ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 1986, p. 260-2660066-4804/86/080260-07$02.00/0Copyright © 1986, American Society for Microbiology

Vol. 30, No. 2

Pharmacokinetics and Pharmacodynamics of Ciprofloxacin inCystic Fibrosis Patients

MARC LEBEL,l 2* MICHEL G. BERGERON,' FRAN1;OIS VALLtE,' CELINE FISET 1,2 GIStLE CHASSt,'PIERRE BIGONESSE,3 AND GEORGES RIVARD3

Service d'Infectiologiel* and Departement de Pe'diatrie,3 Le Centre Hospitalier de l'Universite Laval, Quebec,Quebec GIV 4G2, and Ecole de Pharmacie, Universite Laval, Quebec, Quebec GIK 7P4,2 Canada

Received 20 December 1985/Accepted 29 May 1986

The pharmacokinetics and blister fluid penetration of oral ciprofloxacin were compared in 11 cystic fibrosis(CF) patients who had sputum colonization but were asymptomatic and in 12 healthy volunteers after a singledose (500 mg) and at steady state (500 mg every 8 h). The antibacterial effect of ciprofloxacin therapy was alsoevaluated by bacterial counts of colonizing pathogens in the respiratory secretions of CF patients. The CFpatients were 15.9% lighter in weight than the controls (P < 0.05). After a single dose, the elimination half-lifeof ciprofloxacin was decreased by a third in the CF patients as compared with the controls (2.62 versus 3.93h, respectively; P < 0.01). This was the result of a diminished apparent volume of distribution in CF subjects.Interestingly, we observed no statistically significant difference in total apparent and renal clearances betweenthe groups. Suction-induced blister fluid penetration was not different between CF patients and healthyvolunteers. In CF patients, ciprofloxacin exhibited levels in respiratory secretions above the reported MIC forPseudomonas aeruginosa: 1.36 and 1.86 ,ug/ml at 2 h after a single dose and at steady state, respectively. Animportant fall (mean, 3.9 loglo/ml) in the log titer in 10 patients with P. aeruginosa in their respiratorysecretions was observed after 5 days of treatment. However, this improvement was short-lived; the secondaryincrease in bacterial counts observed in five patients and the development of five resistant strains were causesfor concern. The pharmacokinetic results presented here showed that ciprofloxacin should be administeredevery 8 or even every 6 h in CF patients.

Among the quinolones presently under investigation,ciprofloxacin has shown superior in vitro activity, especiallyagainst Pseudomonas aeruginosa (3, 22). This microorgan-ism, especially the mucoid strains, is extremely difficult toeliminate from the respiratory secretions of cystic fibrosis(CF) patients who are chronically colonized (19).Ciprofloxacin, which can be administered orally, may be-come a useful drug for the treatment of this infection. In fact,several clinical trials are presently being done to study theclinical efficacy of ciprofloxacin in the treatment of acutepulmonary exacerbations in patients with CF (S. W. Bender,H.-G. Posselt, R. Wonne, B. Stover, R. Strehl, and P. M.Shah, Ninth International Cystic Fibrosis Congress,Brighton, United Kingdom, June 1984; M. E. Hodson, M. J.Smith, and J. C. Batten, Proc. 14th Int. Congr. Chemother.,p. 200, 1985).The pharmacokinetics of several antibiotics have been

shown to be disturbed in CF patients. Increased clearanceand altered volume of distribution for aminoglycosides andbeta-lactam antibiotics have been described in patients withCF as compared with normal subjects or non-CF children(11, 12, 15, 25; L. Cliche, M. LeBel, and M. G. Bergeron,Can. J. Hosp. Pharm., in press). Conflicting results havebeen reported on impaired oral absorption of drugs in thispopulation (6, 10, 17, 21).The purposes of this study were (i) to compare the

single-dose and steady-state pharmacokinetics ofciprofloxacin in CF patients and in healthy volunteers (con-trols) and (ii) to determine the effect of ciprofloxacin therapyon bacterial counts (with special reference to P. aeruginosa)in the respiratory secretions of CF patients.

* Corresponding author.

MATERIALS AND METHODS

Subjects. A total of 11 CF patients (7 males and 4 females;ages 19 to 25 years) and 12 healthy volunteers (6 males and6 females; ages 19 to 25 years) gave their informed consent toparticipate in the study. Subject characteristics are de-scribed in Table 1. The protocol was approved by the CentreHospitalier de l'Universitd Laval Human Research Reviewand Pharmacology-Therapeutics committees. The diagnosisofCF was based on a compatible family and clinical history,abnormal sweat test, and pancreatic insufficiency or chronicpulmonary disease. All patients met these criteria. All pa-tients except no. 11 had a good to excellent clinical evalua-tion score by the rating system of Shwachman andKulczycki (23). All subjects were judged to be otherwisehealthy on the basis of a history, physical examination,chemistry profile, complete blood count, and urinalysis.Volunteers were determined to be not pregnant after directlatex agglutination pregnancy tests. The patients were stud-ied during an infection-free period; they had stopped allprophylactic antimicrobial therapy (oral and inhalation) 5days prior to the study. The CF patients were kept onpancreatic enzymes, multivitamins, and any other medica-tions required by their disease (Table 1). The subjects had torestrain from any strenuous or athletic activity during thestudy period but were allowed to circulate around theclinical pharmacokinetic research unit. Alcoholic beveragesand caffeine were withheld 24 h prior to the study and on day1, 6, or 9.Study design. On the morning of day 1 and following an

overnight fast, each subject received a single 500-mg oraldose of ciprofloxacin (Miles Laboratories, Rexdale, Ontario,Canada) taken with 200 ml of drinking water. Starting on themorning of day 2 and continuing through day 5 for healthy

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TABLE 1. Demographic characteristics of subjects

Subject Sexa Age (yr) Ht (cm) Wt (kg) Body surface Lean body Current medications ShwachmanI

area (in) massb (kg) score (%

F 19 156

M 21 174.5

M 25 178

M 21 173F 19 158

F 19 159.5

F 21 161

M 21 170

M 20 170.5

M 20 157.5

M 19 172.5

46.6

65.5

54.4

5244.5

1.43

1.79

1.68

1.621.42

51 1.51

51.3 1.52

45. 1.50

69.1 1.80

35.6

57.9

1.28

1.69

36.7 Pancreatic enzymes,multivitamins, salbutamol(aerosol)

54.0 Pancreatic enzymes,multivitamins, salbutamol(aerosol)

47.9 Pancreatic enzymnes,multivitamins

45.6 Pancreatic enzymes, tolmetin35.9 Pancreatic enzymes,

lactulose, oralcontraceptives

39.4 Salbutamol (aerosol),multivitamins

39.9 Pancreatic enzymes,multivitamins

40.5 Pancreatic enzymes,multivitamins

55.0 Pancreatic enzymes,multivitamins,theophylline, salbutamol(aerosol)

32.6 Pancreatic enzymes,multivitamins, prednisone

49.3 Pancreatic enzymes,multivitamins, theophylline

20.5 + 1.8 166.4 ± 8.0 52.1 ± 9.6 1.57 ± 0.16 43.3 ± 7.5

Healthy volunteers1234S6789101112

F 25 170.0M 21 174.5F 23 155.0F 23 162.0M 19 168.0F 25 166.0M 22 176.7M 22 180.0F 22 176.0M 22 173.0M 19 175.5F 24 178.0

59.867.049.554.469.662.060.075.057.067.562.160.6

1.691.811.461.571.791.691.741.941.701.801.761.76

45.755.337.941.554.647.648.960.345.554.852.347.7

Oral contraceptives

Oral contraceptives

22.3 ± 2.0 164.6 ± 21.4 62.0 ± 7.0 1.73 ± 0.12 49.3 ± 6.4a F, Female; M, male.b Calculated by the following relationships: Lean body mass for men = 1.10 x weight - 128 x (weight2Aheight2); lean body mass for women = 1.07 x weight

- 148 x (weight2/height2).

volunteers or through day 8 for CF patients, a 500-mgciprofloxacin tablet was taken orally in a fasting state every8 h (a total of 12 and 21 doses, respectively). A final 500-mgdose was given on the morning of day 6 for healthy volun-teers and day 9 for CF patients.Serum and urine sampling. Blood samples were drawn via

an intravenous catheter from an antecubital vein accordingto the following sequence: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,4, 5, 6, 8, and 10 h after the first single dose (day 1). After thelast dose (day 6 or 9), an additional sample was drawn at 24h. A dilute heparin solution (33 U/ml) was used to maintainthe patency of the needle, and at least 1 to 1.5 ml of bloodwas removed and discarded before the sample was drawn.Blood samples (10 ml for healthy volunteers, 5 ml for CFpatients to minimize blood loss) were collected intoVACUTAINER tubes (Becton Dickinson Vacutainer Sys-

tems, Rutherford, N.J.) with red stoppers and no anticoagu-lant. The serum was allowed to clot at room temperature for20 min and was then centrifuged within 20 min. The serumwas frozen at -80°C until assayed.

Urine was collected immediately before administrationand after the first (single) dose and the last dose at intervalsof 0 to 2, 2 to 4, 4 to 8, and 8 to 24 h after dosing. Aliquotsof each urine sample were stored at -80°C until assayed.

Saliva, blister fluid, and respiratory secretion sampling.Mixed saliva was obtained by having the subjects chew on apiece of paraffin wax (Parafilm; Amnerican Can Co., Green-wich, Conn.). After any food ingestion, the buccal mucosawas rinsed with water. Collection was performed immedi-ately before administration, at 0, 0.5, 1, 3, 5, and 8 h after thefirst dose, and at 0.5, 1, 3, 5, 8, and 24 h after the last dose.Each healthy volunteer had ten skin blisters produced on

CF patients1

2

3

45

7

8

9

10

11

12

65

80

85

6685

77

72

70

85

35

71

Mean ± SD 72 ± 14

Mean ± SD

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ANTIMICROB. AGENTS CHEMOTHER.

the forearm after both the first and last doses. Only six CFpatients (two females, four males) had skin blisters producedon the forearm after the last dose. Suction-induced skinblisters were produced by the slightly modified method ofHellum et al. (7). In brief, a Plexiglas block with 10 bores(diameter, 8 mm) 'was strapped to the volar area of theforearm after the skin had been swabbed with 70%isopropanol. Controlled suction (-400 mm of Hg) wasapplied until semispherical blisters had been produced (1.5to 2 h). The blister fluid was samnpled by puncture with alow-dead-space syringe (Micro-fine III; Becton Dickinsonand Co., Rutherford, N.J.), and aspiration of 0. 10 to 0.15 mlof fluid was performed on one or two blisters, if needed.Each blister was sampled only once. The harvesting timesequence was 0.5, 1, 2, 2.5, 3, 4, 6, and 8 h after the first dosefor healthy volunteers. After multiple doses, the blisterswere punctured at '2, 3, 4, 6, 8, and 10 h for both groups.Additional sampling was performed in the healthy volunteersat 1 and 24 h after the last dose.

Respiratory secretions were obtained by expectoration inCF patients for ciprofloxacin concentration determinationsat 1, 2, and 4 h after the first and last doses. Respiratorysecretions were also collected for cultures and bacterialcounts before the first dose and 2 h after the doses on days5 and 9. On the last day, four patients had difficulty produc-ing sputum, and in one of these a deep pharyngeal swab(Culturette II; Marion Scientific, Div. Marion Laboratories,Inc., Kansas City, Mo.) had to be used to extract secretionsfrom her throat. Cultures and bacterial counts were repeatedon respiratory secretions obtained 60 days after treatment.

Microbiology and susceptibility testing. Respiratory secre-tions were liquefied with equal volumes of Sputolysin(Calbiochem-Behring, La Jolla, Calif.) and cultured on Mac-Conkey, Mannitol, blood, and chocolate agars. Microorgan-ism identification was performed by standard bacteriological

5.0-

E

z0

c

zwUz0Uz

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0

crC-0

TABLE 2. Pharmacokinetic parameters after a single dose of 500mg of ciprofloxacin

Mean + SD for:Parametera

CF patients Controls P

AbsorptionCmax (,ug/ml) 2.84 + 0.63 2.26 ± 0.75Tmax (h) 1.55 ± 0.56 1.33 t 0.46Lag time (h) 0.36 ± 0.31 0.34 ± 0.16Ka (h-1) 1.060 t 0.496 2.792 t 1.304 <0.01

EliminationC8 (,g/ml) 0.39 ± 0.18 0.41 ± 0.13tj,2 (h) 2.62 ± 1.04 3.93 t 1.12 <0.01AUCO, (,ug. h/ml) 11.07 ± 3.43 10.00 ± 2.78CLapp (ml/min) 828.0 ± 287.5 908.0 ± 243.6CLR (ml/min) 474.1 ± 159.5 395.6 ± 139.0CLNR app (ml/min) 353.6 ± 190.4 512.4 ± 204.4Vss app (liters/kg) 2.12 ± 0.75 3.76 ± 0.90 <0.001

a Cmax, maximum concentration of drug in serum; T.ax, time to maximumconcentration of drug in serum; Ka, absorption constant; C8, concentration at8 h; t4/2, half-life.

techniques used routinely in our microbiology laboratory.Serial dilutions of liquefied respiratory secretions (from 101to 1010) were used for determinations in triplicate of bacterialcounts of primary pathogens. MIC determinations weredone on a total of 28 P. aeruginosa strains found in respira-tory secretions by the agar dilution procedure described bySteers and colleagues (18, 26). The final inoculum used was5 x 105 CFU/ml. The antibiotic powers were kindly providedby the following pharmaceutical companies: ciprofloxacin(Miles Laboratories), enoxacin (Parke-Davis Canada Inc.,Scarborough, Ontario, Canada), ceftazidime (Glaxo Labora-tories, Toronto, Ontario, Canada), cefsulodin (LaboratoiresAbbott Ltde, Montreal, Quebec, Canada), ticarcillin(Laboratoires Beecham Inc., Pointe-Claire, Quebec, Can-ada), tobramycin (Eli Lilly Canada Inc., Scarborough,Ontario, Canada), and netilmicin (Schering Canada Inc.,Pointe-Claire, Quebec, Canada). Calcium and magnesiumions were not added in the broth we used, since the Mueller-Hinton broth we used met the specifications of the NationalCommittee for Clinical Laboratory Standards (18).Sample analysis. Serum, urine, saliva, and blister fluid

E

0)

z

0

1.1zw

9z

0

U-0a.

TIME ( H)FIG. 1. Mean concentrations of oral ciprofloxacin in serum after

a single 500-mg dose. Symbols: 0, CF patients; *, healthyvolunteers.

TIME (H)

FIG. 2. Mean concentrations of oral ciprofloxacin in serum atsteady state. Symbols: 0, CF patients; *, healthy volunteers.

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TABLE 3. Pharmacokinetic parameters at ciprofloxacinsteady state

Mean + SD for:Parametera p

CF patients Controls

AbsorptionCmax (ig/ml) 3.78 ± 0.97 3.51 ± 1.33"Tmax (h) 1.72 ± 0.44 1.04 ± 0.42 <0.002ka (h-') 0.862 ± 0.662 2.301 ± 0.824 <0.001

EliminationC8 (p.g/ml) 0.82 ± 0.34c 0.82 ± 0.32bt112 (h) 3.90 ± 1.71 4.87 ± 1.30dAUCO, (,ug- h/ml) 14.61 ± 3.85c 13.93 ± 5.32dCLapp (ml/min) 601.3 ± 133.1b 690.6 ± 297.0dCLR (ml/min) 319.1 ± 156.9b 358.4 ± 135.8CLNR app (ml/min) 283.0 ± 124.74 316.6 ± 246.9dVss app (liters/kg) 2.29 ± 0.98 3.71 ± 0.96 <0.008a See Table 2, footnote a, for definitions.b p < 0.01 (paired t test; single dose versus steady state).c P < 0.001 (paired t test; single dose versus steady state).d p < 0.05 (paired t test; single dose versus steady state).

samples were analyzed for total ciprofloxacin by a reverse-phase, ion-pairing, high pressure liquid chromatographyprocedure we developed (26a). In brief, separation ofciprofloxacin and nalidixic acid (internal standard) wasachieved by using UV absorption at 313 nm and a C18Nova-Pak column (Waters Associates, Inc., Milford,Mass.). The mobile phase consisted of 35% phosphatebuffer, 65% methanol, and 5.5 mM hexadecyltrime thylam-monium (HDTA) and was adjusted to pH 7.4. Serum samplepreparation involved protein precipitation with acetonitrile(1:2), followed by methylene chloride-2-propanol (90:10)extraction. The sensitivity limit of the assay was 0.06 ,ug ofserum and blister fluid per ml. The coefficient of variationfrom day to day was <5.3%, and the serum and urinerecoveries were 55 and 108%, respectively. Linear regres-sion analysis of the standard calibration lines yielded acorrelation coefficient of >0.999, indicating excellent linear-ity of the assay between 0.125 and 10.0 ,ug/ml. Whencompared with a microbiological assay of serum, the corre-lation coefficient was 0.922 (n = 58).

Pharmacokinetic analysis. Pharmacokinetic analysis wasperformed by using model-independent methods. The elim-ination rate constant (kel) was calculated from the terminalexponential phase of semilogarithmic plots (4).The area under the serum concentration-time curve

(AUC) from time zero to time t (AUC,},) was calculated withconventional linear trapezoidal and extrapolation methods.The apparent serum clearance (CLapp) of ciprofloxacin wasestimated from the model-independent pharmacokineticsequation CLapp = dose/AUC> ,, where 0-t is 0 to infinityafter a single dose and 0 to T after the last dose (here, T = 8h). Although we previously used an absolute bioavailabilityvalue (f) of 70% to better estimate total clearance (14), wecould not assume identical bioavailability in healthy volun-teers and CF patients.The renal clearance (CLR) of ciprofloxacin was calculated

from the relationship CLR = Ae(ti -- t2)/AUC(t1 -* t2), whereAe is the amount of ciprofloxacin found unchanged in urinefrom time t1 to time t2. The apparent nonrenal clearance(CLNR app) was estimated from substraction of CLR from theapparent total clearance. The apparent volume of distribu-tion (Vapp) after a single dose was calculated from therelationship Vapp = (dose [area under the first moment

of the concentration-time curve {AUMC}/AUC2]) -(dose ka[AUC]) (20). The Vapp at steady state (Vss app) wasdetermined by the equation, derived from the work of Smithand Schentag (24), V,s app = (dose[AUMC/AUC2]) -(dose/ka [AUC]), where AUC = AUCSS o and AUMC =AUMCSS o - (AUCss t_/ka) + TAUCss (David Nix,personal communication).We did not calculate separately the pharmacokinetic pa-

rameters for men and women because of data from Hoffier etal., who showed that the disposition of ciprofloxacin isindependent of sex (9).

Statistical analysis. Comparisons of pharmacokinetic databetween both groups were made with a one-way analysis ofvariance. The paired t test was used to determine thestatistical significance between single-dose and steady-statedata. A P value of <0.05 was considered statistically signif-icant.

RESULTSStudy groups. The demographic characteristics of both

controls and CF patients are shown in Table 1. On themorning of day 1, patient 6 chose not to participate in thestudy; we were unable to replace her. Although an attemptwas made to select healthy volunteers with less-than-idealbody weight to match underweight CF patients, CF patientswere 15.9% lighter in weight than controls (P < 0.05).

Pharmacokinetics. Mean levels of ciprofloxacin in serumfollowing the first (single) dose in CF patients and controlsare shown in Fig. 1, and the corresponding pharmacokineticdata are shown in Table 2. Mean peak ciprofloxacin concen-trations in serum were slightly higher in CF patients than incontrols (2.84 + 0.63 versus 2.26 + 0.75 ,ug/ml, respectively)but did not reach the level of statistical significance. Al-though not visually apparent, the absorption phase wasslower in CF patients, as shown by absorption constantvalues of 1.06 + 0.50 versus 2.79 ± 1.30 h-1 in CF andhealthy subjects, respectively.

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z0UJ

zw

0za0

0cc

0-0~

1.0

0 2 4 6 8 10

TIME (H)FIG. 3. Mean concentrations of ciprofloxacin in blister fluid at

steady state. Symbols: 0, CF patients; *, healthy volunteers.

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The elimination half-life of ciprofloxacin was decreased bya third in CF patients as compared with controls (2.62 ± 1.04versus 3.93 ± 1.12 h, respectively; P < 0.01). This differencein mean half-life values cannot be visually observed in Fig. 1,since representation of mean concentrations in serum vanishthis difference (16). Interestingly, we observed no statisti-cally significant difference in apparent total clearance andbetween CF and healthy subjects. Furthermore, we normal-ized the apparent total clearance to lean body mass for eachsubject (Table 1). Both apparent total clearances were fairlysimilar (945.3 versus 918.5 ml/min per 50 kg of lean bodymass for CF and healthy subjects, respectively). The de-creased half-life was the result of a diminished apparentvolume of distribution (2.12 ± 0.75 versus 3.76 ± 0.90liters/kg in CF patients and healthy volunteers, respectively;P < 0.001).Although not completely comparable, steady-state

ciprofloxacin levels in serum after the last dose for CF andcontrol subjects (doses 22 and 13, respectively) are shown inFig. 2. As anticipated from pharmacokinetic theory, peakconcentrations in serum for both CF and healthy subjectswere higher (3.78 versus 2.84 and 3.51 versus 2.26 ,ug/ml,respectively) after the last dose than after the first dose(Table 3). As observed in healthy volunteers, the apparenttotal clearance of ciprofloxacin in CF patients showed asignificant decrease after multiple doses. In contrast tohealthy volunteers, no increase in half-life could be demon-strated in this patient population when single-dose andsteady-state data were compared.We performed an analysis of covariance with weight, body

surface area, and lean body mass as covariables; thesecovariables were not statistically significant for any of thepharmacokinetic parameters, either for a single dose or forsteady state, except for weight, which was a covariable (P <0.02) for the time to maximum concentration of drug inserum after a single dose.Mean peak concentrations of ciprofloxacin after a single

dose in saliva were higher in controls than in CF patients(1.32 versus 1.01 ,ug/ml, respectively), but the difference wasnot statistically significant. At steady state, these peak levelsin saliva were similar (1.57 jig/ml for normal volunteers and1.51 pug/ml for CF patients). No statistically significantdifference could be observed in peak levels in saliva betweenboth groups. The ratios of the peak concentration in saliva tothe simultaneous concentration in serum yielded remarkablyconstant values, except for controls after a single dose (0.78+ 0.36). The ratio after a single dose in CF patients was 0.49,and those at steady state were 0.55 and 0.53 in CF andhealthy subjects, respectively.

Steady-state blister production was more erratic in CFpatients; fewer blisters were obtained than in controls. Meanlevels of ciprofloxacin in blister fluid for CF patients andcontrols are shown in Fig. 3. The mean peak ciprofloxacin

TABLE 4. MIC90 against 28 P. aeruginosa isolates

MIC90 (,ug/ml) on day:Antibiotic

0 (n = 22) 5 (n = 10) 9 (n = 15) 60 (n =18)

Ciprofloxacin 1 1 4 1Enoxacin 4 2 16 4Ceftazidime 4 4 4 4Cefsulodin 8 4 4 4Ticarcillin 32 32 64 32Tobramycin 16 16 8 8Netilmicin >128 >128 128 64

PATIENT

FIG. 4. P. aeruginosa counts in the 11 CF patients before thefirst dose (0) and on days 5 (5), 9 (9), and 60 (60) after treatment.

concentrations observed after the last dose in CF patientsand controls were similar (1.79 + 0.51 versus 1.87 + 0.66pug/ml, respectively). From the elimination portion of indi-vidual curves, a half-life of 4.40 ± 1.78 h was obtained in CFpatients, a value which was not significantly different fromthe value obtained in controls (3.32 ± 2.40 h).

Respiratory secretions. Peak concentrations in respiratorysecretions observed at 2 h were 1.36 and 1.86 ,ug/ml after asingle dose and at steady state, respectively. Before therapy,seven CF patients harbored P. aeruginosa in respiratorysecretions, one had Staphylococcus aureus, two had boththese bacteria, and one had P. maltophilia, P. cepacia, andS. aureus. The MICs of ciprofloxacin and other antibacterialagents for 90% (MIC%0) of a total of 28 P. aeruginosa isolatesare shown in Table 4. Ciprofloxacin had lower MIC90s thanthe other six antibiotics tested. Five ciprofloxacin-resistantstrains (MICgo, >4) of P. aeruginosa appeared in threedifferent patients during therapy. Also of interest was theincreased MIC90 observed with enoxacin (Table 4); ninestrains of P. aeruginosa developed resistance to enoxacin(MIC90, >4) under ciprofloxacin treatment.The bacterial counts ofP. aeruginosa in the 11 CF patients

is shown in Fig. 4. An important fall (mean, 3.9 log1l/ml) inthe log titer in 10 patients with P. aeruginosa in theirrespiratory secretions can be observed after 5 days oftreatment; five patients had increases in bacterial countsfrom days 5 to nine. Five still had lower bacterial counts 60days after treatment; the other six had the same level or ahigher level of colonization by P. aeruginosa than beforetreatment.

Subjective clinical improvement was noted in at least fivepatients; four of them had difficulty in producing respiratorysecretions on the last day and also had a significant decreasein colony counts.

DISCUSSION

Ciprofloxacin is eliminated by a combination of hepaticbiotransformation and renal excretion. Four metabolites ofciprofloxacin in urine are currently known, and their renalexcretion amounts to 13.5% (H. J. Zeiler, U. Peterson, andW. Gau, Program Abstr. 24th Intersci. Conf. Antimicrob.Agents Chemother., abstr. no. 983, 1984). Ciprofloxacinexhibits a large apparent volume of distribution and low

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protein binding (20 to 43%). Renal excretion is the mainelimination pathway, with tubular secretion being somewhatmore important than glomerular filtration (2, 8, 27, 28).

In this study, CF patients had a shorter ciprofloxacinelimination half-life in serum than did controls (2.62 versus3,93 h after a single dose, respectively); this observation isconsistent with other reports of increased drug elimination inpatients with CF (11, 12, 15; F. Sorgel, U. Stephan, H. G.Wiesemann, I. Bruning, H. C. Dominick, and C. Hesseling,Proc. 14th Int. Congr. Chemother. p. 178, 1985). Since theapparent total clearance of ciprofloxacin did not appear to bemodified by CF, this shorter half-life was mainly due to asmaller apparent volume of distribution (2.12 versus 3.76liters/kg; P < 0.001). It has been speculated that the in-creased volume of distribution of hydrosoluble drug in CFpatients is secondary to the reduced adipose tissue in thesepatients (13). The same hypothesis may apply in the oppositeway to explain a decreased volume of distribution ofciprofloxacin, a slightly liposoluble drug. In contrast totheophylline, the protein binding of ciprofloxacin is too lowto significantly affect its apparent volume of distribution inCF patients (10). Moreover, ciprofloxacin concentrations insaliva, grossly representative of the free fraction, were notdifferent between the groups.

Since we initiated this study, the results of four studies onthe pharmacokinetics of ciprofloxacin in CF patients havebeen presented or published (1, 5; J. F. Blumer, R. C. Stern,C. M. Myers, J. D. Klinger, and M. D. Reed, Proc. 14th Int.Congr. Chemother., p. 178, 1985; Sorgel et al., Proc. 14thInt. Congr. Chemother.). They reported a meanciprofloxacin half-life in CF patients of 3.6 to 5.15 h. In thetwo studies comparing CF and healthy subjects, neitherreported accelerated elimination of ciprofloxacin in CF pa-tients (Blumer et al., Proc. 14th Int. Congr. Chemother.;Sorgel et al., Proc. 14th Int. Congr. Chemother.). In fact, adecreased total clearance was observed by Blumer andco-workers (Blumer et al., Proc. 14th Int. Congr. Chemo-ther.). Potential discrepancies between our data and those ofothers are unclear. Differences between our observationsand those of other authors may be the result of the clinicalheterogeneity of CF. Strict adherence to severity scores anddetermination of blood volume, extracellular volume, andtrue lean body mass and surface area might allow directcomparisons between studies. Possible explanations wouldalso include a shorter blood-drawing period, since it hasbeen shown that a longer half-life could be obtained forciprofloxacin if blood levels are followed for longer than 10 h(single dose) (W. Wingender, personal communication).We also found in this study higher peak levels in serum for

CF patients than for controls, although this difference wasnot significant. Sorgel and co-workers made similar obser-vations when they speculated that the decreased bicarbonatesecretion in CF patients, which could influence the ioniza-tion of ciprofloxacin in the gastrointestinal tract, makesciprofloxacin more absorbable (Sorgel et al., Proc. 14th Int.Congr. Chemother.). Surprisingly, high ciprofloxacin con-centrations in serum in CF patients may be the result of acombination of slower and more complete absorption and asmaller apparent volume of distribution than in controls.Blumer and co-workers showed that pancreatic enzymes hadno effect on absorption, distribution, and elimination ofciprofloxacin (Blumer et al., Proc. 14th Int. Congr. Chemo-ther.). According to blister fluid data, the distribution ofciprofloxacin in extracellular fluid did not seem to be affectedin CF patients, as compared with normal volunteers.The pharmacokinetic results presented here showed that

ciprofloxacin should be administered every 8 or even every6 h in CF patients.

Ciprofloxacin induced a significant reduction in counts ofP. aeruginosa, but this improvement was short-lived. Weacknowledge the limitations of quantitative bacteriology inrespiratory secretions obtained by expectoration, but webelieve that this information is valuable in studies of thepharmacodynamic effects of antibacterial agents in clinicalsituations such as sputum colonization of CF patients. Thesecondary increase in bacterial counts observed in fivepatients and the development of five resistant strains arecauses for concern. Others have recently observed bacterialresistance to ciprofloxacin after long-term oral administra-tion (S. T. Chapman, D. C. E. Speller, and D. S. Reeves,Letter, Lancet ii:39, 1985; S. M. Crook, J. B. Selkon, andP. D. McLardy Smith, Letter, Lancet i:1275, 1985; C. M.Roberts, J. Batten, and M. E. Hodson, Letter, Lanceti:1442, 1985). One of these reports concerns CF patients.Caution against the use of ciprofloxacin in this populationshould prevail before clinical and microbiological studiesevaluate the in vivo importance of these observed in vitroresistance patterns.

ACKNOWLEDGMENTS

This study was supported by a grant from Miles Laboratories.We are grateful to Louise Cliche, Daniel Croteau, and the

personnel of the Centre Hospitalier de l'Universite Laval CysticFibrosis Clinic for their collaboration. We also thank Michael Spinofor his helpful comments.

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