Ciprofloxacin is a broad spectrum fluoroquinolone that has been effective in treating severe infections caused by multiresistant Gram-negative bacteria. It is generally well-tolerated when used in adults. Its most frequently reported adverse reactions are gastrointestinal disturbances (2 to 6%), headache (1.2%), photosensitivity (1.1%) and transient increases of serum transaminases and creatinine. 1 Experimental studies have shown that quinolones can induce arthropathy in juvenile animals. 2–4 For this reason the use of fluoroquinolones in children has been limited to very special indications. 5 However, clinical studies in children, especially in patients with cystic fibrosis, have found no evidence of cartilage toxicity and no increased risk for myoskeletal adverse effects. 6–8
Data regarding ciprofloxacin toxicity in neonates are limited to few reports of uncontrolled personal experience. 9–15 Ciprofloxacin use in our neonatal intensive care unit (NICU) began in 1994 as salvage treatment during an outbreak of multiresistant Klebsiella pneumoniae sepsis refractory to the treatment with other antimicrobials. In that preliminary experience ciprofloxacin was effective with no serious adverse effects (unpublished data). Hence ciprofloxacin continued to be administered to septic neonates in our NICU either alone or in combination with other antimicrobial agents. To investigate comprehensively the short term adverse effects of ciprofloxacin on hematologic indices and on the hepatic and renal function as well as any potential adverse effects on the joints and growth during the first year of life this observational, prospective, comparative study was designed.
PATIENTS AND METHODS
Two groups of neonates with microbiologically proven or probable sepsis admitted to the NICU of the first Neonatology Department of Aristotle University from 1994 to 2000 were studied. Ciprofloxacin group consisted of 116 neonates who received ciprofloxacin for the treatment of proven or probable sepsis. The control group consisted of 100 randomly selected septic neonates matched for gestational age and birth weight who were hospitalized in the NICU during the same period but did not receive ciprofloxacin. The study was observational, and the decision on the kind of antimicrobial regimen given to each neonate was taken by the attending physician on the basis of clinical, epidemiologic and laboratory data, including antimicrobial drug susceptibility pattern of the isolates from the NICU. Ciprofloxacin was administered in a dosage of 10 mg/ kg/day in 2 divided doses. The neonates who died before the 15th day after the initiation of the treatment or who did not complete the laboratory follow-up were excluded from the study. The study was approved by our institution, and oral informed consent regarding the follow-up was taken from the parents. Informed consent did not include the regimen of antimicrobial agents given, because the attending physicians were those who were taking the decision of the kind of treatment.
Blood cultures were taken at the onset of “sepsis” signs and then on the third day or when indicated by clinical or laboratory findings. White blood cell and differential counts, platelets, serum levels of transaminases (glutamate oxalate and glutamate pyruvate), bilirubin, total protein, albumin, urea and creatinine were routinely measured before initiation of treatment and every 5 days thereafter according to the policy of our department for all septic neonates. The neonates were clinically evaluated for signs of arthropathy up to discharge. Seventy-seven and 83 infants of the ciprofloxacin and the control group, respectively, were followed up to the 12th month of life. During follow-up the development of clinical signs of arthropathy and the growth were recorded. The length, weight and head circumference were corrected for prematurity. No ultrasound or magnetic resonance imaging was performed.
Statistical analysis was performed by one way analysis of variance and Fisher’s exact test.
A total of 216 neonates were prospectively studied. Of them 116 (89 preterm and 27 term neonates) comprised the ciprofloxacin group and 100 (88 preterm and 12 term neonates) comprised the control group. The clinical data are shown in Table 1. The age at entry to the study was 14 ± 19 (range, 1 to 44) days and 12 ± 8 (range, 1 to 31) days for the ciprofloxacin-treated and the control groups, respectively. Seventy-four percent of each group had microbiologically proven sepsis. The pathogens isolated from the blood cultures taken from these cases and their susceptibilities to ciprofloxacin are shown in Table 2. All the neonates in the ciprofloxacin group received one or more antimicrobial drugs other than ciprofloxacin during their stay in the NICU, namely penicillin, ampicillin, gentamicin, vancomycin, cephalosporins, trimethoprim-sulfamethoxazole and amphotericin B. Similarly the control group received a broad range of antimicrobials including ampicillin (n = 14), penicillin (n = 7), gentamicin or amikacin (n = 45), imipenem (n = 33), cephalosporins (n = 24), vancomycin (n = 23), amphotericin B (n = 3), metronidazole (n = 6) and trimethoprim-sulfamethoxazole (n = 8).
The mean values of the hematologic and biochemical indices as well as the numbers of neonates with abnormal values did not differ significantly between the two groups at any time. No clinical evidence of articular damage or other adverse events attributable to ciprofloxacin were observed during the initial hospitalization or the follow-up period. During the first year of life one neonate from each group developed greenish discoloration of the teeth. Moreover at the end of the first year, there was no significant difference of the percentages of infants in the two groups having growth indices below the 10th percentile (Table 3).
Several researchers reported their experience from the compassionate use of ciprofloxacin in children with chronic or recurrent infections. 6, 8 These reports showed that it was well-tolerated with no evidence of arthropathy. 6, 8, 16–17 Moreover prospective, randomized, controlled studies in children with cystic fibrosis demonstrated efficacy and safety of ciprofloxacin. 7, 18
The use of broad spectrum antimicrobial agents in NICUs resulted in increased frequency of neonatal sepsis caused by multiresistant bacteria. 19–22 In such cases ciprofloxacin may provide a life-saving treatment because of the susceptibility of many multiresistant bacteria. The susceptibility of isolated bacteria to ciprofloxacin has been reported to range from 20 to 96%, depending on the pathogen and the duration of the ciprofloxacin use in each individual unit. 19, 20, 23–26 In our study the overall susceptibility to ciprofloxacin was 89% with only Enterococcus spp. and Pseudomonas spp. being commonly resistant (60 and 67% of the isolates, respectively). However, these organisms are infrequent causes of bacteremia in our NICU as shown in Table 2.
Data regarding the short term and long term adverse effects of ciprofloxacin in neonates are limited. Before 1990 ciprofloxacin had been administered to very few neonates with serious infections, mainly meningitis. 15, 27–29 Its use in neonates increased during the last decade. Thus far ciprofloxacin administration to neonates has been reported without any significant adverse effects. 10–15, 26–35 The most commonly reported adverse effects have included thrombocytopenia, hyperbilirubinemia and elevated hepatic enzymes and creatinine. 9–11 However, these pathologic conditions are well-documented complications of neonatal sepsis. Thus the contribution of ciprofloxacin could not be clarified without an appropriate control group. In our controlled study no significant differences in the hematologic indices and the biochemical markers of hepatic and renal function were found between the ciprofloxacin-treated neonates and controls.
The main concern that has restricted the ciprofloxacin use in children has been the potential of inducing arthropathy, an effect that has not been shown in previous studies in older children. 6, 16–18 Although no ultrasound and magnetic resonance imaging of the joints was performed in our study, no clinical evidence of arthropathy was observed during either the initial hospitalization or follow-up. In addition no potential effects on growth were observed, although height may be totally independent of cartilage damage. Growth rate was comparable in the two groups studied. These results unequivocally demonstrated what was suggested by a previous study, which found that the growth of nine infants who had received ciprofloxacin did not differ from that of the respective controls. 13
We conclude that ciprofloxacin administration to neonates with sepsis is not associated with increased risk for hematologic, hepatic or renal dysfunction and is not associated with clinical arthropathy or growth impairment of the treated infants during the first year of life.
1. Orenstein DM, Pattishall EN, Noyes BE, et al. Safety of ciprofloxacin in children with cystic fibrosis. Clin Pediatr 1993;32:504–6.
2. Burkhardt J, Walterspiel J, Schaad UB. Quinolone arthropathy in animals versus
children. Clin Infect Dis 1997;25:1196–204.
3. Linseman DA, Hampton LA, Branstetter DG. Quinolone-induced arthropathy in the neonatal mouse: morphological analysis of articular lesions produced by pipemidic acid and ciprofloxacin. Fundam Appl Toxicol 1995;28:59–64.
4. Stahhnann R, Merker HJ, Ffinz N, et al. Ofloxacin in juvenile non-human primates and rats: arthropathy and drug plasma concentrations. Arch Toxicol 1990;64:193–204.
5. Schaad UB, Salam MA, Aujard Y. 1995. Use of fluoroquinolones in pediatrics: consensus report of an international society of chemotherapy commission. Pediatr Infect Dis J 14(Suppl 1):1–9.
6. Chysky V, Kapila K, Hullman R, Arciery G, Schacht P, Echols R. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use—emphasis on joint evaluation. Infection 1991;19:289–96.
7. Richard DA, Nousia-Arvanitakis S, Sollich V, Hampel BJ, Sommerauer B, Schaad UB. Oral ciprofloxacin vs.
intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of antipseudomonas efficacy and assessment of safety with ultrasonography and magnetic resonance. Pediatr Infect Dis J 1997;16:572–8.
8. Hampel B, Hullman R, Schmidt H. Ciprofloxacin use in pediatrics: worldwide clinical experience based on compassionate use-safety report. Pediatr Infect Dis J 1997;16:127–9.
9. Lumbiganon P, Pengsaa K, Sookpranee T. Ciprofloxacin in neonates and its possible adverse effect on the teeth. Pediatr Infect Dis J 1991;10:619–20.
10. Wlazlowski J, Krzyzanska-Oberbek A, Sikora JP, Chlebna-Sokol D. Use of the quinolones in treatment of severe bacterial infections in premature infants. Acta Pol Pharm 2000;57(Suppl):28–31.
11. Van den Oever HLA, Versteegh FGA, Thewessen EAPM, van den Anker JN, Mouton JW, Neijens HJ. Ciprofloxacin in preterm neonates: case report and review of the literature. Eur J Pediatr 1998;157:843–5.
12. Khaneja M, Naprawa J, Kumar A, Piecuch S. Successful treatment of late-onset infection due to resistant Klebsiella pneumoniae
in an extremely low birth weight infant using ciprofloxacin. J Perinatol 1999;19:311–14.
13. Gurpinar AN, Balkan E, Kilic N, Kiristioglu I, Dogruyol H. The effects of a fluoroquinolone on the growth and development of infants. J Int Med Res 1997;25:302–6.
14. Chotigeat U. Successful treatment of late onset infection due to multi-drug resistant Acinetobacter lwoffii
in a low birth weight neonate using ciprofloxacin. J Med Assoc Thai 2001;84:910–13.
15. Bannon MJ, Shutchfield PR, Weindling AM. Ciprofloxacin in Enterobacter cloacae
septicaemia. Arch Dis Child 1989;64:1388–91.
16. Bethell DB, Hien TT, Phi LT, et al. Effects on growth of single short courses of fluoroquinolones. Arch Dis Child 1996;74:44–6.
17. Danisovicova A, Brezina M, Belan S, et al. Magnetic resonance imaging in children receiving quinolones: no evidence of quinolone induced arthropathy—a multicenter survey. Chemotherapy 1994;40:209–14.
18. Church DA, Kanga JF, Kuhn RJ, et al. Sequential ciprofloxacin therapy in pediatric cystic fibrosis: comparative study vs.
ceftazidime/tobramycin in the treatment of acute pulmonary exacerbations. Pediatr Infect Dis J 1997;16:97–105.
19. Kumhar GD, Ramachandran VG, Gupta P. Bacteriological analysis of blood culture isolates from neonates in a tertiary care hospital in India. J Health Popul Nutr 2002;20:343–7.
20. Choi SH, Kim YS, Chung JW, et al. Serratia
bacteremia in a large university hospital: trends in antibiotic resistance during 10 years and implications for antibiotic use. Infect Control Hosp Epidemiol 2002;23:740–7.
21. Joshi SG, Ghole VS, Niphadkar KB. Neonatal Gram-negative bacteremia. Indian J Pediatr 2000;67:27–32.
22. Rodriguez CH, Juarez J, de Mier C, et al. Bacterial resistance to antibiotics in gram-negative rods isolated from intensive care units: comparative analysis between two periods (1998 and 2001). Medicina (B Aires) 2003;63:21–7.
23. Leelarasamee A, Janyapoon K. Antimicrobial resistance of 100 serial gram-negative isolates in two intensive care units. J Med Assoc Thai 1992;75:680–7.
24. Karki BM, Parija SC. Analysis of blood culture isolates from hospitalized neonates in Nepal. Southeast Asian J Trop Med Public Health 1999;30:546–8.
25. Rahman S, Hameed A, Roghani MT, Ullah Z. Multidrug resistant neonatal sepsis
in Peshawar, Pakistan. Arch Dis Child Fetal Neonatal Ed 2002;87:F233.
26. Mishra A, Mishra S, Jaganath G, Mittal RK, Gupta PK, Patra DP. Acinetobacter
sepsis in newborns. Indian Pediatr 1998;35:27–32.
27. Isaacs D, Slach MPE, Wilkinsu AR, Westwood AW. Successful treatment of Pseudomonas
ventriculitis with ciprofloxacin. J Antimicrob Chemother 1986;7:535–8.
28. Ragunathan PL, Potkins DV, Watson JG. Neonatal meningitis due to Salmonella typhimurium
treated with ciprofloxacin. J Antimicrob Chemother 1990;26:727–8.
29. Humphrey B, Sanders G, Marviak J. Flavobacterium odoratum
sepsis in neonate treated with ciprofloxacin. Arch Dis Child 1989;64:1119–20.
30. Belobovodova NV, Birggarkov AV, Kurchavov VA. Clinical and bacteriological experience with ciprofloxacin in neonates [Abstract N 129]. In: Rubenstein E, ed. Fifth Symposium on New Quinolones, Singapore, August 28 to 30, 1994.
31. Aujard Y. Quinolones in neonates. In: Adam D, Rubio T, eds. The use of quinolones in paediatric medicine. Fortschr Anti-microb Chemother (Munich) 1992;11:233–7.
32. Pillay T, Pillay DG, Adhikari M, Pillay A, Sturm AW. An outbreak of neonatal infection with Acinetobacter
linked to contaminated suction catheters. J Hosp Infect 1999;43:299–304.
33. van Ogtrop ML, van Zoeren-Grobben D, Verbakel-Salomons EM, van Boven CP. Serratia marcescens
infections in neonatal departments: description of an outbreak and review of the literature. J Hosp Infect 1997;36:95–103.
34. Green SD, Ilunga F, Cheesbrough JS, Tillotson GS, Hichens M, Felmingham D. The treatment of neonatal meningitis due to Gram-negative bacilli with ciprofloxacin: evidence of satisfactory penetration into the cerebrospinal fluid. J Infect 1993;26:253–6.
35. Krcmery Jr V, Filka J, Uher J, et al. Ciprofloxacin in treatment of nosocomial meningitis in neonates and in infants: report of 12 cases and review. Diagn Microbiol Infect Dis 1999;35:75–80.