Ciprofloxacin Administered Intravenously - Antimicrobial Agents and

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Single 200-, 300-,and 400-mg intravenous doses of ciprofloxacin were given over 30 mmn ...... Bactericidal activity of ciprofloxacin, norfloxacin and ofloxacin in ...
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1994, p. 837-841

Vol. 38, No. 4

0066-4804/94/$04.00+0

Copyright C 1994, American Society for Microbiology

Comparative Serum Bactericidal Activities of Three Doses of Ciprofloxacin Administered Intravenously M. DAN,1* F. POCH,1 C. QUASSEM,' AND R. KITZES2 Infectious Disease Unit, The E. Wolfson Hospital, Holon 58100,1 and Clinical Pharmacology Unit, Carmel Hospital, Haifa,2 Israel Received 2 June 1993/Returned for modification 5 September 1993/Accepted 20 December 1993

The pharmacokinetics and serum bactericidal activities of three intravenous doses of ciprofloxacin were studied comparatively in 30 patients. Single 200-, 300-, and 400-mg intravenous doses of ciprofloxacin were given over 30 mmn to 10 patients each, and serum samples were obtained at 0.5, 1, 2, 3, 4, 8, and 12 h after the start of the infusion. Serum drug concentrations were determined by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by using noncompartmental analysis methods. Serum bactericidal activity against clinical isolates of Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, and Staphylococcus aureus was determined for samples obtained at 0.5, 4, 8, and 12 h. Excellent activity was demonstrated up to 12 h by all doses against E. coli and E. cloacae. Much poorer titers were observed for the remaining organisms, although the 400-mg dose prompted improved results against P. aeruginosa with a mean bactericidal titer of 1:2.9 at 8 h. In conclusion, while the 200-mg dose appears to be largely adequate for infections caused by members of the family Enterobacteriaceae, it seems that when P. aeruginosa is involved, 400 mg twice a day or even three times a day is more appropriate. Intravenous ciprofloxacin performs poorly against A. calcoaceticus and S. aureus, even at a higher dose.

Although ciprofloxacin was released for intravenous use in 1987 in Europe and in 1991 in the United States, controversy still exists regarding the recommended dosage. While in Europe a standard 200-mg twice-a-day (b.i.d.) regimen is advocated, in the United States a dosage of 400 mg b.i.d. is recommended for most infections (other than mild and moderate urinary tract infection) (21). In an effort to clarify this issue, we have elected to compare the activities of different intravenous doses against common bacterial pathogens by the serum bactericidal testing method. The serum bactericidal activity (SBA) test is an ex-vivo method that may provide a meaningful measure of the potential usefulness of antimicrobial agents (5, 15, 28, 32, 34, 35). The test takes into consideration the achievable concentrations of the drug in serum as well as its inherent antibacterial activity in the natural environment. The test is now well standardized, and guidelines for the method have been recently published (22, 24). Although the significance of the SBA as a single criterion for determining the outcome of antibiotic therapy is controversial (2, 7), it has been shown that there is correlation between clinical efficacy and SBA (28, 31, 34). Klastersky et al. have demonstrated that an SBA value of at least 1:8 1 h after drug administration correlates with a favorable clinical outcome (16), and titers of at least 1:16 are necessary in patients with granulocytopenia

laboratory tests consisting of serum chemistries and complete blood cell and platelet counts were performed before and after the study. All relevant laboratory results were normal, and physical examination showed no change during or following completion of the study. There was no significant difference among the patient groups in mean age, weight, and underlying condition. Administration of the antimicrobial agent. Single doses of ciprofloxacin, 200, 300, or 400 mg, were administered to 10 patients each. The drug was infused over 30 min into a peripheral vein in the arm. Standard analytical powder was provided by the manufacturer of the drug (Bayer, Leverkusen, Germany) and was used for determination of MICs and MBCs as well as for concentration analysis controls. Sampling. Blood samples were obtained from a cannula inserted in the contralateral arm at 0, 0.5, 1, 2, 3, 4, 8, and 12 h after the start of the infusion. A diluted heparin solution was used to maintain patency of the needle, and 1 ml of blood was removed and discarded before blood for testing was drawn. Blood samples were collected into tubes with no anticoagulant and were allowed to clot at room temperature for 30 min, after which they were centrifuged to obtain serum. Serum samples were placed in polypropylene tubes and promptly frozen at - 80°C until analysis. Microorganisms and microbiologic assays. Five clinical isolates each of the following microorganisms were selected for analysis: Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, and Staphylococcus aureus. All strains were isolated from bacteremic patients at the E. Wolfson Hospital, Holon, Israel. The MIC and the MBC of ciprofloxacin against each microorganism were determined by the microdilution method established by the National Committee for Clinical Laboratory Standards (23). These data are displayed in Table 1. SBA was determined by the standardized microdilution method according to the guidelines proposed by the National Committee for Clinical Laboratory Standards (22, 24). As recommended, the diluent for testing was 50% pooled human

(28). MATERIALS AND METHODS Patients. Thirty patients admitted for minor surgery provided written informed consent for participation in the study, which had been approved by the E. Wolfson Hospital Ethics Committee. There were 15 men and 15 women. The mean age of the patients was 50.6 years (range, 23 to 65 years), and the mean weight was 66 kg (range, 50 to 90 kg). None had received antimicrobial agents in the 2 weeks preceding entry into the study. A medical history, physical examination, and a panel of *

Corresponding author. 837

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ANTIMICROB. AGENTS CHEMOTHER.

DAN ET AL.

TABLE 1. Susceptibilities of test organisms to ciprofloxacin MBC (mg/liter) MIC (mg/liter) Meanb Meanb Range Range 0.015 0.013 0.007-0.015 0.015 Escherichia coli 0.038 0.019-0.078 0.050 0.019-0.078 Enterobacter cloacae 0.109 0.078-0.156 0.202 0.078-0.31 Pseudomonas aeruginosa Acinetobacter calcoaceticus 0.575 0.078-0.62 0.575 0.078-1.25 0.443 0.078-0.62 0.575 0.078-1.25 Staphylococcus aureus

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and 50% cation-supplemented Mueller-Hinton broth, which showed no bactericidal activity against the test organisms. Serum inhibitory and bactericidal activities were determined at 0.5, 4, 8, and 12 h after the beginning of drug administration. All samples were serially diluted in a doubling process from 1:2 to 1:512. After 18 h of incubation at 37°C, 10 [lI from each well was transferred onto cation-supplemented Mueller-Hinton agar and incubated for 18 h at 37°C. The rejection value for a 99.9% kill was 11 colonies (24). Concentration determination. Serum ciprofloxacin concentrations were determined by a high-performance liquid chromatography procedure described previously (13). The linearity of the assay was 0.997 over a range of 0.05 to 10.0 ,ug/ml. The limit of sensitivity of the method in serum was 0.05 ,ug/ml; the coefficients of variation determined for the concentration of 0.05 ,ug/ml were 5.7% for intraday variations and 4.9% for interday variations. Pharmacokinetic analysis. Pharmacokinetic values were determined by noncompartmental methods of analysis by using MK-MODEL software (version 4; Elsevier-Biosoft, Cambridge, Mass.). The pharmacokinetic parameters maximum concentration of drug in serum (Cm,x) and time to Cmn, were determined directly from the serum concentration-time curve. The area under the concentration-time curve from 0 h to infinity (AUCO,) was calculated by using the linear trapezoid rule. Pharmacodynamic analysis. Calculations of SBA were done by converting each reciprocal bactericidal titer to its log2 + 1 value to allow use of parametric statistical tests. The arithmetic mean serum bactericidal titer (SBT) was then calculated. Following the calculations, the results were reconverted (antilog) to the corresponding reciprocal SBT. The duration of SBA was defined as the time in hours during which SBA greater than 1:2 could be detected at a given time point. Statistical analysis. All statistical tests were done by using BMDP statistical software (version 1988; BMDP Statistical Software, Inc., Los Angeles, Calif.). Analysis of variance with repeated measures was used to test the effect of time on SBTs for the same dose. Comparisons between dosages were tested by one-way analysis of variance with Bonferroni pairwise serum

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12 h were 0.17, 0.24, and 0.5 ,ug/ml for the 200-, 300-, and 400-mg doses, respectively. SBA. Mean SBTs over time for the various dosing regimens against the bacterial species tested are shown in Table 3. Excellent bactericidal activity was demonstrated up to 12 h by all doses (200, 300, and 400 mg) against E. coli and E. cloacae. Mean peak bactericidal activities were -1:469 against E. coli and .1:354 for E. cloacae. Much poorer titers were observed for the remaining organisms (P. aeruginosa, A. calcoaceticus, and S. aureus): although the mean peak bactericidal activities improved with increasing doses, the 200- and 300-mg doses already produced unsatisfactory activity (