PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50(~5.5 × 105) spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax(1 hour post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.6
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
Clinical response rates observed in this study were as follows:
| Outcomes |
Ciprofloxacin/Piperacillin
N = 233 Success (%) |
Tobramycin/Piperacillin
N = 237 Success (%) |
Clinical Resolution of
Initial Febrile Episode
with No Modifications of
Empirical Regimen * |
63 (27.0%) |
52 (21.9%) |
Clinical Resolution of
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
|
187 (80.3%) |
185 (78.1%) |
|
Overall Survival
|
224 (96.1%) |
223 (94.1%) |
|
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2) microbiological eradication of infection (if an infection was microbiologically documented); (3) resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
|
|
COMPLICATED URINARY TRACT INFECTION AND PYELONEPHRITIS - EFFICACY IN PEDIATRIC PATIENTS:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
|
|
CIPRO |
Comparator |
|
Randomized Patients
|
337
|
352
|
|
Per Protocol Patients
|
211
|
231
|
|
Clinical Response at 5 to 9 Days Post-Treatment
|
95.7% (202/211) |
92.6% (214/231) |
|
95% CI [-1.3%, 7.3%] |
|
Bacteriologic Eradication by Patient at 5 to 9 Days Post-Treatment * |
84.4% (178/211) |
78.3% (181/231) |
|
95% CI [-1.3%, 13.1%] |
|
Bacteriologic Eradication of the Baseline Pathogen at 5 to 9 Days Post-Treatment
|
|
| Escherichia coli |
156/178 (88%) |
161/179 (90%) |
|
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections. |
|
REFERENCES
-
National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically
- Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
-
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests
- Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
-
Report presented at the FDA's Anti-Infective Drug and Dermatological Drug Products Advisory Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
-
21 CFR 314.510 (Subpart H - Accelerated Approval of New Drugs for Life-Threatening Illnesses).
-
Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
-
Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167: 1239-42.
-
Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195.
-
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6): 1336-1339.
-
Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
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