ANTIMICROBIL AGENTS AND CHEMOTHERAPY, Feb. 1979, p. 165-170 0066-4804/79/02-0165/06$02.00/0

Vol. 15, No. 2

Pharmacology of Cmnoxacin in Humans HENRY R. BLACK,* KAREN S. ISRAEL, ROBERT L. WOLEN, GORDON L. BRIER, BOYD D. OBERMEYER, EDGAR A. ZIEGE, AND JAMES D. WOLNY Lilly Laboratory for Clinical Research, Wishard Memorial Hospital, Indianapolis, Indiana 46202 Received for publication 10 November 1978

Cinoxacin was almost completely absorbed when given orally and was found to be approximately 60 to 70% protein bound. Peak serum concentrations were reached within 2 h, and detectable serum concentrations persisted up to 12 h after administration of 0.25-, 0.5-, and 1-g multiple oral doses. Although food delayed the absorption and caused a 30% reduction in mean peak serum concentrations, the overall 24-h urinary recovery was not significantly altered. Approximately 50 to 55% of the drug was excreted in the urine as unchanged drug. At 12 h, urine concentrations were still above the minimal inhibitory concentration for most common gram-negative urinary pathogens. Cinoxacin was well tolerated when administered to 23 volunteers from 10 to 28 days. Resistance among fecal isolates initially susceptible to cinoxacin was not observed in nine volunteers who were administered 0.5 g every 12 h for 4 to 28 days.

Cinoxacin (Cinobac; 1-ethyl-1,4-dihydro-4-oxo [1,3] dioxolo-[4,5-g] cinnoline-3-carboxylic acid) is a synthetic organic antibacterial which has good in vitro antimicrobial activity against Enterobacteriaceae but negligible activity against Pseudomonas aeruginosa and gram-positive cocci (5, 9, 10, 12, 13, 16). As expected from in vitro activity, cinoxacin has been shown to be clinically effective in the treatment of urinary tract infections caused by these microorganisms (2, 11, 14, 15, 17; C. E. Cox, Abstr. 9th Int. Congr. Chemother., 1975, Abstr. no. M-663). The following studies present the pharmacology of cinoxacin when administered to humans in single and multiple oral doses and with and without food. Preliminary results of this study have been reported (H. R. Black, G. Brier, and J. Wolny, Abstr. 9th Int. Congr. Chemother., 1975, Abstr. no. M-665). MATERIALS AND MERHODS Cinoxacin. Cinoxacin for human studies was supplied as the free acid by Eli Lilly and Co. in 0.25- and 0.5-g capsules. Stool microflora studies. Stool microflora was examined in those volunteers receiving multiple doses of cinoxacin, 0.5 g every 12 h, for up to 28 days. Each volunteer received a standardized hospital diet for 4 to 5 days before the first stool collection and remained on this diet throughout the study period. A control stool specimen was collected from each volunteer just before the administration of the drug. A stool specimen was obtained in the first 24 h after the last dose in the 28-day multiple-dose study. Aerobic microorganisms were isolated by plating 102 and 103 dilutions of fecal suspension on various selective media. Fecal suspension was made by kneading 1 g of feces and

adding 10 ml of prereduced salt solution, mixing, and making serial 10-fold dilutions in molten agar. The plates were incubated for 18 h at 35°C, at the end of which time the organisms on the plates were counted. Only those aerobic organisms previously determined to be within the spectrum (16) of cinoxacin were tested for susceptibility to this antimicrobial agent as well as to ampiciflin and nalidixic acid. All facultative gramnegative rods isolated were identified by using Analytab API 20E strips (Analytab Products, Inc., Plainview, N.Y.). Susceptibility studies. The minimal inhibitory concentration was established using a serial twofold broth microdilution procedure with a Canalco Autotiter IV (Canalco, Inc., Rockville, Md.). The medium used was Mueller-Hinton (Baltimore Biological Laboratory, Cockeysville, Md.) broth, and the inoculum size was 10i to 106 organisms per ml of medium. At the end of the incubation period (15 to 18 h at 3500), the minimal inhibitory concentration was determined. The minimal inhibitory concentration was defined as the lowest concentration of antibiotic at which growth was totally inhibited. Human volunteers. Fifty-five healthy men, between 21 and 55 years of age, were admitted to the Lilly Research Ward. Their weights ranged from 50 to 91 kg. Prestudy physical examination and clinical laboratory parameters were normal. Signed statements of consent were obtained. Procedure. All volunteers were placed on a controlled hospital diet: 300 g of carbohydrate, 120 g of protein, and 150 g of fat, equivalent to approximately 3,000 calories daily. The volunteers were fasted 8 h before and until 2 h after the drug was given only on days when blood and urine specimens were obtained. When the effect of food was evaluated, volunteer subjects received a standardized breakfast which consisted of 33.6 g of protein, 41 g of fat, and 111.3 g of carbohydrate (911 calories). 165

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The following laboratory tests were obtained before and after the study period: complete blood count, urinalysis, serum creatinine, blood urea nitrogen, glucose, serum glutamic oxaloacetic transaminase, lactic dehydrogenase, alkaline phosphatase, cholesterol, total protein, albumin, total bilirubin, uric acid, phosphorus, and calcium. Drug administration. Volunteers received single oral doses of 0.25, 0.5, and 1 g of cinoxacin. Multiple oral doses of 0.25 g every 6 h, 0.5 g every 6 h, and 1 g every 12 h were administered for 10 days to four, six, and four volunteers, respectively. Multiple oral doses of 0.5 g every 12 h were given to nine volunteers from 4 to 28 days to assess the safety and tolerance to prolonged administration. Another group of ten volunteers received a single oral dose of 0.5 g with and without a standardized breakfast in a crossover study designed to evaluate the effect of food on the serum and urine concentrations of cinoxacin. Each dose was administered 72 h apart. One subject received a single dose of 250 mg of cinoxacin containing 50 ,Ci of 14C labeled at the carboxyl group. Blood and urine collection. Venous blood specimens were collected and immediately centrifuged. The serum was recovered and kept frozen at -26°C until assayed. Just before drug administration, a urine sample was obtained for use as a blank to detect interfering substances other than cinoxacin. Urine was collected in sterile containers, refrigerated during each collection period, and then measured and filtered. Twentymilliliter aliquots were frozen at -26°C until assayed. Cinoxacin assay. All samples were assayed by using a semiautomated fluorometric assay developed by Eli Lilly and Co., Indianapolis, Ind. Each urine (0.1 ml) or serum (0.2 ml) sample was acidified with 1.0 ml of 0.1 N HCl. Solvent extraction was performed with 8.0 ml of chloroform, the sample was centrifuged, and the aqueous phase was discarded. Five milliliters of the chloroform layer was mixed with 5.0 ml of USP borate buffer at pH 9.0 and centrifuged. A 1.2-ml amount of the aqueous phase was sampled on the Autoanalyzer Sampler IV (Technicon Instruments Corporation, Tarrytown, N.Y.) and acidified with 0.27 ml of 5% H2SO4, after which fluorescence was measured on a filter fluorometer at an emission wavelength of 445 nm and an excitation wavelength of 356 nm. The concentration of cinoxacin in each sample was calculated from the standard calibration curve for serum at drug concentrations of 0, 2, 5, 10, and 20 Jug/ml and for urine at drug concentrations of 0, 25, 50, 100, and 250 jug/ml, using a least-squares analysis of the calibration standards. Detection limits of the method were 0.1 ,ug/ml for serum and 1 ug/ml for urine. Precision and accuracy data were obtained from the assay of replicate. samples containing 1.0 and 5.0 ,ug of cinoxacin per ml of plasma and 25 and 100 .ug of cinoxacin per ml of urine (Table 1). The assay measured only parent drug (J. F. Quay, R. F. Childers, D. W. Johnson, J. F. Nash, and J. F. Stucky II, J. Pharm. Sci., in press). A similar fluorometric assay method has been reported by Andersson et al. (1). Protein binding studies. (i) In vitro. Various concentrations of cinoxacin were made in normal human plasma, and a trace amount of "4C-labeled drug was added to each dilution. Ultracentrifugation at

ANTIMICROB. AGENTS CHEMOTHER.

TABLE 1. Precision and accuracy data for the fluorometric assay Mean ± Cinoxacin in:

No. of

replicates

standard deviation

Mean error

Wg/mi) Plasma

1,ug/ml

5.0 ftg/ml Urine 25 jug/ml 100 ,tg/ml

6 6

0.9 ± 0.05 5.1 ± 0.08

-0.1 +0.1

6 6

23 ± 0.51 101 ± 1.21

-2.0 +1.0

98,000 rpm for 4 h and at a temperature of 25 to 300C was performed on each sample, using a microultracentrifuge (Beckman Airfuge, Beckman Instruments, Palo Alto, Calif.). The pH was controlled at 7.4 during centrifugation. A portion of the protein-free supernatant was removed from the tube and subjected to liquid scintillation counting. The concentration (,f drug in plasma water was calculated from the counting data, with correction for any small amount of residual protein. Adsorption of drug to the tube surface was examined and not observed. An estimate of the protein binding of drug was made: (Cp-Cf x 100)/Cp, where C. represents total plasma concentration of drug in micrograms per milliliter and Cf represents the concentration of unbound drug found in the protein-free layer expressed in micrograms per milliliter. The total plasma protein concentration was 6.26 g/100 ml, and the albumin concentration was 3.87 g/100 ml. (ii) In vivo. Plasma samples from the subject receiving '4C-labeled cinoxacin obtained at the 0-, 2-, 3-, and 4-h sampling periods were studied for protein binding. Samples were ultracentrifuged, and plasma concentrations were calculated as described previously. The total plasma protein concentration was 7.32 g/100 ml, and the albumin concentration was 4.82 g/100 ml. Statistical analysis. Data were analyzed for significance using analysis of variance, appropriate for the experimental design. The mean of the peak serum concentration of drug for each individual and the mean of the time of peak for each individual were determined.

RESULTS Serum concentrations. Peak mean serum concentrations of 7.1, 15.5, and 20.9 ug/ml were observed 1 h after the administration of single oral doses of 0.25, 0.5, and 1 g (Table 2). Serum concentrations of 2 ,ug/ml or more were present at 4 h for all doses, and very low, but detectable, concentrations persisted through 12 h. Food delayed the absorption of cinoxacin and decreased the mean peak serum concentration by 30% (from 14.2 ,ug/ml fasted to 9.8 jig/ml fed) (Table 3). Peak mean serum concentrations of 3 to 10, 13 to 21, and 18 to 28 ,ug/ml were observed 0.5 to 2 h after multiple oral doses of 0.25 g every 6 h, 0.5 g every 6 h, and 1 g every 12 h for 10 days

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PHARMACOLOGY OF CINOXACIN IN HUMANS

167

TABLE 2. Serum concentrations of cinoxacin after single oral doses Concn (,Lg/ml; mean ± standard deviation)

study for non-drug-related reasons. Serum concentrations observed during the study are presented in Table 5. after dose of: Time interval Urine concentrations. Mean urinary conafter dose (h) centrations of 432 and 390 ,ug/ml were observed 1.0 g (8) 0.5 g (14) 0.25 g (9)a in the first 2 h after 0.25- and 0.5-g single doses. 0 0 0 0 After the 0.5-g dose, the mean urinary concen0.3 ± 0.6 1.9 ± 2.4 0.25 tration in the 10- to 12-h period was 12 ,ug/ml. 8.5 ± 7.2 19.0 ± 13.6 4.7 ± 4.2 0.50 Mean 24-h urine recoveries after these single 9.7 ± 8.6b 6.1 ± 3.7 0.75 doses ranged from 48 to 54% (Table 6). Ninety15.5 ± 1.1 20.9 ± 13.8 7.1 ± 2.6 1 two percent of the administered dose of 14C12.4 ± 1.5 17.7 ± 11.3 5.8 ± 1.6 2 labeled cinoxacin was recovered in the urine 4.2 ± 1.1 10.5 ± 5.8 2.3 ± 0.9 4 over a 24-h period. 14C-labeled drug was not 4.4± 2.2 1.4± 0.6 0.7± 0.7 6 0.5 ± 0.2 0.4 ± 0.1 8 detected in the feces or breath. 0.6 ± 0.3 10 The 24-h urine recovery did not appear to be 0.3± 0.2 0.2±0 0.1± 0.1 12 influenced by the presence or absence of food. Mean 24-h urine recoveries of 53% were observed 16.1 ± 1.5 26.2 ± 9.3 7.9 ± 3.0 Mean peak when volunteers were fasted as compared to 50% Number in parentheses is number of volunteers. when they were fed. b Average of three volunteers (no sample for fourth Higher urine recovery was noted in the mulvolunteer). tiple-dose studies, which was felt to reflect carryover from the previous dosing period (Table 7). Aerobic microorganisms isolated within the TABLE 3. Effect of food on serum concentrations of spectrum of susceptibility to cinoxacin included cinoxacin (500 mg) Escherichia coli, Klebsiella species, EnterobacConcn (yg/ml; mean ± standard deter species, and Proteus mirabilis. Resistance to viation)' Time interval (h) cinoxacin, nalidixic acid, and ampicillin did not With food Without food develop among the aerobic microorganisms isolated. 0 0 0 No subjective untoward effects were reported 4.3 ± 6.1 5.6 ± 5.2 0.5 11.0±4.7 4.6±6.1 by volunteer subjects after single and multiple 0.75 5.9 ± 5.3 11.1 ± 5.1 1 oral doses of cinoxacin. Clinical laboratory val6.6 ± 4.6 11.3 ± 4.4 1.5 ues measuring renal, hepatic, and hematological 12.1±4.1 6.5±4.3 2 parameters were not adversely affected. 6.7 ± 4.0 7.8 ± 2.7 3 The percent protein binding of cinoxacin in ± ± 5.0 2.2 5.9 3.0 4 vitro ranged from 63 to 65%. No significant dif4.0 ± 1.8 2.3± 1.5 6 ference in degree of binding was observed at 1.9 ± 1.5 1.3 ± 1.8 8 plasma drug concentrations that ranged from 2.3 0.7±1.4 1.2±1.1 10 to 11.6 ,ug/ml. The results of the in vivo study 0.4 ± 0.5 0.2 ± 0.5 12 showed 68 to 73% protein binding at plasma drug 13.9 ± 4.2 9.8 ± 5.3 Mean peak concentrations which ranged from 0.7 to 4 ,ug/ml, (,.g/Ml)b as measured by fluorometric assay. Free drug 2.9 2.1 Time of peak (h)C was calculated by counting total '4C-labeled drug 1.7 ± 0.5 1.3 ± 0.3 Serum half-life present, which would include any measurable (h)c metabolites and might produce a small differa Eleven volunteers (two-way crossover, 72-h inter- ence in the results when compared with the in val). vitro data. b a

c

p< 0.01. No significant difference.

(Table 4). Serum accumulation of cinoxacin was not observed. Nine volunteers were administered multiple oral doses of 0.5 g of cinoxacin every 12 h up to 28 days; one completed 4 days, one completed 18 days, three completed 25 days, and four completed 28 days. The five volunteers who did not complete the 28-day period discontinued the

DISCUSSION These data indicate that cinoxacin is rapidly and almost completely absorbed after oral administration. Peak serum concentrations were achieved within 2 h and detected up to 12 h after the dose. Studies in patients (14; P. 0. Madsen and T. B. Kjaer, Abstr. 9th Int. Congr. Chemother., 1975, Abstr. no. M-666) have indicated similar findings. Variability in individual peak serum concen-

168

ANTIMICROB. AGENTS CHEMOTHER.

BLACK ET AL.

TABLE 4. Serum concentrations of cinoxacin after multiple oral doses for 10 days Concn (pg/ml; mean ± standard deviation) Dose 19 (day Dose 7 10)

Time interval (h)

Dose

DoselI 0 0.9 ± 2.4 ± 2.7± 2.4± 1.8 ±

0 0.5 1 2 4 6 8 12

250 mg every 6 h (4)

Mean peak 0 0.5 1 2 4 6 8 10 12 24 Mean peak

500 mg every 6 h (6)

1 g every 12 h (4)

0 0.5 1 2 4 6 8 10 12

Dosel13

3.7±1.8 7.4 ± 2.2 8.5± 1.5 8.8± 3.3 4.2± 1.1 1.8 ± 0.4

1.1 2.8 3.0 1.0 0.9

6.0 3.0 0.9 0.5

10.0 ± 4.0 17.0 ± 8.0 21.0 ± 4.0 15.0 ± 3.0 5.0±2.0 3.0± 1.0

18.6 ± 6.7

22.2 ± 3.8

0 10.0 ± 13.0 ± 13.0 ± 4.0± 1.0±

12.0

2.0 ± 1.0

0

10.0 ± 10.0 18.0 ± 23.0 ± 22.0 28.0 ± 17.0 ± 6.0 25.0 ± 11.0 ± 5.0 10.0 ± 4.0± 3.0 4.0± 2.0± 1.0 1.0± 0.8 ± 0.8 0.6 ± 0.3 ± 0.3 0.4 ± 27.2 ± 17.4 33.9 ± Mean peak a Number in parentheses is number of volunteers.

10) 5.1±3.1 8.2 ± 5.8 9.8±5.3 9.9±4.5 3.8±0.8 1.5 ± 0.4

0.5±0.2 0.3 ± 0.2 11.1 ± 4.4

10.2 ± 1.9

4.2 ± 2.0

Dose 37 (day

7.0 ± 5.0 10.0 ± 5.0 17.0 ± 9.0 12.0 ± 4.0 6.0± 3.0 3.0± 2.0 1.0±0.9 0.7 ± 0.6 0.4 ± 0.4 0.1+0.2 14.5 ± 3.3 2.0 ± 3.0 11.0 ± 9.0 18.0 16.0 14.0 ± 9.0 13.0 ± 7.0 5.0±2.0

14.0 14.0 6.0 2.0 1.0 0.8 0.4 0.3 8.7

2.0±0.8 0.7 ±0.4 0.4 ±0.2 25.0 ± 0.3

TABLE 5. Serum concentrations of cinoxacin after 500 mg every 12 h for 28 days Concn (pg/ml; mean ± standard deviation)a

Time interval (h)

Dose lb,

0

0 1 2 4 6 10 12

6.3 ± 6.4 7.9 ± 5.0 4.2 ± 1.3 2.7 ± 2.2 0.6 ± 0.8 0.4 ± 0.5

Mean peak

9.8 ± 4.2 Total of nine volunteers. b Average of eight volunteers. ' Volunteer 9 did not receive dose. d Average of four volunteers.

0.5 10.2 6.7 1.0 1.3 0.9 0.5

Dose 13b 0.4 ± 0.4 7.5 ± 6.8 8.8 ± 5.3 5.6 ± 2.8 2.2 ± 1.3 0.6 ± 0.5 0.1 ± 0.1

Dose 27b 0.6 ± 0.5 6.5 ± 6.2 8.3 ± 6.5 4.0 ± 1.8 3.4 ± 2.8 0.7 ± 0.9 0.4 ± 0.6

Dose 55 (day 28)d 0.5 ± 0.3 13.1 ± 6.3 10.1 ± 2.7 3.8 ± 1.5 1.7 ± 0.9 0.3 ± 0.1 0.2 ± 0.06

12.0 ± 8.4

12.4 ± 4.0

10.4 ± 6.0

14.8 ± 4.2

Dose 5

0.6 ± 7.4 ± 8.4 ± 5.4 ± 3.8 ± 0.8 ± 0.4 ±

a

trations and the time at which peak concentrations were reached was noted. Other investigators reported this phenomenon in patients after 0.25-g (14) and 0.5-g doses (3, 4). Similar variations in peak serum concentrations and time to

reach peak concentrations have been observed with other orally administered agents (7, 8). Since the variability is greatest during the period of absorption and distribution of cinoxacin (as seen with other agents) and less pronounced

PHARMACOLOGY OF CINOXACIN IN HUMANS

VOL. 15, 1979

during the excretory phase, it is concluded that the variations are due to individual differences in absorption rates. Although food delayed the absorption of ci-

169

noxacin and lowered the mean peak serum concentration by 30%, the overall 24-h urine recovery was not affected. Therefore, the effect of food is probably not of great significance when

TABLE 6. Urinary excretion of cinoxacin after single oral doses + Urine recovery of adminisTimne mterval interval (h) (h) Mean urinay concn Urine recovery (mg DoseDose tered dose (% ± SD) SD) (yg/ml ± SD)a 24 ± 17 43 58± 0-2 432 ±429 (9)b 0.25g 16 ± 8 42 ± 19 303 ± 162 2-4 11 ± 4 28 ± 9 4-8 53 ± 48 2 ± 1 4± 2 8-12 10± 6 0.2 1 2± 1 12-24 3± 1 54 ±17 134 ± 43 0-24

T5me

0.5g (4)

0-2 2-4 4-6 6-8

8-10 10-12 12-24 0-24

(8)

lg

0-6 6-12

12-18 18-24

±12

390 ± 315 590± 266 239± 167 59± 47 41 ± 27 12 ± 8 4 2

83 ± 58 118± 54 21 44 6 14 6 4 3 1 4± 1 272 32

17 24 9 3 1 1 1 54

450 176 76 28 7 8 0

438± 155 3

44 ±15 2 4 0.3

0 479± 148

0 48 ±15

38± 14 3±

0-24

± 7 ± 4 1 1 ± 0.5 0 6

a SD, Standard deviation. '

Number in parentheses is number of volunteers.

TABLE 7. Urinary excretion of cinoxacin after multiple oral doses for 10 days Dose no.

Time inter-

250 mg every 6h

1 13 37 (day 10)

0-6 0-6 0-6 6-12 12-24 0-24

500 mg every 6h

1 13 37 (day 10)

0-6 0-6

Dose

val (h)

0-6 6-12 12-24 0-24

1 g every 12 h

1

7

19 (day 10)

a

SD, Standard deviation.

0-4 4-8 8-12 0-12 0-4 4-8 8-12 0-12 0-4 4-8 8-12 0-12

of adUrine recovery Urine recovery ministered dose (% (jug/ml SD) (m± (mgSD) SD)a

Mean urinary

concn

125 ± 29 449 ± 55 306± 121 36 ± 18 8± 2

89 160 187 26

35 10 37 15 7± 2 220 46

36 ± 14 64 ± 4 75 ± 15 10± 5 3± 1 88 ± 18

243 471 502

214 83 357± 94 347 85 36± 20 5 3 388 67

43 ± 17 72 ± 19 70 ± 17 7± 4 1± 0 78 ± 13

418 ± 262 275±210 74 ± 68

286 133± 35 454 386 98 24 507 358 152 18± 528

29 ± 10 13± 6 4± 2 46 ± 9 39± 7 10 ± 7 2± 1 51 ± 6 36 ± 9 15 ± 15 2± 1 53 ± 12

88 286 320 39± 22 5 2

655±182 239 ± 99 42± 13 388 ± 69 233 ± 203 46± 25

102 59 22 94 67 74 9 62 92 151 9 121

170

ANTIMICROB. AGENTS CHEMOTHER.

BLACK ET AL.

this drug is used in the clinical setting for the treatment of lower urinary tract infections. Approximately 50 to 55% of the ingested dose was excreted in the urine as unaltered drug within 2 h after single and multiple oral doses. Urine concentrations exceeded the miniimal inhibitory concentration for 95 to 100% of the common gram-negative urinary pathogens 12 h after the administered dose. After the first study day, higher urine recovery was observed in the multiple-dose studies, which probably reflected carry-over from the previous dosing period. A study by Madsen and Kjaer (Abstr. 9th Int. Congr. Chemother., 1975, Abstr. no. M-666) indicated carry-over phenomena when cinoxacin was administered to patients at 0.5 g every 12 h and 0.25 g every 6 h. Recovery of 50 to 60% of the administered dose of cinoxacin in the urine as unaltered drug in this study is consistent with reports by others who have studied cinoxacin excretion in patients undergoing treatment. Recovery of 92% of a radiolabeled dose in the urine reported here indicates that cinoxacin is almost completely absorbed and eliminated entirely by the kidneys. Urine metabolism studies (R. L. Wolen, B. D. Obermeyer, J. Welles, J. Wold, and H. R. Black, Abstr. 9th Int. Congr. Chemother., 1975, Abstr. no. M-662; R. L. Wolen, B. D. Obermeyer, E. A. Ziege, and H. R. Black, Clin. Pharm. Ther. 19: 119, 1976) have shown that in addition to the parent compound, cinoxacin is metabolized to at least four microbiologically inactive metabolites which represent approximately 30 to 40% of the ingested dose. Cinoxacin was found to be 63 to 73% bound by serum proteins. Wick et al. (16) examined binding of cinoxacin and nalidixic acid by serum proteins by comparing standard assay curves for cinoxacin and nalidixic acid diluted in physiological saline or in 100% pooled human serum. In these studies, cinoxacin was approximately 16% bound and nalidixic acid was reported to be 60 to 70% bound. Estimates of drug binding by serum proteins performed by different methods do not always agree, and calculated percentage of protein binding of antibiotics determined by microbiological techniques may differ significantly from values obtained with ultracentrifugation or dialysis methods (6). Whereas the former methods may have undoubted clinical and/or pharmacological significance, the present methods used are not subject to the variables encountered in microbiological methodology and may be a more accurate measure of the single phenomenon of affinity between drugs and serum proteins. The spectrum of gram-negative antibacterial activity, pharmacology, low order of toxicity of

cinoxacin, and lack of preliminary evidence to indicate development of resistance among fecal isolates suggest that this antimicrobial agent may be useful for prophylaxis and treatment of acute and chronic urinary tract infection. ACKNOWLEDGMENTS We thank Nancy Werner for technical assistance. LITERATURE CITED 1. Andersson, K.-E., S. Colleen, and P.-A. Mardh. 1977. Studies on cinoxacin. 2. Assay of cinoxacin in body fluids and tissues. J. Antimicrob. Chemother. 3: 417-422. 2. Bennett, A. H. 1976. The use of cinoxacin in urinary tract infections. Chemotherapy 5:417-418. 3. Burt, R. A. P., T. Morgan, J. P. Payne, and R. M. Bonner. 1977. Cinoxacin concentrations in plasma urine and prostatic tissue after oral administration to man. Br. J. Urol. 49:147-152. 4. Colleen, S., K.-E. Anderason, and P.-A. Mardh. 1977. Studies on cinoxacin. 3. Concentrations of cinoxacin in serum, urine and tissues of urological patients. J. Antimicrob. Chemother. 3:579-584. 5. Giamareliou, H., and G. G. Jackson. 1975. Antibacterial activity of cinoxacin in vitro. Antimicrob. Agents Chemother. 7:688-692. 6. Gordon, R. C., C. Regamey, and W. M. M. Kirby. 1972. Serum protein binding of the aminoglycoside antibiotics. Antimicrob. Agents Chemother. 2:214-216. 7. GriMth, R. S., and H. R. Black. 1971. Blood, urine and tissue concentrations of the cephalosporin antibiotics in normal subjects. Postgrad. Med. J. Suppl. 47:32-40. 8. Harrison, L H. and C. E. Cox. 1970. Bacteriologic and pharmacodynamic aspects of nalidixic acid. J. Urol. 104:908-913. 9. Jones, R. N., and P. C. Fuchs. 1976. In vitro antimicrobial activity of cinoxacin against 2,968 clinical bacterial isolates. Antimicrob. Agents Chemother. 10:146-149. 10. Kurtz, S., and M. Turck. 1975. In vitro activity of cinoxacin, an organic acid antibacterial. Antimicrob. Agents Chemother. 7:370-373. 11. Landes, R. R., and J. W. Hall. 1977. Cinoxacin: a new antimicrobial agent for urinary tract infections. Urology 10:310-311. 12. Lumish, R. M., and C. W. Norden. 1975. Cinoxacin: in vitro antibacterial studies of a new synthetic organic acid. Antimicrob. Agents Chemother. 7:159-163. 13. Mardh, P.-A., S. Colleen, and K.-E. Andersson. 1977. Studies on cinoxacin. 1. In vitro activity of cinoxacin, as compared to nalidixic acid, against urinary tract pathogens. J. Antimicrob. Chemother. 3: 411416. 14. Panwalker, A. P., H. Giamarellou, and G. G. Jackson. 1976. Efficacy of cinoxacin in urinary tract infections. Antimicrob. Agents Chemother. 9:502-505. 15. Santos, M., B. Llopis, J. M. Cisnal, J. Roman, and M. Gobernado. 1977. Cinoxacin in the treatment of chronic urinary tract infections, p. 696-697. In W. Siegenthaler and R. Luthy (ed.), Current chemotherapy. Proceedings of the 10th International Congress of Chemotherapy, vol. 1. American Society for Microbiology, Washington, D.C. 16. Wick, W. E., D. A. Preston, W. A. White, and R. S. Gordee. 1973. Compound 64716, a new synthetic antibacterial agent. Antimicrob. Agents Chemother. 4:

415-420. 17. Wilson, P. 1977. Comparative trial of cinoxacin and nalidixic acid in urinary tract infection, p. 699-700. In W. Siegenthaler and R. Luthy (ed.), Current chemotherapy. Proceedings of the 10th International Congress of Chemotherapy, vol. 1. American Society for Microbiology, Washington, D.C.

Pharmacology of cinoxacin in humans.

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