Vol. 34, No. 3ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1990, p. 4424470066-4804/90/030442-06$02.00/0Copyright C 1990, American Society for Microbiology

Multiple-Dose Pharmacokinetics of Concurrent Oral Ciprofloxacinand Rifampin Therapy in Elderly PatientsMARY H. H. CHANDLER,'* STEVEN M. TOLER,1 ROBERT P. RAPP,'

ROBERT R. MUDER,2 AND JOYCE A. KORVICK3College ofPharmacy, University of Kentucky, Lexington, Kentucky 4053600821*; Department ofMedicine,

Mercy Hospital, Pittsburgh, Pennsylvania 152192; and College of Medicine,University of Kentucky, Lexington, Kentucky 40S36-00843

Received 21 August 1989/Accepted 15 December 1989

The purpose of this clinical study was to investigate the influence of concomitant drug therapy withciprofloxacin and rifampin on the individual pharmacokinetic profile of each agent in elderly patients. Twelvenursing home patients (age, 74 7 years), colonized with methiiillin-resistant Staphylococcus aureus, wererandomized to receive 14-day therapy with oral ciprofloxacin (750 mg every 12 h) (group A; n = 6) orciprofloxacin (750 mg every 12 h) and oral rifampin (300 mg every 12 h) (group B; n = 6). Serial blood sampleswere obtained from 0 to 12 h following ciprofloxacin doses 1 and 13 and from 0 to 36 h after the lastciprofloxacin dose. No significant differences (P > 0.05) were found between or within groups in anypharmacokinetic parameter. The mean ciprofloxacin oral clearance values were 0.35 ± 0.06, 0.41 ± 0.15, and0.38 ± 0.11 liter/h per kg for doses 1, 13, and 28, respectively, in group A patients. The mean oral clearancevalues in group B patients for the respective doses were 0.53 ± 0.36, 0.32 ± 0.13, and 0.36 ± 0.17 liter/h perkg. Likewise, no significant differences (P > 0.05) in rifampin pharmacokinetic parameters were found whencompared with historical controls. These data suggest that ciprofloxacin and rifampin may be givenconcomitantly in standard clinical dosing regimens. The combination results in therapeutic levels of both drugsand appears to be safe for adminiration to elderly nursing home patients.

Colonization and infection with methicillin-resistantStaphylococcus aureus are becoming serious problemsamong debilitated patients and those in chronic care institu-tions, such as nursing homes (10). Combination therapy withciprofloxacin and rifampin is a potential regimen for treat-ment of these conditions. The addition of rifampin to variousantistaphylococcal regimens has been shown to enhancetheir bactericidal activity in animal models (4, 11, 16). Thecombination of these antimicrobial agents may prove to beuseful and provide better therapeutic outcomes.

Ciprofloxacin and other metabolized quinolones undergobiotransformation via the hepatic microsomal cytochromeP-450 system. Concomitant use of ciprofloxacin and otherdrugs that share the same site of metabolism has resulted inelevated concentrations of those other drugs in plasma (20,23, 25, 26). Rifampin, a classic enzyme inducer, is alsometabolized by the microsomal enzyme system (1, 3). Con-sequently, concurrent therapy with the antibiotics ciproflox-acin and rifampin may affect the disposition of one another.The purpose of this clinical research was to explore theinfluence of concomitant drug therapy with ciprofloxacin andrifampin on their individual pharmacokinetic profiles.

MATERIALS AND METHODSSubjects. Twelve elderly male nursing home residents

were enrolled after informed consent was obtained. The agesof the study subjects ranged from 67 to 95 years (mean, 74).All patients were documented to have methicillin-resistantS. aureus colonization of the nares. The patients had nosurgical or medical condition known to alter the dispositionof ciprofloxacin or rifampin. Exclusion criteria included thefollowing: history of allergy to quinolones; inability to takemedications by mouth; serum creatinine level of >3 mg/dl;

* Corresponding author.

concurrent therapy with theophylline or warfarin; abnormalliver function tests; and anemia (defined as a hemoglobinlevel of <11 g/dl or hematocrit below 34%) (17). The subjectsdid not consume any caffeine-containing foods or beveragesor alcoholic beverages, beginning at least 48 h before andthroughout the study period. None of the subjects smokedcigarettes.

Protocol. The study protocol and consent form wereapproved by our institutional review board. Subjects wererandomized to one of two treatment groups. Group Apatients received one 750-mg ciprofloxacin tablet (Miles Inc.Pharmaceutical Division, West Haven, Conn.) orally every12 h for 14 days. Group B patients received, in addition tociprofloxacin orally every 12 h for 14 days, one 300-mgrifampin capsule (CIBA Pharmaceuticals, Summit, N.J.)orally every 12 h for 14 days. The first rifampin dose beganwith the second ciprofloxacin dose (Fig. 1). On blood sam-pling days, the doses were ingested with 180 ml of tap waterafter an 8-h fast, and food was withheld for an additional 4 h.Patients on continuous tube feedings (n = 3 in each group)fasted for 2 h prior to and 4 h after each dose. In patients forwhom antacid and histamine H2-blocker therapy could notbe discontinued, these medications were omitted on thepharmacokinetic study day until at least 4 h after dosing withciprofloxacin. One subject in group A had been on previousrifampin therapy; five subjects in group B had been onprevious rifampin therapy. No subject, however, had re-ceived rifampin within 2 months prior to the study period.Blood samples for pharmacokinetic analysis were ob-

tained through an indwelling heparin lock placed in a fore-arm vein. The blood samples (10 ml) were collected at 0,0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 12.0h (immediately prior to the next dose) after ciprofloxacindose 1, dose 13, and the last dose (dose 28). Two additionalsamples were obtained by venipuncture at 24 and 36 h after

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1I 2 1 3 4 1 5 16 17 18 19 110111211314115116117118191202112212314 24 27

1213 14 1516 17 18 19 11011112113114115116117 18199120121122123124152 27

147STUDY DAY

FIG. 1. Ciprofloxacin (*) and rifampin (**) dosing (O) and bloodsampling (U) schematic.

the last ciprofloxacin dose. The samples were allowed to clotat room temperature, and the serum was separated bycentrifugation. Each group B sample was divided into twopolyethylene storage vials to allow separate assays of cipro-floxacin and rifampin. All serum samples were stored at-70°C until analysis.

Analysis. Serum ciprofloxacin samples were analyzed byusing a high-performance liquid chromatography procedurewith fluorescence detection (18). Standard curves werelinear from 0.1 to 8.0 p.g/ml (r = 0.999). The lowest concen-tration of standard used routinely was 0.1 ,ug/ml. The intra-day coefficients of variation at ciprofloxacin concentrationsof 0.1, 1.0, and 8.0 ,ug/ml were 9.7, 2.1, and 5.4% (n = 4),respectively. The interday coefficients of variation, at thesame concentrations, were 12.4, 8.7, and 0.6% (n = 4),respectively. Rifampin concentrations were quantitated byhigh-performance liquid chromatography with UV detection(14). Standard curves were linear from 0 to 20 ,ug/ml (r =0.998). The minimum detectable level was 0.2 ,ug/ml. Thelowest concentration of standard used routinely was 5 ,ug/ml.The intraday coefficients of variation at rifampin concentra-tions of 5, 10, 15, and 20 jig/ml were 5.0, 2.5, 1.1, and 1.7%(n = 2), respectively. The interday coefficients of variation,at the same concentrations, were 6.9, 2.2, 3.6, and 2.4% (n =4), respectively.

Pharmacokinetic parameters. Pharmacokinetic parametersfor ciprofloxacin and rifampin were calculated by noncom-partmental methods. The maximum concentration of drug inserum (Cmax) and the time to the maximum concentration ofdrug in serum (Tm.) were determined directly by observa-tion of the data. The area under the concentration-time curve(AUC) from 0 h to Xo for the first ciprofloxacin dose wasdetermined by the trapezoidal rule. The values were extrap-olated to infinity by dividing the last measured concentrationin serum by P, the slope of the terminal elimination phaseobtained by least-squares linear regression. The AUC from 0to 12 h was calculated via the trapezoidal rule for doses 13and 28 of ciprofloxacin and doses 12 and 27 of rifampin. Theelimination half-life (t4/2) was calculated by ln 2 divided by ,B.The presumed tissue washout terminal elimination half-life,a parameter proposed by Guay et al. (9), for ciprofloxacinwas calculated from serum concentration-versus-time datafrom 12 to 36 h postdose. The apparent oral clearance (CLO)was determined by dividing the dose by the AUC andstandardizing to body weight. Creatinine clearance (CLCR)was estimated by the method of Cockcroft and Gault (6) andstandardized to 1.73 m2 body surface area.

Statistics. Statistical comparison of group A and group Bdemographic data was performed by using the Mann-Whitney test (age, body weight, CLCR). Two-way analysis ofvariance with repeated measures (followed by Fisher's leastsignificant difference test, if appropriate) was used to assess

TABLE 1. Subject demographicsa

Subject no. Age (yr) Wt (kg) CLCR (ml/minper 1.73 in2)

Group A (n = 6)1 76 62.4 66.63 74 64.5 96.95 73 69.5 67.37 74 47.7 41.59 72 60.9 66.211 68 67.5 44.8

Mean ± SD 73 ± 3 62.1 ± 7.7 63.9 ± 19.9

Group B (n = 6)2 75 49.0 49.84 67 69.5 73.36 70 74.1 72.18 74 58.6 77.210 95 84.5 27.312 72 57.2 45.3

Mean ± SD 76 ± 10 65.5 ± 13.0 57.5 ± 19.8

a P > 0.05 for group A versus group B.

significant differences in ciprofloxacin pharmacokinetic pa-rameters between group A and group B and within thegroups (at doses 1, 13, and 28 of ciprofloxacin). Rifampinpharmacokinetic parameters were compared with historicalcontrols (2). Statistical significance was defined a priori as P< 0.05. The sample size (n = 6 per group) was selected toresult in a statistical test with 80% power (p = 0.2) againstHo (null hypothesis) at the 5% level of significance to detecta difference in CLo of 50% or more (27).

RESULTS

The ages, weights, and estimated CLCRs of the subjectsare presented in Table 1. The mean age, weight, and CLCRwere not significantly different (P > 0.05) between group Aand group B subjects. Medical conditions present among thesubjects included the following: diabetes mellitus (subjectsno. 11 and 12), glaucoma (no. 4), cataracts (no. 4, 5, and 7),Parkinson's disease (no. 6), multiple infarct dementia (no. 5to 8 and 10), cortical atrophy (no. 6), hypertension (no. 4, 6,and 8 to 12), bronchitis (no. 10 and 12), congestive heartfailure (no. 2), seizure disorder (no. 6, 8, and 11), Alzhei-mer's disease (no. 1, 3, and 9), chronic urinary tract in-fection (no. 4 and 8), and histories of cerebrovascularaccident (no. 1, 5, 8, and 11) and myocardial infarction (no.1). Chronic medications taken by the patients included thefollowing: ascorbic acid (subjects no. 1, 4, and 10), aspirin(no. 1, 3 to 5, and 9), atenolol (no. 1), carbamazepine (no. 8),chlorpromazine (no. 7), diazepam (no. 1, 4, and 5), digoxin(no. 2), diltiazem (no. 8 and 11), docusate sodium (no. 1 to 6and 9), folic acid (no. 2 and 6), furosemide (no. 11), haloper-idol (no. 3, 4, and 9), hydrochlorothiazide (no. 9), hydrox-yzine (no. 10), isosorbide dinitrate (no. 2, 4, and 8),levodopa-carbidopa (no. 6), methenamine mandelate (no. 4),oxazepam (no. 1), oxybutynin (no. 2 and 4), phenytoin (no.6, 8, and 11), potassium chloride (no. 5, 9, and 11), procain-amide (no. 11), propranolol (no. 4), quinine (no. 4), ranitidine(no. 2, 7, 11, and 12), and triazolam (no. 1, 4, 5, and 12).Mean (± standard deviation [SD]) ciprofloxacin serum con-centration-time profiles from both subject groups are de-picted in Fig. 2. The mean (±SD) rifampin serum concen-tration-time profile for group B subjects is shown in Fig. 3.

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444 CHANDLER ET AL.

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Pharmacokinetic parameters for ciprofloxacin (Cm,,x,Tmax, ,B, AUC, and CLO) are summarized in Tables 2 and 3.No significant differences (P > 0.05) were found between orwithin groups for any of these pharmacokinetic parameters.Likewise, no significant difference (P > 0.05) was detectedin tl2 between or within groups, with group A values of 3.42+ 0.23 h (dose 1), 3.82 ± 0.71 h (dose 13), and 4.26 ± 0.63 h(dose 28) and group B values of 3.98 ± 1.36 h (dose 1), 3.32+ 0.84 h (dose 13), and 3.76 ± 0.73 h (dose 28). Furthermore,the mean tissue washout elimination half-life values were not

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significantly different (P > 0.05) between groups A and B(6.5 ± 2.6 versus 4.6 ± 1.3 h, respectively).Rifampin pharmacokinetic parameters (Cmax, Tmax, 13,

AUC, and CLO) and their corresponding historical controlvalues (2), when pertinent, are summarized in Table 4. Nosignificant differences (P > 0.05) existed between pharma-cokinetic parameters determined from dose 12 versus dose27 data. Likewise, our pharmacokinetic parameters did notdiffer significantly (P > 0.05) from those of historical con-trols (2). The mean t412 values were 2.66 ± 1.57 (dose 12),2.32 ± 0.99 (dose 27), and 4.09 ± 6.34 (historical control) h(P > 0.05).

TABLE 2. Ciprofloxacin pharmacokinetic parameters'

Group Cmax Tmax h- AUCand dose (mg/liter) (h) 13 () (mg h/liter)

A1 5.9 ± 0.7 2.2 ± 1.4 0.20 ± 0.01 35.1 ± 6.313 6.2 ± 1.8 1.5 ± 1.1 0.19 ± 0.03 33.1 ± 12.228 6.2 ± 1.6 2.0 ± 1.2 0.17 ± 0.03 34.7 ± 9.8

B1 4.2 ± 1.4 1.9 ± 1.1 0.19 ± 0.06 30.0 ± 14.713 7.5 ± 2.3 2.0 ± 1.1 0.22 ± 0.07 39.4 + 10.528 6.9 ± 1.8 2.3 ± 0.9 0.19 ± 0.04 36.7 ± 12.8

a Values are means + SD. P > 0.05 for group A versus group B and dose1 versus dose 13 versus dose 28.

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TABLE 3. Ciprofloxacin CLOCLo (liter/h per kg)a after dose:

Subject no.1 13 28

Group A (n = 6)1 0.38 0.38 0.343 0.42 0.50 0.425 0.37 0.29 0.297 0.38 0.46 0.469 0.26 0.21 0.2211 0.30 0.62 0.52

Mean + SD 0.35 ± 0.06 0.41 ± 0.15 0.38 ± 0.11

Group B (n = 6)2 0.96 0.49 0.364 0.27 0.27 0.206 0.39 0.29 0.338 1.02 0.46 0.6910 0.17 0.16 0.3112 0.39 0.27 0.28

Mean ± SD 0.53 ± 0.36 0.32 ± 0.13 0.36 ± 0.17

a P > 0.05 for group A versus group B and dose 1 versus dose 13 versusdose 28.

DISCUSSION

Currently, approximately 1.5 million Americans reside inskilled-nursing facilities (22). On a given day, more patientsreside in nursing homes than in acute care settings (5).Methicillin-resistant S. aureus colonization and infection areincreasing problems among chronic care patients in nursinghomes (10). Combination oral therapy with ciprofloxacinplus rifampin provides an attractive potential treatment forthese conditions and other infections not only in nursinghomes but in the outpatient setting as well (4, 11, 16).

In humans, rifampin is a potent inducer of drug metabo-lism (1, 3). Rifampin has been shown to produce prolifera-tion of hepatic smooth endoplasmic reticulum and increasesin cytochrome P-450 content (3, 12). Ciprofloxacin under-goes hepatic oxidative metabolism, with approximately 15%of a dose converted to three main metabolites (sulfocipro-floxacin, oxociprofloxacin, and desethylene-ciprofloxacin)(32). Recently, Barriere et al. demonstrated a significantincrease in ciprofloxacin clearance in rabbits after 6 days ofrifampin therapy (4).

Previous reports also suggest an increase in theophyllineand caffeine levels in the presence of ciprofloxacin (20, 23,25, 26). It is plausible that these interactions are the result ofinhibition of drug metabolism by ciprofloxacin at the hepaticmicrosomal P-450 level, at which these agents are metabo-lized (23). Consequently, the possibility of enhanced cipro-floxacin clearance and/or reduced rifampin clearance led toour pharmacokinetic evaluation of concurrent ciprofloxacinand rifampin therapy in elderly nursing home patients.Pharmacokinetic parameters under evaluation consisted

of Cmax Tmax, P, t1/2, AUC, and CLo. We evaluated CLo

since this parameter reflects absorption, first-pass extrac-tion, and elimination (8). On the other hand, we chose not tocalculate the volume of distribution since this parameter isdependent upon bioavailability and would not offer mean-

ingful comparisons with oral dosing, in this case.

Our findings demonstrate no significant difference in cip-rofloxacin pharmacokinetic parameters either between or

within (dose 1 versus 13 versus 28) the ciprofloxacin treat-ment group and the ciprofloxacin and rifampin treatmentgroup. Likewise, no significant differences in rifampin phar-macokinetic parameters occurred, compared with historicalcontrols (2).A number of explanations for these findings are possible.

First, selectivity exists in the enzyme induction effect ofrifampin, and thus an induction phenomenon would not beexpected for every drug undergoing hepatic oxidative me-

tabolism (15). Second, wide interspecies differences in drugmetabolism exist, and the presence of an enzyme inductioneffect in animals is not usually predictive of occurrences inhumans (4). Third, several clinical studies have suggested a

decrease in enzyme induction effects in the elderly byrifampin and other inducers (24, 28, 29, 33). Finally, the mostlikely explanation for the absence of a significant effect ofrifampin on ciprofloxacin clearance in our elderly patients isrelated to the extent of hepatic metabolism of ciprofloxacin.Ciprofloxacin is excreted primarily by the kidneys (7, 30).Since the group A and group B subjects were well matchedfor renal function, any observed differences in CLo forciprofloxacin could be attributed to changes in metabolism.Hepatic oxidative metabolism accounts for only 15% of theclearance of ciprofloxacin, and our study was designed todetect a 50% change in clearance. However, rifampin ismetabolized in the liver mainly by desacetylation and hy-drolysis and its urinary clearance is only 12% of the glomer-ular filtration rate (13). Consequently, the maximum possibleeffect of ciprofloxacin on rifampin clearance was greaterthan 50%, but we did not find a significant change.The wide intra- and interpatient variabilities in pharmaco-

kinetic disposition of ciprofloxacin and rifampin in ourelderly subjects may stem from the heterogeneity of theirdisease states and concurrent medications. This heterogene-ity is not surprising; the intensity of medication use bynursing home patients is well documented in the literature(5). Both phenytoin and carbamazepine have enzyme-in-ducing properties (19), whereas diltiazem has been reportedto inhibit the metabolism of various xenobiotics (21). Sub-jects 6, 8, and 11 were taking one to all three of thesemedications while participating in our study. However, theconcomitant administration of these medications with cipro-floxacin or ciprofloxacin and rifampin did not appear toincrease the intra- or interpatient variability in ciprofloxacinor rifampin pharmacokinetic parameters. No patterns in

intra- and interindividual variabilities were observed.All of our patients were in a stable state of health through-

out the study period. Furthermore, attempts were made to

TABLE 4. Rifampin pharmacokinetic parametersa

Patient group C,,na Tm. h1) AUC CLoand dose (mg/liter) (h)

0 (h) (mg b/liter) (liter/h per kg)

Group B, dose 12 9.4 + 3.1 2.32 + 1.20 0.44 + 0.40 33.27 + 17.85 0.19 + 0.12Group B, dose 27 7.3 + 2.3 2.56 ± 1.97 0.35 + 0.15 23.91 + 4.03 0.20 ± 0.04Historical control (2) 1.17 ± 0.41 0.24 + 0.35 0.21 ± 0.24

a Values are means + SD. P > 0.05 for dose 12 versus dose 27 versus historical control.

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minimize the changes in concurrent medication therapy forpatients in the study. Care was exercised to stagger theschedules of medications such as ranitidine and antacidsaround the ciprofloxacin dosing, to prevent alterations instomach pH and drug complexation, respectively (31). Six ofthe subjects (three in each group; subjects 3, 5, 6, 8, 11, and12) received their medications via nasogastric tubes. Theirmean pharmacokinetic parameters did not differ from thoseof the other patients. Recent findings by Yuk et al. alsosuggest that enteral feedings do not interfere with the ab-sorption of ciprofloxacin (34).Our results were similar to those of Guay et al., who found

mean ciprofloxacin CLO values of 0.40 and 0.34 liter/h per kgin a group of elderly patients during a first-dose evaluation ofacutely ill patients and a convalescent steady-state evalua-tion, respectively (9)'. The mean values in their patients forciprofloxacin tv,2 (5.0 and 4.9 h during the acutely ill patientevaluation and the convalescence evaluation, respectively)were also similar to those in our study. However, Guay et al.demonstrated a longer hypothesized tissue washout terminalelimination half-life (8.2 h) than the mean pooled value forour 12 subjects (5.5 h) (9). Thus, results of our investigationcould not confirm the existence of a prolonged ciprofloxacint1/2 when blood sampling was extended beyond 12 h.

In summary, our data do not indicate the occurrence of amajor pharmacokinetic interaction between ciprofloxacinand rifampin in elderly patients. The data demonstrate wideintra- and interpatient variabilities. However, our findingssuggest that the usual clinical dosing regimens for ciproflox-acin and rifampin may be used when administering bothdrugs concomitantly. Therapeutic levels of both drugs areachieved, and the combination appears to be safe for con-comitant administration to elderly nursing home patients.However, future studies are warranted to fully evaluate thepotential for an interaction between ciprofloxacin and ri-fampin in younger patients.

ACKNOWLEDGMENTS

This work was supported by a grant from Miles Inc. Pharmaceu-tical Division.The invaluable assistance of E. Dean Martin, John R. Meek, and

Joseph A. Jansen, Jr., is gratefully acknowledged.

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