From the Departments of Surgery (Drs Heggers, Wolf, Desai, and Herndon), Pharmacy (Ms Villarreal), Pediatrics (Drs Klein and John), and Radiology (Dr John), University of Texas Medical Branch, and Shriners Hospital for Children, Burns Hospital (Drs Heggers, Wolf, Klein, Desai, and Herndon, and Mss Villarreal and Edgar), Galveston.
Food and Drug Administration regulations state that ciprofloxacin hydrochloride may cause arthropathies. For this reason, such therapy is contraindicated in the pediatric population. However, several studies in children with cystic fibrosis have found the drug to be efficacious. Our hypothesis was that ciprofloxacin treatment is justified in the case of multiresistant organisms in burn populations.
During a 4-year period (January 1, 1993, to December 31, 1997) we treated 56 of our pediatric burn patients with ciprofloxacin when cultures proved resistant to other antibiotics. The burn area was 65% of the total body surface area. The average patient age was 8.4 years. Of the 56 patients who received ciprofloxacin, 50 received the recommended dose. Biopsy specimens were assessed for quantitative bacteriology and antibiotic sensitivity. Radiologic review was conducted to examine for arthropathy.
All patients showed unequivocal reduction in quantitative bacterial counts, and susceptibility to ciprofloxacin remained stable without the development of resistance. Of the 56 patients treated, 42 had a major reduction in their quantitative wound biopsies from 106 to less than 100 colonies per gram of tissue, while the remaining 14 were observed to have a 2- to 3-log decrease. No arthropathy was detected in any of the 56 patients receiving ciprofloxacin. Review of the patients' charts showed no documented adverse events associated with the use of ciprofloxacin. All patients survived their thermal injury and the complications associated with it without any untoward problems or complications of arthropathy.
On the basis of these data, ciprofloxacin therapy in the treatment of immunosuppressed pediatric burn patients is efficacious and does not cause arthropathy.
THE MOST important class of antimicrobial agents discovered in recent years is the quinolones. The era of these antimicrobials spans a quarter of a century. After the discovery of norfloxacin in 1980, accelerated international development followed, and, to date, more than 10,000 analogs have been described.1 Ciprofloxacin hydrochloride is one of the best analogs in clinical use today.1
Ciprofloxacin is efficacious in the treatment of recurrent uncomplicated cystitis, complicated cystitis, and pyelonephritis.2,3 Its efficacy and safety have been noted in the treatment of serious respiratory infections and biliary sepsis.1,4,5 Goldfarb et al6 showed that ciprofloxacin monotherapy was effective for acute exacerbations caused by cystic fibrosis. Bacteriological eradication rates for prolonged periods (90 days) were 57% for Staphylococcus aureus and 83% for Pseudomonas aeruginosa in patients with diabetes mellitus and/or peripheral vascular disease.1,7
Ciprofloxacin's in vitro antimicrobial spectrum covers both gram-positive and gram-negative organisms and includes Streptococcus pneumoniae; S aureus; Haemophilus influenzae; P aeruginosa; the enterics, Mycoplasma, Legionella, and Chlamydia;; and Mycobacterium tuberculosis.1,3,8
Because arthropathic toxic effects of quinolones were demonstrated in growing animals, these antibiotics were not originally recommended for pediatric patients.9 However, to date, obvious quinolone-induced skeletal damage has never been documented in the pediatric population. A recent study compiled clinical, radiological, and magnetic resonance imaging data in patients with cystic fibrosis who received a 3-month course of ciprofloxacin. The results, together with the data on quinolone therapy in pediatrics, sug-gest that ciprofloxacin does not cause arthropathy in children.8,10
Since further studies on the toxic effects of ciprofloxacin are necessary in patients with diseases other than cystic fibrosis, we examined the efficacy and safety of such therapy in our severely burned pediatric population.
We retrospectively reviewed data from all patients who were admitted to our burn hospital and whose cultures yielded multiresistant organisms sensitive to ciprofloxacin. The recommended dosage of ciprofloxacin, 20 to 30 mg/kg per day, was administered for 7 to 10 days. The patients were examined for arthropathy by radiological review after therapy.
Biopsy specimens were assessed 3 times weekly for quantitative presence of bacteria and antibiotic susceptibility. Respiratory cultures were assessed in a similar fashion. Panels were used to identify gram-positive organisms (MicroScan Pos BP combo type 8, B1017-104) and gram-negative organisms (MicroScan Neg BP combo type 10, B1017-102) (Dade Behring MicroScan, Sacramento, Calif). Both panels included ciprofloxacin among the antimicrobials tested. All panels were read on the WalkAway 40 (Dade Behring MicroScan), an automated machine that incubates identification panels, adds reagents, and scans the panels for biochemical changes and prints out the biotype and identification of the bacteria.
Radiological films were routinely obtained for clinical purposes and were reviewed at least once a week. A critical assessment of the major bone joints, such as knees, wrists, hips, shoulders, and anterior part of the chest, were evaluated for arthropathy by our pediatric radiologist.
During a 4-year period (January 1, 1993, to December 31, 1997) we treated 56 of our pediatric burn patients with ciprofloxacin when cultures proved to be multiresistant and sensitive to ciprofloxacin. The average age of our patient population was 8.4 years (range, 6 weeks to 17 years). The sex distribution was 38 boys vs 18 girls. The average burn size for the study population was 65% or total body surface area (range, 16%-100%).
Of the 56 patients who received the antibiotic, 50 received the recommended dose. Forty-two (75%) had a major reduction in the bacterial counts in their quantitative wound specimens, from 106 to less than 100 colonies per gram of tissue. The remaining 14 patients (25%) were observed to have a 2- to 3-log decrease in bacteria count. Respiratory cultures showed a decrease in density or an elimination of the gram-negative agents. None of the patients exhibited any adverse effects from the ciprofloxacin therapy. All were discharged and sent home. Six-month follow-up disclosed no untoward effects.
A total of 180 organisms were isolated from the burn wounds and respiratory cultures. Of the 180 isolates, 67 (37.2%) were gram positive, while 113 (62.8%) were gram negative. The distributions according to genus and species for both groups are reflected in Table 1 and Table 2. It is interesting that the staphylococci accounted for 70.2% of the gram-positive isolates, with more than 50% showing ciprofloxacin susceptibility, while the enterococci were more susceptible to ciprofloxacin (Table 1). This is consistent with the findings of Peterson et al.7Table 2 shows that P aeruginosa accounted for more than 30% of the isolates and was 87.2% susceptible to ciprofloxacin. The remaining gram-negative isolates proved to be more susceptible, for an overall susceptibility of gram-negative organisms of 92.9%.
Radiographic findings were consistent with burn-associated metabolic bone disease. Figure 1, Figure 2, Figure 3, andFigure 4 are representative views from 4 of the patients studied.The bone findings included osteoporosis, decreased bone density and formation, and increased bone resorption; however, there were no radiographic findings consistent with arthropathy. Patients who exhibited bone abnormalities were not limited to those treated with ciprofloxacin. All patients with major burns had burn-associated metabolic bone disease but not drug-related arthropathy.11,12
Representative radiograph of the anterior part of the chest showing no apparent arthropathy in burned children treated with ciprofloxacin hydrochloride (20-30 mg/kg per day for 7-10 days).
Representative radiograph of the wrist joint showing no apparent arthropathy in burned children treated with ciprofloxacin hydrochloride.
Representative radiograph of the knee joint showing no documented drug-associated arthropathy in burned children treated with ciprofloxacin hydrochloride.
Representative radiograph of the wrist joint showing no documented drug-associated arthropathy in burned children treated with ciprofloxacin hydrochloride.
For the past decade, ciprofloxacin has been the major drug in the treatment of pediatric bronchopulmonary exacerbation in cystic fibrosis, pyelonephritis, and cholangitis caused by P aeruginosa.1,3,6,8 We found 11 studies or case reports from 7 countries where ciprofloxacin therapy was used in a total of 98 pediatric patients and the efficacy of ciprofloxacin was reported. Preliminary results in infants and children were promising with the use of oral ciprofloxacin in the treatment of complicated urinary tract infections caused by P aeruginosa (12 patients), subacute osteomyelitis caused by S aureus (2 patients) or P aeruginosa (2 patients), and ventriculoperitoneal shunt infection caused by Staphylococcus epidermidis (2 patients).8 Schaad et al10 conducted clinical, radiological, and magnetic resonance imaging investigations in 13 prepubertal patients (aged 6 to 13 years) and 5 postpubertal patients (aged 14 to 24 years) with cystic fibrosis at the beginning and end of a 3-month course of ciprofloxacin (30 mg/kg per day) administered twice daily, and at follow-up at 4 to 6 months later. Their comprehensive monitoring unequivocally showed no evidence of any arthropathogenic effects. However, data based on magnetic resonance imaging investigations performed in juvenile dogs indicated that these studies could predict ciprofloxacin-induced histopathological changes of the knee joint.10 Consequently, the therapeutic application of ciprofloxacin in the pediatric population other than for cystic fibrosis was considered contraindicated; experts advised against performing efficacy and safety studies of these promising new agents in children because of toxic effects on cartilage in weight-bearing joints. However, in treating our pediatric burn patients, we are frequently confronted with multiresistant gram-negative bacilli, particularly P aeruginosa, which accounted for more than 30% of our wound and respiratory infections. The Enterobacteriaceae accounted for the remaining 70%. Therefore, encouraged by the data accumulated in the pediatric cystic fibrosis studies, we chose to use ciprofloxacin as one of our antimicrobials for treatment of gram-negative infections.
Our findings of major reductions in burn-wound bacterial counts and reduction or elimination of the gram-negative population in respiratory and sputum cultures are consistent with the findings of Smith et al,13 who showed that minimum inhibitory concentrations for ciprofloxacin in sputum mirrored those in serum and were sufficient to abrogate a chronic bronchopulmonary exacerbation in patients with cystic fibrosis caused by P aeruginosa. Similarly, Regelmann and his coworkers14 demonstrated a reduction of P aeruginosa density in sputum of patients with cystic fibrosis treated with ciprofloxacin. Their conclusion was that the antibiotic improves lung function in these patients more than bronchodilators and chest physiotherapy do alone.
We used vancomycin hydrochloride for primary coverage of the gram-positive organisms, even though some of the staphylococci and enterococci were fairly susceptible to ciprofloxacin (Table 1). In addition, we noted that ciprofloxacin in combination with either a carbapenem (imipenen-cilastatin), monobactam, or piperacillin sodium/tazobactam sodium provided a synergistic response against the gram-negative invaders.
All children and adults with burns covering more than 40% of total body surface area are subject to osteopenia and bone loss because of decreased bone formation, increased resorption, hypoparathyroidism, immobilization, and several other factors.11,12,15 The patients treated with ciprofloxacin also were subject to these abnormalities but had no documented drug-associated arthropathy. Consequently, a control group for comparison was deemed unnecessary.
The overall efficacy and safety of ciprofloxacin therapy in the treatment of burn wound and respiratory infections is 92.9% based on these data (Table 2). Therefore, we believe that when multiresistant gram-negative infections occur in the pediatric burn population, ciprofloxacin is both efficacious and safe and is the primary drug of choice in these immunocompromised hosts.16
Presented as a poster at the 18th Annual Meeting of the Surgical Infection Society, New York, NY, May 1-2, 1998.
We are indebted to Cassie Maness for preparation of the manuscript; Lewis Milutan, Tina Garcia, and Sandy Baxter for the photographic work and poster preparation; and Rick Goodheart for retrieving an exhaustive list of references.
Reprints: John P. Heggers, PhD, 815 Market St, Galveston, TX 77550 (e-mail: email@example.com).
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