Treatment of Bone, Joint, and Soft-Tissue Infections with Oral Ciprofloxacin

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1987, p /87/ $02.00/0 Copyright C) 1987, American Society for Microbiology Vol. 31, No. 2 Treatment of Bone, Joint, and Soft-Tissue Infections with Oral Ciprofloxacin R. N. GREENBERG,'* D. J. KENNEDY,' P. M. REILLY,' K. L. LUPPEN,' W. J. WEINANDT,' M. R. BOLLINGER,' F. AGUIRRE,' F. KODESCH,2 AND A. M. K. SAEED' Departments of Medicine' and Ophthalmology,2 St. Louis University School of Medicine, St. Louis, Missouri Received 10 February 1986/Accepted 8 November 1986 We treated 52 patients with orally administered ciprofloxacin. In this study of 34 men and 18 women who completed therapy and who could be evaluated, there were 29 patients with nonhematogenous osteomyelitis, 20 patients with skin or soft-tissue infections, and 3 patients with joint infections. During the study, 92 isolates of pathogenic facultative aerobic bacteria, including 37 members of the family Enterobacteriaceae, 30 Staphylococcus aureus isolates, and 21 Pseudomonas aeruginosa isolates, were recovered, and 88 (96%) of the isolates were found to be susceptible to ciprofloxacin. Of the 29 patients with osteomyelitis, 14 have not experienced relapse after a follow-up of at least 1 year. Overall, 61% of infections were resolved, as judged by both clinical and microbiological criteria, during therapy. One patient developed Streptococcus salivanius sepsis during ciprofloxacin therapy, and one patient developed a rash which required discontinuation of ciprofioxacin. Otherwise, there were no serious reactions or complications. Ciprofloxacin is a quinoline carboxylic acid compound with significant in vitro activity against members of the family Enterobacteriaceae (MIC for 90% of the strains tested [MIC90], c.1,ug/ml), Pseudomonas aeruginosa (MIC90, '1 jig/ml), and Staphylococcus species (MIC90, <0.8,ug/ml) (1, 3, 4, 6, 15). Unlike nalidixic acid, ciprofloxacin is no more likely to select resistant mutants than are the aminoglycosides (15, 16, 18). The agent is well absorbed after oral administration, is bactericidal at concentrations two- to fourfold greater than its MIC, and has a relatively long half-life (4 to 7 h) in serum, which permits dosing every 12 h (5, 9, 10, 19). Ciprofloxacin is effective in the eradication of P. aeruginosa in animal models of osteomyelitis and pneumonia (12, 17). Studies with humans have not found any unusual incidence of adverse reactions (9, 10). On the basis of these reports, we administered an oral preparation of ciprofloxacin to 29 patients with nonbacteremic osteomyelitis, to 20 patients with infections of skin and soft tissue, and to 3 patients with joint infections. (This work was presented in a preliminary form at the 14th International Congress of Chemotherapy, June 1985, in Kyoto, Japan.) MATERIALS AND METHODS Patients. Patients seen at the St. Louis University Hospitals between March 1984 and July 1985 were considered for the study. Those who were under 13 years of age, were pregnant, had a history of allergy to carboxyquinoline derivatives, had severe infections which required parenteral antimicrobial therapy, or had renal impairment (creatinine, >1.6 mg/dl of serum) were excluded. Sixty-one patients infected by organisms suspected to be susceptible to ciprofloxacin were enrolled in the study, and all initial isolates were susceptible to ciprofloxacin by Kirby-Bauer disk susceptibility testing (zone size, >17 mm). Informed consent was obtained from each patient before ciprofloxacin was administered. Therapy was initiated in the hospital, and * Corresponding author. 151 many patients with osteomyelitis were permitted to receive outpatient treatment once their infection appeared to respond to ciprofloxacin. Clinical definitions, isolation, identification, and susceptibility testing of bacteria. Osteomyelitis was defined by the isolation of a pathogen, accompanied by inflammatory changes within bone detectable by gross inspection or histopathology of biopsied material or by bone destruction detectable by roentgenogram examination. Isolates from bones and joints were obtained either by open biopsy or from material aspirated through povidone-iodine-prepared uninfected skin. All specimens were plated on sheep's blood agar, chocolate agar, and MacConkey agar. Facultative aerobic bacteria were isolated and identified by standard laboratory techniques (11). Antibiotic susceptibilities for aerobic bacteria were determined by the Kirby-Bauer disk diffusion technique with cation-supplemented Mueller-Hinton agar (2, 11). Bacteria displaying >17-mm zones with the 5-pxg ciprofloxacin disk were labeled susceptible, those with 12- to 17-mm zones were labeled indeterminate, and those with <12-mm zones were labeled resistant. Microtiter MIC and MBC assays of ciprofloxacin were performed with most isolates in cation-supplemented Mueller-Hinton broth. For these assays, microtiter trays (GIBCO Laboratories, Lawrence, Mass.) were used. Ciprofloxacin concentrations ranged from to 4,ug/ml. The MBC was determined at 24 h by methods previously described (13). Anaerobic cultures were done when anaerobic infection was suspected; in this study, no anaerobes were isolated. Serum was obtained 1 to 3 h after drug administration and was measured- for bactericidal activity by inoculation of microtiter dilutions of serum (diluted with cation-supplemented Mueller-Hinton broth) with 105 CFU/ml. Bactericidal activity in serum was defined as a 99.9% reduction in viable organisms (11). Levels of ciprofloxacin in serum. Levels of ciprofloxacin in the sera of 21 patients were determined by reverse-phase high-pressure liquid chromatography by a modification of the method reported by Gau et al. (8). Serum samples (10,ul) were injected onto an RP-300 C-8 column (Brownlee Labo-

2 152 GREENBERG ET AL. ratories, Santa Clara, Calif.) maintained at 50 C in a column heater. Samples were eluted isocratically with a mobile phase consisting of 5% acetonitrile in M H3PO4 adjusted to ph 3 with tetrabutyl ammonium hydroxide at a flow rate of 2 m/min in a Waters liquid chromatograph system (Waters Associates, Inc., Milford, Mass.). Peaks were detected by a fluorescence detector (Waters model 420-AC) at an excitation of 280 nm and an emission of 450 nm. Various concentrations of a ciprofloxacin standard were made, and a reliable standard curve was established. Under the conditions of our analysis, ciprofloxacin levels as low as 5 ng/ml of serum were detectable. Therapeutic regimen and evaluation of response. Patients were treated orally with either 500 mg (20 patients) or 750 mg (41 patients) of ciprofloxacin every 12 h. In general, the dose was increased to 750 mg when the manufacturer determined the higher dose to be safe for humans. Patients were not permitted to receive other antibiotics with activity against ciprofloxacin-susceptible organisms (as demnonstrated by Kirby-Bauer disk testing). Concomitant therapy with penicillin G (to treat the patient who developed streptococcal sepsis on ciprofloxacin therapy), vancomycin (to treat a ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus which was isolated from a mixed infection in a patient receiving ciprofloxacin therapy), or metronidazole (when anaerobes were clinically suspected because of a foul odor, despite a negative culture) was used with seven patients. Adjunctive surgical drainage and debridement were performed when appropriate in the judgment of the attending physician. The duration of ciprofloxacin administration in assessable patients ranged from 5 to 181 days. Most patients were monitored for 3 months after therapy, and the patients with osteomyelitis were monitored for as long as possible. Monitoring for adverse drug effects included periodic physical examinations and blood tests for evidence of hematologic, hepatic, renal, or electrolytic abnormalities and a detailed ophthalmologic examination (color perception, visual acuity, and direct examination of the fundi) by an ophthalmologist (F.K.). These studies were performed at the time of enrollment, during treatment, and within 2 weeks after completion of therapy. The results of therapy were judged by both clinical and microbiological criteria. Cure was defined as the disappearance of all signs and symptoms related to the infection, improvement was defined as substantial improvement of the signs and symptoms without complete clinical resolution, and failure was defined as the absence of any substantial improvement in signs and symptoms. Microbiological resolution was defined as the eradication of the infecting organism(s). Rtelapse was defined as the reappearance of the infecting organism(s) (as identified by species and susceptibilities to antimicrobial agents) at the infected site any time after the end of therapy. Reinfection was defined as eradication of the infecting organism(s) followed by the appearance of a different organism(s) at the infected site within 1 month after the end of therapy. Superinfection was defined as the appearance of a different organism(s) at the infected site during therapy, with the new organism(s) judged to be the cause of an infectious process. Microbiological failure was defined as continued isolation of the infecting organism(s) at the site of infection. RESULTS Of the 61 patients initially enrolled, 52 could be evaluated for clinical and bacterial response and 9 could not be ANTIMICROB. AGENTS CHEMOTHER. evaluated: 6 patients had negative cultures, a 51-year-old male developed a maculopapular rash on day 6 which required discontinuation of ciprofloxacin, 1 patient was given alternative therapy once culture data were available, and 1 patient with a soft-tissue infection did not return for follow-up. The patient given alternative therapy had "Streptococcus viridans" soft-tissue infection, and the referring physician switched the patient to penicillin therapy on day 3 of the study. Overall, we could evaluate the effectiveness of ciprofloxacin therapy for 52 patients (34 men and 18 women), with a mean age of 41 years. Osteomyelitis. There were 29 patients with osteomyelitis who completed therapy. The ages of the patients ranged from 15 to 85 years, with a mean age of 39 years. There were 24 males and 5 females. The duration of treatment ranged from 17 to 181 days, with a median duration of 51 days. The 29 patients with osteomyelitis could be divided into those without a metal appliance at the infection site (26 patients, numbers 1 through 26) and those with metal appliances at the infection site (3 patients, numbers 27 through 29) (Table 1). In the group of 26 patients without a metal appliance, 24 initially responded to ciprofloxacin therapy. The two patients with whom there was a primary failure of treatment (numbers 19 and 20) were infected with a ciprofloxacin-susceptible, methicillin-resistant S. aureus strain which became resistant to ciprofloxacin (as determined by Kirby-Bauer susceptibility testing) during therapy. Four patients have had relapse of infection more than 1 year after the end of treatment. Three of these patients (numbers 21 through 23) had chronic osteomyelitis of 1 to 4 years duration prior to surgical debridement and treatment with ciprofloxacin. The other patient (number 24) was an 85-year-old male with retinopathy, diabetes mellitus, and peripheral vascular disease who developed osteomyelitis of the calcaneus secondary to a pressure sore. Two patients (numbers 25 and 26) with infections caused by Enterobacteriaceae initially responded both clinically and microbiologically but experienced a relapse of infection within 3 months after discontinuation of therapy. One of these patients was a paraplegic with multiple decubitus ulcers, and the other was a diabetic. It is possible that both patients still had an infected nidus of dead bone which was not adequately debrided at the time of enrollment. All three patients with metal appliances (numbers 27 through 29) showed significant clinical improvement while on ciprofloxacin, but their infections relapsed both clinically and microbiologically soon after the drug was discontinued. The remaining 18 patients were seen in follow-up more than 1 year after the completion of therapy, and 14 had not experienced a relapse (Table 1). All initial isolates from patients with osteomyelitis were susceptible to ciprofloxacin. Of the 13 patients with P. aeruginosa infections, 9 still had not had relapse after 1 year of follow-up. Of the 12 S. aureus isolates, 6 were methicillinresistant. Four of the six patients with infection caused by methicillin-resistant S. aureus experienced failures of treatment or relapse, and only one of these patients had a metal appliance. Of 17 infections due to Enterobacteriaceae (23 isolates) or S. epidermidis, 14 were without relapse. Overall, for 22 patients without metal appliances who were monitored for more than 1 year after treatment, the infections were cured in 14, treatment failed in 2, and there was relapse of infection in 6. Bactericidal levels in serum were obtained in 20 patients with bone infections. In six patients, levels were greater than 1:32 against Enterobacteriaceae. The best activity against

3 VOL. 31, 1987 TREATMENT OF INFECTIONS WITH ORAL CIPROFLOXACIN 153 TABLE 1. Results of treatment of osteomyelitis Case no. duration Treatment (days) Infecting Inetn organism(s)(bacteacidal raims bceiia dilution iuini in serum) eu)otoe Outcome' duration Follow-up (mo) Additional therapyb 1 45 Enterobacter cloacae C 8c OX/P 2 50 Pseudomonas aeruguinosa, methicillin-resistant Staphylococcus aureus C Pseudomonas aeruginosa C Enterobacter cloacae (32) C Pseudomonas aeruginosa (2), Proteus mirabilis (64) C Proteus mirabilis, methicillin-susceptible Staphylococcus aureus C Enterobacter cloacae, Pseudomonas aeruginosa C Providencia spp. (16), Pseudomonas aeruginosa (2) C Serratia marcescens, Klebsiella spp. C Pseudomonas aeruginosa (none) C Enterobacter cloacae (16), methicillin-susceptible Staphylococcus aureus C 15 V (8), Klebsiella spp. (64), Escherichia coli (32) Klebsiella spp., Citrobacter spp., methicillin-resistant Staphylococcus aur- C 15 eus Pseudomonas aeruginosa (4) C Klebsiella spp. (16), Pseudomonas aeruginosa (none), Enterobacter clo- C 12 acae (8) Methicillin-susceptible Staphylococcus aureus (8) L Methicillin-susceptible Staphylococcus aureus L Staphylococcus epidermidis (2) L Providencia spp. (128), methicillin-susceptible Staphylococcus aureus (16) L Methicillin-resistant Staphylococcus aureus (none) F Methicillin-resistant Staphylococcus aureus (none) F Methicillin-resistant Staphylococcus aureus (undiluted) R Pseudomonas aeruginosa (4), Serratia marcescens (4) R 13 P, MT Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus R Escherichia coli (64), Pseudomonas aeruginosa (2) R 16 MT Proteus mirabilis, Escherichia coli R Proteus mirabilis (128), Escherichia coli (128) R 5 27d 63 Methicillin-resistant Staphylococcus aureus, Serratia marcescens (2) R 1 28d 67 Pseudomonas aeruginosa (2) R 1 29d 67 Pseudomonas aeruginosa (none) R 1 a C, Cure; L, lost to follow-up; R, relapse; F, failure. b OX, Oxacillin; P, penicillin; MT, metronidazole; V, vancomycin. c Died 8 months after end of treatment; death not due to infection. d Metal appliance present. Staphylococcus spp. was 1:16, and against P. aeruginosa, it was 1:4. No bactericidal activity in serum was observed in the two osteomyelitis patients infected by methicillinresistant S. aureus for whom ciprofloxacin treatment failed (Table 1). Skin and soft-tissue infections. Twenty patients had skin and soft-tissue infections. Associated with these 20 infections were 38 pathogens including 9 isolates of Enterobacteriaceae (Proteus mirabillis [5 isolates ], Enterobacter cloacae [1 isolate], Citrobacter diversus [1 isolate], Serratia marcescens [1 isolate], and Klebsiella pneumoniae [1 isolate]), 5 isolates of P. aeruginosa, 5 isolates of methicillinsusceptible S. aureus, 7 isolates of methicillin-resistant S. aureus and 3 Streptococcus isolates (groups C [2 isolates] and A [1 isolate]). Overall, 18 of the 20 patients were cured. Treatment failed in a patient with a group C Streptococcus infection and in a patient with a P. aeruginosa infection who developed a methicillin-resistant S. aureus superinfection. Joint infection. Three patients with joint infections were treated. One patient with a hip infected with Escherichia coli was cured after 28 days of therapy and remained free of signs of infection 16 months later. A second patient with a prosthetic hip infected with methicillin-susceptible S. aureus, Proteus mirabilis, Enterobacter aerogenes, and E. coli responded to therapy, but the infection relapsed about 2 weeks after treatment. The prosthetic hip was not removed during therapy. The third patient had a knee joint infected with P. aeruginosa, methicillin-resistant S. aureus, and Proteus mirabilis. Despite drainage procedures, her infection failed to respond; subsequent cultures done during therapy grew a ciprofloxacin-resistant P. aeruginosa and a ciprofloxacin-resistant, methicillin-resistant S. aureus. Adverse reactions. One patient with osteomyelitis developed a Streptococcus salivarius bacteremia (with fever and leukocytosis) during treatment. His Streptococcus infection was due to severe dental problems and was resolved by the addition of parenteral penicillin and dental extractions. Ciprofloxacin was discontinued on day 6 for another patient with osteomyelitis because of the appearance of a pruritic maculopapular truncal rash. This patient was not included in the evaluation of treatment results. Other adverse reactions did not require any change in treatment. Among the 52 patients evaluated, 4 patients complained of a bad taste after swallowing the pill, 3 patients demonstrated calcium oxalate crystalluria, 3 patients had moderate (less than fourfold) increases in liver enzymes, 1 patient had a rise in cholesterol levels in serum, and one patient experienced slight nausea. No ophthalmologic abnormalities were noted. Ciprofloxacin levels in serum. Patients receiving 500 mg of ciprofloxacin every 12 h had a mean concentration of the drug in serum of 0.626,ug/ml, with a range of to 1.320,ug/ml (n = 9). Patients receiving 750 mg of ciprofloxacin every 12 h had a mean concentration of the drug in serum of 0.552,ug/ml, with a range of to pug/ml (n = 24). Although the levels of ciprofloxacin in serum were measured

4 154 GREENBERG ET AL. at random times during the course of therapy to document patient compliance, in most patients the drug level peaked 2 h after patients were dosed. Levels in serum were within the expected range in 31 of 33 monitored patients (9). Bacterial susceptibilities. During the study period, 88 aerobic pathogens initially isolated from clinical infections (27 S. aureus isolates, 20 P. aeruginosa isolates, 37 isolates of the Enterobacteriaceae, and 4 streptococcal isolates) were tested in vitro for susceptibility to ciprofloxacin and other antimicrobial agents. Only one bacterial isolate of a particular species was studied from each patient. All 88 of these initial isolates were susceptible to ciprofloxacin. Both MICs and MBCs were '1.0 jig/ml for all isolates of the Enterobacteriaceae tested (35 strains); the MBC for 90% of the strains tested (MBC90) was 0.125,ug/ml. For 18 of 20 P. aeruginosa isolates, the MBC%0 was <1.0,ug/ml. For eleven of 15 methicillin-resistant S. aureus strains, MBCgos were '1.0,ug/ml, and for 10 of 11 methicillin-susceptible S. aureus strains MBC90s were '1.0,ug/ml. In all instances, the MBC was no more than 2 dilutions greater than the MIC. During ciprofloxacin therapy, there were two cases of osteomyelitis in patients without metal appliances (one case caused by methicillin-susceptible S. aureus and one caused by methicillin-resistant S. aureus) and one case of septic arthritis (methicillin-resistant S. aureus and P. aeruginosa) during which ciprofloxacin resistance developed. The development of resistance was associated with clinical failure in these three cases. In addition, there were four S. aureus and four P. aeruginosa isolates recovered during treatment that indicated colonization and were resistant to ciprofloxacin. Interestingly, resistance to other antibiotics appeared in the isolates that developed ciprofloxacin resistance; one P. aeruginosa isolate was resistant to ticarcillin and two S. aureus isolates were resistant to aminoglycosides. ANTIMICROB. AGENTS CHEMOTHER. DISCUSSION Of the 22 patients with nonhematogenous osteomyelitis and no metal appliance, 14 were cured as shown by data collected for a period of 1 year following treatment. These patients had infections caused by S. aureus, P. aeruginosa, and Enterobacteriaceae. Therapy was also effective in 90% of skin and soft-tissue infections. Our results are similar to those reported by Eron et al., who found that three of four patients with osteomyelitis were cured and 80% of skin and soft-tissue infections responded satisfactorily to orally administered ciprofloxacin (7). Similarly, Ramirez et-al. reported clinical resolution of a variety of clinical infections in 88 (90%) of 98 patients, including 11 of 15 patients with P. aeruginosa infections (14). Our study results, therefore, support the earlier reports that ciprofloxacin appears to be an effective oral agent for the treatment of osteomyelitis and joint infections when these infections are due to susceptible organisms. However, it is apparent from our data that certain qualifications to the above statement are needed. First, ciprofloxacin did not eradicate osteomyelitis or skin and soft-tissue infection whenever there was an underlying metal appliance. Nevertheless, during ciprofloxacin therapy there was a reduction or elimination of drainage. Second, we observed two treatment failures in patients without a metal appliance who were infected by methicillin-resistant S. aureus; both infections responded to vancomycin therapy and further debridement. Third, bactericidal levels of drug in serum were clearly much higher against Enterobacteriacae than against P. aeruginosa and S. aureus. Fourth, ciprofloxacin-resistant isolates of S. aureus and P. aeruginosa developed in three patients, two of whom had osteomyelitis (one of these patients had a metal appliance) and one of whom had skin and soft-tissue infection. MICs of ciprofloxacin increased during ciprofloxacin therapy for seven S. aureus and five P. aeruginosa isolates. Last, orally administered ciprofloxacin at 750 mg every 12 h was not uniformly effective against Streptococcus species. In fact, one serious case of S. salivarius sepsis occurred during ciprofloxacin therapy. In our study, only one major adverse reaction was observed. One patient developed a pruritic maculopapular truncal rash after 6 days of therapy. The rash resolved after ciprofloxacin was discontinued. We did note a few instances of calcium oxalate crystalluria and moderate elevations in levels of liver enzymes. Neither of these abnormalities was considered serious, and each resolved after the end of treatment. No ophthalmologic, central nervous system, bone, or joint abnormalities were observed. Such problems have been reported with other quinoline agents including nalidixic acid, rosoxacin, norfloxacin, and enoxacin (10). This study demonstrates that oral ciprofloxacin treatment in adequately debrided cases of osteomyelitis due to ciprofloxacin-susceptible bacteria can be effective. If these results compare favorably with standard treatment regimens in current studies and if ciprofloxacin continues to be without demonstrable major toxicity, it is apparent that this agent, along with other quinolines, may dramatically reduce the duration of hospitalization and intravenous therapy now necessary in the treatment of osteomyelitis. Our findings support the need for randomized trials comparing oral ciprofloxacin with currently accepted agents in the treatment of nonbacteremic infections due to susceptible aerobic gramnegative organisms and S. aureus. ACKNOWLEDGMENTS We gratefully acknowledge the enthusiastic support of Clayton Perry and Mark K. Vossen (Department of Orthopedics, St. Louis University) and the secretarial assistance of Sue Stevens. This work was supported by a grant from Miles Pharmaceuticals, West Haven, Conn. LITERATURE CITED 1. Barry, A. L., R. N. Jones, C. Thornsberry, L. W. Ayers, E. H. Gerlach, and H. M. Sommers Antibacterial activities of ciprofloxacin, norfloxacin, oxolinic acid, cioxacin, and nalidixic acid. Antimicrob. Agents Chemother. 25: Bauer, A. W., W. M. M. Kirby, J. C. Sherris, and M. Turck Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol. 45: Bavernfeind, A., and C. 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