30.
13. Van Crugten J, Bochner F, Keal J, Somogyi A. Selectivity of the cimetidine-induced alterations in the renal handling of organic substrates in humans: studies with anionic, cationic, and zwitterionic drugs. J Pharmacol Exp Ther. 1986;236: 481-487.
14. Snyder NJ, Tabas LB, Berry DM, Duckworth DC, Spry DO, Dantzig AH. Structure-activity relationships of carbacephalosporins and cephalosporins: antibacterial activity and interaction with the intestinal proton-dependent dipeptide transport carrier of Caco-2 cells. Antimicrob Agents Chemother. 1997;41: 1649-1657.[Abstract]
15. Tamai I, Tomizawa N, Takeuchi T, Nakayama K, Higashida H, Tsuji A. Functional expression of transporter for B-lactam antibiotics and dipeptides in Exenopus laevis oocytes injected with messenger RNA from human, rat and rabbit small intestines. J Pharmcol Exp Ther. 1995;273: 26-31.
16. Kumar A, Murray D, Hanna C, et al. Comparative study of cephalexin hydrochloride and cephalexin monohydrate in the treatment of skin and soft tissue infections. Antimicrob Agents Chemother. 1988;32: 882-885.
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