Pharmacokinetics of Single-Dose Oral Ciprofloxacin in Patients Undergoing Chronic Ambulatory Peritoneal Dialysis

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 1986, p /86/ $02.00/0 Copyright 1986, Americn Society for Microbiology Vol. 30, No. 1 Phrmcokinetics of Single-Dose Orl Ciprofloxcin in Ptients Undergoing Chronic Ambultory Peritonel Dilysis ITAMAR SHALIT,' ROBERT B. GREENWOOD,2 MELVIN I. MARKS,'* JAMES A. PEDERSON,3 AND DONALD L. FREDERICK4 Deprtment of Peditrics, Division of Infectious Diseses,' nd Deprtments of Phrmceutics,2 Medicine,3 nd Pthology,4 University of Oklhom Helth Sciences Center, Oklhom City, Oklhom Received 12 December 1985/Accepted 30 April 1986 The prevention nd tretment of peritonitis in ptients undergoing peritonel dilysis is often complicted by severl fctors, including nephrotoxicity, requirement for hospitliztion, prenterl ntibiotic therpy, nd infection cused by resistnt microorgnisms. Ciprofloxcin, new crboxyquinolone derivtive, my offer the dvntges of orl dministrtion, brod spectrum of ntibcteril ctivity, nd sfety for the mngement of these ptients. The phrmcokinetics of ciprofloxcin in serum nd peritonel fluid of eight dult ptients undergoing chronic mbultory peritonel dilysis (CAPD) were investigted. Ech ptient ingested single 750-mg dose of ciprofloxcin, nd drug concentrtions were mesured by high-pressure liquid chromtogrphy in serum nd peritonel fluid for 48 h fter the dose. Serum concentrtions reched men pek of 3.6,ug/ml 1 to 2 h fter the orl dose. The men terminl serum hlf-life ws 16.8 h, nd the men peritonel fluid/serum concentrtion rtio ws The men pek ciprofloxcin concentrtion in peritonel fluid ws 1.3,ug/ml, nd the bioctivity of the drug in peritonel fluid ws confirmed. These dt indicted tht therpeutic concentrtions of ciprofloxcin ginst bcteril pthogens commonly ssocited with peritonitis in CAPD ptients my be chievble in the peritonel fluid fter orl dministrtion to ptients undergoing CAPD. In ddition, the phrmcokinetic dt provide guidelines for further clinicl studies of orl ciprofloxcin in CAPD ptients. Chronic mbultory peritonel dilysis (CAPD) is commonly used for the tretment of end-stge renl filure. Peritonitis is the mjor compliction ssocited with CAPD, the most common custive bcteri being grm-positive cocci (Stphylococcus epidermidis, Stphylococcus ureus, nd Streptococcus spp.) nd grm-negtive rods (members of the fmily Enterobctericee nd Pseudomons eruginos) (3). Ciprofloxcin (1-cyclopropyl-6-fluoro-1,4-dehydro-4-oxo-7-[1-piperzinyl]-3-quinolinecrboxylic cid hydrochloride), new crboxyquinoline derivtive, is highly effective in vitro ginst these orgnisms. Moreover, ciprofloxcin ws found to hve bctericidl ctivity in vitro ginst P. eruginos in peritonel fluid obtined from ptients undergoing CAPD (6). Thus, ciprofloxcin my prove to be useful therpeutic gent in CAPD-relted peritonitis, provided tht dequte concentrtions re chievble in peritonel fluid. The phrmcokinetics of ciprofloxcin hve been studied previously fter single nd multiple doses in helthy volunteers nd fter single orl dose in ptients with renl dysfunction, including ptients undergoing hemodilysis (1). In the bove studies, ciprofloxcin ws found to be sfe nd well tolerted. Since phrmcokinetics of quinolones in ptients on CAPD hve not been reported, we determined these prmeters in the serum nd peritonel fluid fter single orl dose of ciprofloxcin in uninfected ptients undergoing CAPD. MATERIALS AND METHODS Eight mle subjects between the ges of 38 nd 74 yers (men, 56.8 yers) were enrolled in the study. Approvl for the study ws obtined from the Institutionl Review Bord * Corresponding uthor. of the Oklhom Teching Hospitls, nd informed consent ws obtined from ech subject before enrollment. Enrollment criteri included the following: ge, over 18 yers; dignosis of chronic, end-stge renl filure treted by CAPD for more thn 1 month; no ntibiotic therpy during the 14-dy period before the study; nd no evidence of peritonitis during the sme time period, s evidenced by clinicl signs nd peritonel fluid cell count nd cultures. Before enrollment, detiled medicl history ws obtined nd complete physicl exmintion ws performed on ech subject, long with complete blood count nd differentil, cogultion studies, chemistry profiles (including blood glucose, blood ure nitrogen, cretinine, electrolytes, clcium, phosphorus, lkline phosphtse, serum glutmic pyruvic trnsminse, lctte dehydrogense, gmm-glutmyltrnsferse, bilirubin, totl protein, nd lbumin), urinlysis (in ptients who produced urine), nd peritonel fluid cell count nd cultures. Except for bnormlities ssocited with their end-stge renl disese, subjects demonstrted no other biochemicl bnormlities nd were judged to be in stble clinicl condition. Physicl exmintion nd the bove-mentioned lbortory tests were repeted 24 nd 48 h fter drug dministrtion to ssess sfety nd monitor potentil side effects. On the dy of the study, fter n overnight fst, n indwelling intrvenous ctheter with heprin lock ws plced in forerm vein of ech subject for repeted blood smpling. To enble frequent peritonel fluid smpling, three-wy stopcock connector ws plced, under sterile conditions, between the dilysis bg extension tubing nd the peritonel dilysis ctheter. Smples were obtined through sterilely plced rubber-cp extension dptor (PRN Adptor) ttched to the three-wy connector. The rubber cp ws clensed with povidone-iodine solution before smpling. Between smplings, the entire connector 152

2 VOL. 30, 1986 PHARMACOKINETICS OF CIPROFLOXACIN IN CAPD PATIENTS 153 TABLE 1. Concomitnt medictions received by ech ptient Presence (+) or bsence (-) of the following mediction: Ptient Vitmin Stool Phosphte Others supplement softener binders Digoxin ZnSO4 FeSO4 CCO2 A Clonidine B Allopurinol C Diphenhydrmine D Trnsderml nitroglycerin E Synthroid F G Trnsderml nitroglycerin, proprnolol H _ site ws plced between two lyers of povidone-iodine- mtogrphy (HPLC) (7). Smple processing ws done in the soked guzes. following wy. Serum smples were filtered through 0.45-,um After bse-line peritonel fluid nd blood smples were membrne filters (Nihon Millipore, Kgyo, Jpn). These obtined, ech subject received single 750-mg cplet of filters re designed for smll smple volumes nd prevent ciprofloxcin (By , Miles Phrmceuticls, West H- clogging of the HPLC columns by smll fibrin prticles. ven, Conn.) with 200 ml of tp wter. The subjects remined Some ser were diluted 1:1 with mobile phse. Urine smfsting until 1 to 2 h fter dosing, when they were llowed to ples were diluted with mobile phse until the vlues were ingest their usul brekfst nd their medictions tken between 0.5 nd 12,ug/ml, which ws the liner rnge. The regulrly for underlying conditions (Tble 1). Blood smples peritonel fluids were used directly without processing. The for drug ssy were obtined predose nd 0.25, 0.5, 1, 1.5, 2, HPLC ws performed by using 1084 HPLC device (Hew- 2.5, 3, 4, 6, 8, nd 10 h fter the dose. The venous ctheter lett-pckrd Co., Plo Alto, Clif.) with fluorescence ws removed fter the 10-h smple. Additionl smples were detector (McPherson model FL-749). The detector ws obtined by venipuncture t 24 nd 48 h fter the dose. All operted with n excittion wvelength of 278 nm nd n blood smples were centrifuged, nd the serum ws sep- emission wvelength of 447 nm. The flow rte ws 1.80 rted, smpled, nd stored t -70 C until drug ssy ws ml/min, nd the oven temperture ws 45 C. A Brownlee performed. C-18 (5,um) column nd precolumn were used. The mobile The peritonel dilysis schedule in ech ptient included phse ws composed of 1.45 ml of ortho-phosphoric cid two consecutive 6-h cycles followed by 3- to 4-h cycle nd dded to pproximtely 500 ml of distilled wter nd titrted n 8-h overnight cycle. The dilysis fluid used ws Dinel to ph of 3.0 with tetrbutylmmonium hydroxide (40% by (Trvenol Lbortories, Morton Grove, Ill.) contining 1.5% weight solution; Aldrich Chemicl Co., Milwukee, Wis.), glucose for the first three cycles nd 4.25% glucose for the followed by dilution to 1,000 ml with deionized wter. overnight cycle. The study drug ws dministered in ech Methnol, t finl concentrtion of 5% (HPLC grde), ws cse immeditely upon strting the first 6-h cycle in the used s the orgnic modifier for ll nlyses. Stndrds were morning. Peritonel fluid smples were collected predose mde from ciprofloxcin powder dded to the mobile phse. nd 0.5, 1, 2, 3, 4, 6, 6.5, 7, 8, 8.5, 9, 10, 12, 16, 24, 30, 36, Stndrds were lso mde in ech of the fluids nlyzed, but 40, nd 48 h fter drug dministrtion. The smples collected there ws no observed difference in the pek heights befter 12 h were obtined from the drined peritonel fluid t tween the queous nd fluid-bsed stndrds. Quntittion the end of ech dilysis cycle. Smples were stored t -70 C ws bsed on pek heights. The within-run coefficients of until drug ssy. vrition t levels between 0.4 nd 12.0,ug/ml were 2 to Drug ssy in ech of the fluids tested (serum, peritonel 3.5%. The limit of detection ws 20 nglml, with within-run fluid, nd urine) ws done by high-performnce liquid chro- precision (coefficient of vrition) of 20%. TABLE 2. Concentrtion of ciprofloxcin in serum of CAPD ptients fter single 750-mg orl dose Ciprofloxcin concn (1Lg/ml) in ptient: Time (h) Men concn + SD H B C D F G E A 0 ND ND ND ND ND ND ND ND ND ND ND ± ± ± ± ± ± ± ± ± ± ND ND 0.60 ND 0.30 ND 0.20 ND, Not detectble (s0.20,ug/ml).

3 154 SHALIT ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 3. Ciprofloxcin concentrtion in dilysis fluid during first exchnge in eight CAPD ptients fter single 750-mg dose Ciprofloxcin concn (,ug/ml) in ptient: Time (h) C F D B G H E Men concn ± SD (rnge) C F D B G H E A 0 ND ND ND ND ND ND ND ND ND 0.5 ND ND ND ND 0.27 ND ND ND ND ND ND ND 0.37 ± 0.35 (0-1.0) ± 0.64 ( ) ± 0.67 ( ) ± 0.67 ( ) ± 0.63 ( ) ± 0.60 ( ) ND, Not detectble (<0.20,uglml). After initil phrmcokinetic dt indicted tht pek ciprofloxcin concentrtions in peritonel fluid were ttined 6 h fter drug dministrtion, the 6-h peritonel smples of six ptients were evluted for their bctericidl ctivity ginst the most common microorgnisms ssocited with CAPD-relted peritonitis (in two dditionl ptients, the mount of peritonel fluid smples were insufficient). The microorgnisms tested were S. epidermidis ATCC 12228, S. ureus ATCC 29213, Escherichi coli ATCC 28522, nd P. eruginos ATCC The bctericidl ctivity of the peritonel fluid smples ws tested by seril twofold dilution in Mueller-Hinton broth (1:2 to 1:128 dilutions), inoculted with 5 x 105 CFU of the microorgnisms per ml. After 18 h of incubtion, the tubes were ssessed for gross turbidity. Peritonel fluid inhibitory power ws defined s the highest dilution showing no turbidity; to ssess bctericidl ctivity, 10 R1 ws trnsferred from ech tube onto blood gr. Pltes were red fter 18 h of incubtion, nd the bctericidl ctivity ws defined s the highest dilution showing c5 colonies on subplting (.99.9% killing). Phrmcokinetic dt nlysis. Concentrtions of ciprofloxcin obtined in serum nd peritonel dilysis fluid versus time were plotted semilogrithmiclly. The hlf-life of the slowest phse nd the corresponding rte constnt (1) 0 4 -J TME IN HOURS FIG. 1. Men ciprofloxcin concentrtion in serum nd dilysis fluid fter single orl dose (750 mg). Bgs were exchnged t 6, 12, 16, 24, 30, 36, 40, nd 48 h.!, Serum; *, dilysis fluid. were clculted from visully determined best-fit lines drwn to the terminl log-liner segment of the curve. Mximum concentrtion in plsm nd time to mximum plsm concentrtion were lso obtined grphiclly, while re under the curve from 0 h to infinity (AUCO) ws clculted by the trpezoidl rule, with AUC48 estimted by dividing the 48-h plsm concentrtion by P. Rtios of peritonel dilysis concentrtions to serum concentrtions were clculted to determine pproch to equilibrium during the 4-, 6-, or 8-h-cycle exchnge lengths. Vlues of systemic clernce divided by frction of dose bsorbed (F) were obtined by dividing the dose by the AUC from 0 to oo. Volumes of distribution (Vp) divided by F were obtined by dividing the rtio of systemic clernce nd F vlues by the rte constnt,,b. RESULTS All eight subjects completed the study s scheduled. The procedures enbling multiple blood nd peritonel fluid smplings were well tolerted nd cused no complictions. The subjects did not experience ny side effects fter the single ciprofloxcin dose. Physicl exmintion nd lbortory tests performed 24 nd 48 h fter drug dministrtion disclosed no significnt chnges from bse-line dt obtined before drug dministrtion. Concentrtions of ciprofloxcin in serum for the entire 48-h period re shown in Tble 2, nd the concentrtions in peritonel fluid for the first dilysis cycle re shown in Tble 3. Plots of these vlues re shown in Fig. 1. Serum concentrtions rose rpidly, with peks in 1 to 2 h, nd declined slowly with cler multiexponentil chrcter. During ech dilysis exchnge, the concentrtions rose rpidly in the first severl hours, then more slowly pproched equilibrium. The functionl bioctivity of ciprofloxcin in the peritonel fluid of six ptients ws tested ginst four representtive bcteril pthogens. The results generlly demonstrted bctericidl ctivity tht correlted well with the peritonel fluid concentrtion of ciprofloxcin nd the MBC of the bcteri (Tble 4). For ny prticulr ptient, the 4-h exchnges usully produced lower rtios of peritonel fluid concentrtions thn the 6-h exchnges, indicting tht equilibrium hd not been reched (Tble 5). The 8-h overnight exchnges were conducted by using 4.25% glucose solutions, which yielded returned volumes significntly lrger thn those from the 1.5% glucose solutions; this resulted in rtios of peritonel fluid/serum concentrtion lower thn the 6-h exchnge rtios in severl cses. Mximum peritonel fluid/serum rtios occurred t the end of the dilysis exchnge for ll ptients during the first exchnge. Therefter, mximum rtios oc-

4 VOL. 30, 1986 PHARMACOKINETICS OF CIPROFLOXACIN IN CAPD PATIENTS 155 TABLE 4. Bctericidl ctivity of peritonel fluid obtined 6 h fter single 750-mg orl ciprofloxcin dose in ptients undergoing CAPD Bctericidl ctivity of ciprofloxcin ginst: Ciprofloxcin concn Ptient E. coli ATCC S. ureus P. eruginos S. epidermidis in fluid (HPLC) (MBC, ATCC ATCC ATCC (,ug/ml) -0.06) (MBC, 0.25) (MBC, 0.5) (MBC, 0.25) E 1:64 1:4 1:2 1: G 1:64 1:4 1:2 1: II 1:128 1:8 1:4 1: B 1:64 1:4 1:4 1: D 1:128 1:4 1:2 1: A 1:64 1:2 <1:2 1: Expressed s highest dilution demonstrting -99.9% bcteril killing. curred t or before the end of the cycle; this ws due to periods of disequilibrium between the decresing serum concentrtion nd the dilysis fluid in the peritonel cvity. For ll dilysis exchnges conducted, the overll men dilysis fluid/serum concentrtion rtio ws 0.64; in other words, peritonel drug concentrtions pproched 64%, on the verge, during the dilysis cycle. The verge pek concentrtion of ciprofloxcin in peritonel fluid ws 1.32 jig/ml nd occurred during the first dilysis exchnge. The AUC nd terminl hlf-life dt nd other phrmcokinetic prmeters re presented in Tble 6. DISCUSSION Ciprofloxcin ws rpidly bsorbed with men pek serum concentrtions between 1 nd 2 h of 3.61 j,g/ml. This is similr to the dt reported for norml volunteers by Gonzlez et l. (4), who obtined peks of 3.41 to 4.21,ug/ml 1 to 1.5 h fter 750-mg dose. The men terminl serum hlf-life of 16.8 h (rnge, 10.7 to 25.2) in our ptients with end-stge renl disese ptients is not unexpected nd differs drmticlly from the 3.9 to 6.6 h reported for norml subjects (2, 8). Men vlues of systemic clernce divided by F of ml/min nd V,IF of 489 liters from our study must be interpreted crefully, since neither prmeter cn be clculted independently of the biovilbility fctor. Assuming n F of 0.75, which is similr to the vlues of 0.63 to 0.77 found by Hoffken et l. (5), men Vp of 367 liters nd systemic clernce of 280 ml/min re obtined. The lrge Vp vlue indictes extensive tissue distribution of the drug; this vlue is similr to tht reported by Hoffklen et l. for ptients with norml renl function who were dministered 750-mg dose. However, the systemic clernce estimte of 280 ml/min is considerbly lower thn the vlues of ml/min in ptients with norml renl function reported by Wise et l. (8). Becuse our ptients hd compromised clernce mechnisms, this finding ws not unexpected. Since the volume of distribution ws reltively unffected, the vlue of,b ws lower thn norml. It should be pointed out tht the frction of the dose removed vi the peritonel fluid pthwy ws miniml, from 0.4 to 1.6%; likewise, in the few ptients who produced ny urine, the gretest mount eliminted by ny ptient ws only 1% of the dose. Therefore, the kinetic prmeter estimtes would be expected to be reltively unffected by removl of the drug by either of these routes in this popultion. Ciprofloxcin concentrtions in the peritonel fluid pproched 64% of the serum vlues when the exchnge cycles of 4, 6, nd 8 h were used in this study. Concentrtions rose rpidly in the first 1 to 2 h fter ech exchnge. Bctericidl ctivity of the peritonel fluid obtined t the end of the first exchnge showed gretest ctivity ginst E. coli, nd lesser ctivity ginst Stphylococcus nd Pseudomons spp., reflecting the greter in vitro susceptibility of members of the fmily Enterobctericee to ciprofloxcin (Tble 6). The method of superposition ws used with men serum dt to predict eventul stedy-stte levels t dose of 750 mg every 12 h. This yielded predictions of serum concentrtions of 2.4 nd 5.5,ug/ml immeditely before nd t 2 h fter the dose ws given t stedy stte. These vlues re higher thn those of Gonzlez et l. (4), but tht study used helthy volunteers; the longer hlf-life in CAPD ptients would result in greter ccumultion of the drug. Pek levels in dilysis fluid would be predicted to be bout 64% (3.3,ug/ml) of the serum concentrtion of 5.5,ug/ml. It is nticipted tht this peritonel concentrtion of ciprofloxcin would be effective ginst mny orgnisms responsible for peritonel infections in CAPD ptients. Since our dt were derived from CAPD ptients without peritonel inflmmtion, dditionl studies should be conducted in ptients with peritonitis to ssess the permebility of ciprofloxcin through in- TABLE 5. Highest rtio of peritonel fluid concentrtion of ciprofloxcin to serum concentrtions during ech dilysis exchnge nd mximum peritonel fluid concentrtion obtined during ny exchnge Rtio t time (h) (At): Mximum peritonel 6 (6) 12 (6) 16 (4) 24 (8) 30 (6) 36 (6) 40 (4) 48 (8) fluid concn (jjg/rl) Ptient flu pgrl) A B C D E F G H

5 156 SHALIT ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 6. Selected phrmcokinetic prmeters of single 750-mg orl dose of ciprofloxcin in eight CAPD ptients Prmeter Ptient (wt [kg]) (/CPmx t (h)b 1 (h-1) (h) AUCo0 CL/F VWIF t4/21 (j.g/rnl) "' (p.g h/mi) (mi/min) (liters) A (89) B (81) C (88) D (97.5) E (92) F (79.3) c G (72) H (75) Men SD Rnge Cp.,g Mximum plsm concentrtion; t,,, time to mximum plsm concentrtion; t:/20, elimintion hlf-life; CL, systemic clernce. b Estimted grphiclly. C 48-h smple missing. flmed peritonel membrnes. It is difficult to predict the effect of peritonel inflmmtion on ciprofloxcin concentrtions in the peritonel cvity. On one hnd, inflmmtion with ssocited hyperemi my increse locl drug concentrtion nd increse permebility in mnner similr to conditions such s meningel Qr synovil inflmmtion; on the other hnd, the function of the peritonel membrne s dilysis membrne is usully hmpered by inflmmtion nd the overll drug clernce my be reduced. Nevertheless, the phrmcokinetis fetures demonstrted in our study, s well s the orl route of dministrtion nd brod spectrum of ntimicrobil ctivity, support potentil role for ciprofloxcin in the mngement of peritonitis nd provide guidelines for further clinicl studies of orl ciprofloxcin in CAPD ptients. LITERATURE CITED 1. Boelert, J., Y. Vlcke, M. Schurgers, R. Dneels, M. Rosseneu, M. T. Rosseel, nd M. G. Bogert The phrmcokinetics of ciprofloxcin in ptients with impired renl function. J. Antimicrob. Chemother. 16: Brumfitt, W., I. Frnklin, D. Grdy, J. M. T. Hmilton-Miller, nd A. Iliffe Chnges in the phrmcokinetics of ciprofloxcin nd fecl flor during dministrtion of 7-dy course to humn volunteers. Antimicrob. Agents Chemother. 26: Gokl, R., D. M. A. Frncis, T. H. J. Goodship, A. J. Bint, J. M. Rmos, R. E. Ferner, G. Proud, M. K. Wrd, nd D. N. S. Kerr Peritonitis in continuous mbultory peritonel dilysis. Lncet ui: Gonzlez, M. A., F. Uribe, S. D. Moisen, A. P. Fuster, A. Selen, P. G. Welling, nd B. Pinter Multiple-dose phrmcokinetics nd sfety of ciprofloxcin in norml volunteers. Antimicrob. Agents Chemother. 26: H6ffken, G., H. Lode, C. Prinzing, K. Borner, nd P. Koeppe Phrmcokinetics of ciprofloxcin fter orl nd prenterl dministrtion. Antimicrob. Agents Chemother. 27: Shlit, I., D. IF. Welch, V. H. Sn Joquin, nd M. I. Mrks In vitro ntibcteril ctivities of ntibiotics ginst Pseudomons eruginos in peritonel dilysis fluid. Antimicrob. Agents Chemother. 27: Weber, A., D. Chffin, A. Smith, nd K. E. Opheim Quntittion of ciprofloxcin in body fluids by high-pressure liquid chromtogrphy. Antimicrob. Agents Chemother. 27: Wise, R., R. M. Lockley, M. Webberly, nd J. Dent Phrmcokinetics of intrvenously dministered ciprofloxcin. Antimicrob. Agents Chemother. 26: