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Ciprofloxacin in critically ill children.

The broad-spectrum activity of fluoroquinolones, along with their favourable pharmacokinetic/ pharmacodynamic characteristics, makes them an appealing option for difficult-to-treat infections of adult and paediatric patients.

Specifically, fluoroquinolones have been used for the treatment of children with cystic fibrosis (with infections caused mainly from Pseudomonas aeruginosa), as well as for children with complicated urinary tract infections and pyelonephritis (1-3). Fluoroquinolones have also been used for outpatient treatment of febrile neutropaenic paediatric cancer patients (4,5), and as a compassionate treatment for children who do not respond to preliminary antibiotic treatment. Safety reports regarding fluoroquinolone use for the above-mentioned cases suggest that they are associated mainly with mild gastrointestinal adverse events, including diarrhoea and abdominal pain, headache and reversible arthralgia (6,7). Reports regarding quinolone-induced QT prolongation in children are rare (1,8).

On the other hand, data regarding the effectiveness and safety of fluoroquinolone use for the treatment of critically ill children without cystic fibrosis are scarce (9). Consequently, in this study we present our experience regarding the effectiveness and safety profile of ciprofloxacin treatment in critically ill children without cystic fibrosis from a tertiary care paediatric hospital in Athens, Greece.

METHODS

Patient population

We prospectively identified all children who received ciprofloxacin treatment in the intensive care unit of the "P. & A. Kyriakou" tertiary-care paediatric hospital during a three-year period (2005 to 2008).

Data regarding patients' demographic characteristics (age, gender), underlying disease, diagnosis, isolated pathogens, duration of hospitalisation and fluoroquinolone-treatment characteristics (type, dosage and duration) were recorded. Data regarding the occurrence of diarrhoea, vomiting, abdominal pain, arrhythmias, headache, increased intracranial pressure and laboratory values (blood gas, blood urea nitrogen and creatinine) assessed at four different time points (before and at the third, fifth and tenth day after institution of fluoroquinolone treatment) were also recorded. The collection as well as the report of the data presented in this study was approved by the hospital ethics committee.

Microbiological testing

Conventional methods were used for sample cultures and pathogen identification. Susceptibility was evaluated with the disk diffusion technique, in accordance with the Clinical and Laboratory Standards Institute guidelines (10). Minimum inhibitory concentrations were evaluated with gradient method Etest (AB Biodisk, Solna, Sweden) when required. Production of extended-spectrum-[beta]-lactamase was confirmed using combined disks (cefotaxime, ceftazidime and cefepime, alone and in combination with clavulanate). The Etest metallo-P-lactamase (AB Biodisk) was used for phenotype detection of metallo-[beta]-lactamase production.

RESULTS

Patient characteristics

Eighteen critically ill children (12 females, mean age 23 months) who received ciprofloxacin during the study period were identified. Various types of comorbidity including malignancy and immunodeficiency were recorded. Detailed data are presented in Table 1. None of the 18 evaluated patients had cystic fibrosis. In three of the 18 evaluated patients, no pathogen was identified. Due to the severity of the clinical manifestations, ciprofloxacin was administered to the latter patients as pre-emptive treatment. Regarding the remaining 15 patients, 14 had bacteraemia and one had pneumonia due to Stenotrophomonas maltophilia. Detailed data regarding the infections of the 18 evaluated patients are presented in Table 1. The mean duration of hospitalisation was 34.7 days.

Treatment characteristics

The reason for the initiation of ciprofloxacin treatment in the evaluated patients was isolation of a ciprofloxacin-only susceptible pathogen in seven patients, prior antibiotic treatment failure in six patients (detailed data regarding the antibiotic agents administered prior to ciprofloxacin are presented in Table 1), and pre-emptive treatment in three patients with severe clinical manifestations. In the remaining two patients, ciprofloxacin treatment was instituted initially but changed to another antibiotic after three days due to the identification of a multi-drug-resistant pathogen. All the 18 evaluated patients received intravenous ciprofloxacin treatment. Seventeen of the 18 evaluated patients received a ciprofloxacin dosage of 30 mg/kg/day in two divided doses, whereas one received a daily dosage of 10 mg/kg due to multiple organ failure following sepsis. None of the 18 patients had an impaired renal and/or hepatic function, thus there was no need for further ciprofloxacin dosage adjustment. Sixteen patients received a 10-day treatment, whereas two patients received a three-day treatment, as discussed previously. In three patients ciprofloxacin was administered con-comitantly with gentamicin, metronidazole and tigecycline, respectively. Specifically, one of the latter three patients had bacteraemia caused by a tigecycline-only susceptible K. pneumoniae strain. In this patient, ciprofloxacin was administered concomitantly to tigecycline in order to achieve a synergistic effect.

Outcomes and adverse events

All of the 15 patients with microbiologically documented infections recovered. Three deaths attributed to the patients' comorbidity were noted. The three patients who died received ciprofloxacin due to prior antibiotic treatment failure. Diarrhoea occurred in two patients on the second day of ciprofloxacin treatment, whereas vomiting occurred in one patient on the fifth day. No case of abdominal pain or headache was noted in the subset of the evaluable non-intubated patients. No case of increased intracranial pressure, as assessed with transcranial Doppler ultrasonography or inferred from complaints of headache, was noted. Supra-ventricular tachycardia was noted in one patient on the fifth day of ciprofloxacin treatment. This arrhythmia was reversible. No case of QT prolongation was reported in our case series. Laboratory abnormalities suggestive of renal function impairment were not observed in this case series. The 10-day follow up of the 18 involved patients precluded the assessment of joint, joint cartilage and tendon toxicity, potentially associated with ciprofloxacin treatment.

DISCUSSION

We report a case series of 18 critically ill paediatric patients who received intravenous ciprofloxacin for the definite (15 patients) or pre-emptive (3 patients) treatment of infections caused mainly from Gram-negative pathogens. All patients with microbiologically documented infections were cured from the infections. However, in two patients the isolated causative pathogen proved to be resistant to ciprofloxacin, whereas another patient had bacteraemia caused from a tigecycline-only susceptible, carbapenemase producing K. pneumoniae strain. In this patient, ciprofloxacin was administered concomitantly to tigecycline. Consequently, in the latter three cases, the observed clinical improvement cannot be solely attributed to ciprofloxacin. Three deaths were noted, all attributed to the patients' co-morbid illness. Within a short-term follow-up of 10 days, three cases of gastrointestinal adverse events (diarrhoea and vomiting) and one case of reversible supraventricular tachycardia occurred. However, long-term adverse events including joint, joint cartilage and tendon toxicity potentially associated with ciprofloxacin treatment were not assessed.

Published evidence from animal studies suggested a potential association between fluoroquinolones and joint toxicity in juvenile animals. This type of toxicity involved immature joint cartilage of weight-bearing joints, epiphyseal growth plates and tendons (11-13). This resulted in a restrictive use of fluoroquinolones to paediatric patients. Fluoroquinolones have been occasionally used for treating children with cystic fibrosis, complicated urinary tract infections, febrile neutropenic children with malignancies, and those with infections unresponsive to conventional antibiotic regimens. However, the encouraging safety data gathered from the experience of fluoroquinolone use for the abovementioned indications (14-16), in combination with other factors including the development of fluoroquinolones active against penicillin-resistant pneumococci (17), intensified the discussion regarding the off-label use of fluoroquinolones for children.

In our study, we focused on 18 critically ill children, without cystic fibrosis, who received intravenous ciprofloxacin. The reasons for ciprofloxacin treatment in our patients included prior antibiotic treatment failure and/or isolation of a ciprofloxacin-only-susceptible pathogen. Yet in three patients ciprofloxacin was administered as pre-emptive treatment, due to the severity of the patients' clinical manifestations, whereas in another patient who had bacteraemia due to a tigecycline-only susceptible K. pneumoniae strain, ciprofloxacin was administered in combination with tigecycline to achieve a synergistic effect (18).

Contemporary studies which have focused on the re-evaluation of antibiotic agents with a restrictive use in paediatric patients due to safety considerations, including colistin, have shown that these drugs appear to have an acceptably safe profile when administered to children with difficult-to-treat infections, such as those caused by multi-drug resistant pathogens (19). In our study, mainly mild adverse events (three cases of gastrointestinal adverse events, including two cases of diarrhoea and one case of vomiting) were noted. Quinolone-induced arrhythmia, including QT prolongation, is regarded as a rare adverse event, associated with specific fluoroquinolones, and most likely to occur in populations at risk for arrhythmias (20,21). Published data regarding ciprofloxacin-induced QT prolongation in children are scarce (8). No case of QT prolongation was reported in our case series. The one case of arrhythmia observed during ciprofloxacin treatment was a reversible supraventricular tachycardia. Similarly, another case series evaluated neonatal and critically ill children who received ciprofloxacin concomitantly with other antibiotic agents and after preliminary antibiotic treatment, for infections caused from multi-drug resistant isolates (9). All these patients recovered from the infections and minor adverse events were noted during ciprofloxacin treatment.

Our study has limitations that should be taken into consideration in the interpretation of its findings. First, the number of the included patients is rather small. One may also consider the inherent limitations of a descriptive, non-comparative study before extrapolating the findings of this specific study. Finally, in our study, the assessment of joint, joint cartilage or tendon toxicity potentially associated with ciprofloxacin treatment was hampered due to lack of a long-term follow-up.

Even though methodological limitations hamper the establishment of firm conclusions, our study adds useful information regarding the effectiveness and safety of intravenous ciprofloxacin treatment in critically ill children without cystic fibrosis. The lack of evaluation of joint, joint cartilage or tendon toxicity potentially associated with ciprofloxacin treatment is also a considerable limitation. However, useful information regarding short-term adverse events associated with ciprofloxacin treatment is derived from our case series. Consequently, clinicians may consider intravenous ciprofloxacin as a treatment option in critically ill children without cystic fibrosis who have infections caused by multi-drug resistant pathogens or do not respond to prior appropriate antibiotic treatment.

Accepted for publication on March 25, 2011.

REFERENCES

(1.) Committee on Infectious Diseases. The use of systemic fluoroquinolones. Pediatrics 2006; 118:1287-1292.

(2.) Fedler KA, Jones RN, Sader HS, Fritsche TR. Activity of gatifloxacin tested against isolates from pediatric patients: report from the SENTRY Antimicrobial Surveillance Program (North America, 1998-2003). Diagn Microbiol Infect Dis 2006; 55:157-164.

(3.) Hansen CR, Pressler T, Hoiby N. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience. J Cyst Fibros 2008; 7:523-530.

(4.) Chamilos G, Bamias A, Efstathiou E, Zorzou PM, Kastritis E, Kostis E et al. Outpatient treatment of low-risk neutropenic fever in cancer patients using oral moxifloxacin. Cancer 2005; 103:2629-2635.

(5.) Petrilli A, Altruda CF, Alberto PPC. Oral gatifloxacin in the outpatient treatment of children with cancer fever and neutro penia. Pediatr Blood Cancer 2007; 49:682-686.

(6.) Chysky V, Kapila K, Hullmann R, Arcieri G, Schacht P, Echols R. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use. Emphasis on joint evaluation. Infection 1991; 19:289-296.

(7.) Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use--safety report. Pediatr Infect Dis J 1997; 16:127-129; discussion 160-162.

(8.) Knorr JP, Moshfeghi M, Sokoloski MC. Ciprofloxacin-induced Q-T interval prolongation. Am J Health Syst Pharm 2008; 65:547-551.

(9.) Nejjari N, Benomar S, Lahbabi MS. [Nosocomial infections in neonatal and pediatric intensive care. The appeal of ciprofloxacin]. Arch Pediatr 2000; 7:1268-1273.

(10.) Clinical and Laboratory Standards Institute. 2008. Performance standards for antimicrobial susceptibility testing; 17th informational supplement. CLSI M100-S18. Clinical and Laboratory Standards Institute W, PA.

(11.) Channa HMA, Ashfaq M, Bangash R, Abbasi A, Qureshi MA. Preventive role of zinc chloride against toxicity of ciprofloxacin on the growing cartilage of Wistar albino rat litter. J Ayub Med Coll Abbottabad 2008; 20:77-81.

(12.) Lozo E, Riecke K, Schwabe R, Vormann J, Stahlmann R. Synergistic effect of ofloxacin and magnesium deficiency on joint cartilage in immature rats. Antimicrob Agents Chemother 2002; 46:1755-1759.

(13.) van der Linden PD, van Puijenbroek EP, Feenstra J, Veld BA, Sturkenboom MC, Herings RM et al. Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998. Arthritis Rheum 2001; 45:235-239.

(14.) Saez-Llorens X, McCoig C, Feris JM, Vargas SL, Klugman KP, Hussey GD et al. Quinolone treatment for pediatric bacterial meningitis: a comparative study of trovafloxacin and ceftriaxone with or without vancomycin. Pediatr Infect Dis J 2002; 21:14-22.

(15.) Schaad UB, Wedgwood J, Ruedeberg A, Kraemer R, Hampel B. Ciprofloxacin as antipseudomonal treatment in patients with cystic fibrosis. Pediatr Infect Dis J 1997; 16:106-111; discussion 123-126.

(16.) Yee CL, Duffy C, Gerbino PG, Stryker S, Noel GJ. Tendon or joint disorders in children after treatment with fluoroquinolones or azithromycin. Pediatr Infect Dis J 2002; 21:525-529.

(17.) Calva-Mercado JJ, Castillo G, Lopez-Vidal Y. [Flouroquinolone activity in clinical isolates of Streptococcus pneumoniae with different susceptibility to penicilline: an epidemiological study in five cities of Mexico]. Gac Med Mex 2005; 141:253-258.

(18.) Petersen PJ, Labthavikul P, Jones CH, Bradford PA. In vitro antibacterial activities of tigecycline in combination with other antimicrobial agents determined by chequerboard and time-kill kinetic analysis. J Antimicrob Chemother 2006; 57:573-576.

(19.) Falagas ME, Sideri G, Vouloumanou EK, Papadatos JH, Kafetzis DA. Intravenous colistimethate (colistin) use in critically ill children without cystic fibrosis. Pediatr Infect Dis J 2009; 28:123-127.

(20.) Owens RC Jr, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis 2005; 41 Suppl 2:S144-157.

(21.) Falagas ME, Rafailidis PI, Rosmarakis ES. Arrhythmias associated with fluoroquinolone therapy. Int J Antimicrob Agents 2007; 29:374-379.

G. SIDERI *, D. A. KAFETZIS ([dagger]), E. K. VOULOUMANOU ([double dagger]), J. H. PAPADATOS ([section]), M. PAPADIMITRIOU **, M. E. FALAGAS ([dagger][dagger])

Pediatric Intensive Care Unit, Department of Microbiology and Second Department of Pediatrics, University of Athens, "P. & A. Kyriakou" Children's Hospital and Alfa Institute of Biomedical Sciences, Athens, Greece

* M.D., Physician, Pediatric Intensive Care Unit, "P. & A. Kyriakou" Children's Hospital.

([dagger]) M.D., Ph.D., Professor, Second Department of Pediatrics, University of Athens, "P. & A. Kyriakou" Children's Hospital.

([double dagger]) M.D., Research Fellow, Alfa Institute of Biomedical Sciences.

([section]) M.D., Ph.D., Director, Pediatric Intensive Care Unit, "P. & A. Kyriakou" Children's Hospital.

** M.D., Physician, Department of Microbiology, "P. & A. Kyriakou" Children's Hospital.

([dagger][dagger]) M.D., M.Sc., D.Sc., Director, Alfa Institute of Biomedical Sciences and Department of Medicine, Henry Dunant Hospital, Athens, Greece and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA.

Address for correspondence: Dr M. E. Falagas, 9 Neapoleos Street, 15123, Marousi, Athens, Greece. Email: m.falagas@aibs.gr
Table 1

Characteristics of the evaluated children

Demographic characteristics
 Age: mean (range), months 23, (5-39)
 Gender, female/male 12/6
Underlying diseases, n/N (%)
 None 5/18 (27.7)
 Cardiomyopathy/rheumatic fever 1/18 (5.5)
 Pancreatitis/pancreatic 1/18 (5.5)
 pseudocyst
 Immunodeficiency 2/18 (11.1)
 Immunodeficiency/secondary 1/18 (5.5)
 haematophagocytic syndrome
 Down syndrome 1/18 (5.5)
 Myelitis 1/18 (5.5)
 Brain tumour (ependymoma) 1/18 (5.5)
 Multi-trauma/craniencephalic 1/18 (5.5)
 injury
 Multi-organ failure/secondary 1/18 (5.5)
 haematophagocytic syndrome
 Wiskott-Aldrich syndrome 1/18 (5.5)
 Acute myelogenous leukaemia 1/18 (5.5)
 Bronchopulmonary dysplasia 1/18 (5.5)
Duration of hospitalisation *, days, 34.7 (5-90)
mean (range)
Infections
 None 3/18 (16.6)
 P. aeruginosa bacteraemia 5/18 (27.7) ([dagger])
 A. baumannii bacteraemia 1/18 (5.5)
 E. aerogenes bacteraemia 1/18 (5.5)
 K. pneumoniae bacteraemia 3/18 (16.6) ([dagger])([dagger])
 Serratia marcescens bacteraemia 1/18 (5.5)
 S. aureus bacteraemia 1/18 (5.5)
 CNS bacteraemia 1/18 (5.5)
 P. aeruginosa + K. pneumoniae 1/18 (5.5)
 bacteraemia
 CNS bacteraemia + P. carinii 1/18 (5.5)
 pneumonia + E. asburiae UTI
 S. maltophilia pneumonia 1/18 (5.5)
Prior antibiotic treatment
 Piperacillin-tazobactam 7/18 (38.8)
 Cefotaxime 3/18 (16.6)
 Vancomycin/teicoplanin/TMX-SMP/ 2/18 (11.1)
 ticarcillin-clavulanate/amikacin
 Meropenem/ceftazidime/gentamicin/ 1/18 (5.5)
 pentamidine/ceftriaxone/netilmicin
 / clindamycin/metronidazole
Concomitant antibiotic treatment
 Gentamicin 1/18 (5.5)
 Metronidazole 1/18 (5.5)
 Tigecycline 1/18 (5.5) ([dagger])([dagger])
 ([dagger])

CNS=coagulase-negative Staphylococcus spp., UTI=urinary tract
infection, TMX-SMP=trimethoprim sulfamethoxazole. * Relevant data were
not available for two of the evaluated patients, ([dagger]) Two of the
isolated P. aeruginosa strains were multi-drug resistant pathogens,
([dagger])([dagger]) One of the isolated K. pneumoniae strains
was a metallo-beta-lactamase and extended spectrum beta-lactamases
producing strain, ([dagger])([dagger])([dagger]) Tigecycline was
administered in the case of bacteraemia caused from a
metallo-beta-lactamase and extended-spectrum beta-lactamases producing
K. pneumoniae strain.
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Article Details
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Author:Sideri, G.; Kafetzis, D.A.; Vouloumanou, E.K.; Papadatos, J.H.; Papadimitriou, M.; Falagas, M.E.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:4EUGR
Date:Jul 1, 2011
Words:2720
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