MINI REVIEW - “What Is The Safety Of Fluoroquinolones For Children?” Dorothy Koech Newton Opiyo Mike English This review addresses the question “What is the safety of fluoroquinolones for children?” The WHO Pocketbook of Hospital Care for Children recommends the use of the following quinolone antibiotics: 1. Ciprofloxacin: Oral 10-15mg/kg per dose given twice per day for five days (maximum 500mg/dose). Use in children is only warranted if the benefits outweigh the risk of arthropathy. (Pocketbook Appendix 2, pg. 333). 2. Nalidixic acid: oral 15mg/kg 4 times a day for five days (Pocketbook Appendix 2, pg.341) Ciprofloxacin is recommended as a suitable first line agent for the treatment of dysentery. It further recommends the possible use of ciprofloxacin for typhoid fever, but not as first line therapy. (Pocket Book Pg. 160) The WHO pocket book does not mention the use of ciprofloxacin in neonates but studies reveal that ciprofloxacin has been safely used as second line treatment for neonatal sepsis with good effect. INTRODUCTION Quinolones first became available in 1962 and their fluorinated derivatives, characterized by broad-spectrum antimicrobial activity, were developed in the early 1980s[1]. Since their development, fluoroquinolones have emerged as an important group of antibiotics particularly ciprofloxacin, a 2nd generation fluoroquinolone. The fluoroquinolones are characterized by a broad spectrum of antibacterial activity including against Staphylococci, Shigella and Pseudomonas and are often useful where there are many multiply-resistant bacterial strains. They act through the inhibition of bacterial DNA gyrase and have good oral bioavailability, extensive tissue penetration, low protein binding and long elimination half-lives. Numerous clinical trials have shown that these compounds are effective and well tolerated in the treatment of adult patients with various infections[2] .However, occasional toxicities among paediatric populations, particularly cartilage toxicity[3] have limited fluoroquinolone use in this population. Common reported adverse effects associated with fluoroquinolones are gastrointestinal, such as nausea and diarrhoea, and central nervous system effects .Less common adverse effects include dermatologic reactions, hepatic enzyme elevation, hypersensitivity, nephrotoxicity, hematological reactions, tendonitis, and tendon rupture [4]. A potentially serious adverse effect is the prolongation of the QTc interval [5] which can lead to cardiac arrhythmias. To date, clinical experience gained with fluoroquinolones in pediatric infections has been mainly from a compassionate-use basis. Potential indications include Pseudomonas infections (mainly exacerbations of cystic fibrosis), urinary tract, gastrointestinal and central nervous system infections, infections in immunocompromised patients, certain otorhinolaryngeal infections and neonatal infections caused by multiply-resistant pathogens. There is currently no recommendation for the use of ciprofloxacin for neonates. The data on safety of quinolone antibiotics was summarized in a recently published ICHRC review by Mitchell RC et al who evaluated a large number of studies (n=29, 9 reviews; 7 RCTs;11 cohorts;1 case control and 1 case report) on the safety of fluoroquinolones for children. They concluded that they are safe and efficacious for paediatric populations when used for specific indications. Although preliminary reports of juvenile arthropathy were a cause of concern such adverse reactions have proven to be very rare. As the WHO and the government of Kenya now recommend Ciprofloxacin as first line treatment of childhood dysentery we wished to update the Mitchell review with any new data relevant to the safety of this drug. METHODOLOGY Search Strategy To update the searches run by Mitchell et al’s ICHRC review [6] the search was rerun through pubmed-clinical queries using the search terms ((ciprofloxacin OR quinolones) AND safety.))The searches were limited to “Newborn: birth – 1 month, Infant 1- 23 months, Preschool Child: 2-5 years, Child: 6 – 12 years with only work on human subjects and published in English included. The studies to be included had to meet the following criteria: (a) Intervention: use of fluoroquinolones - irrespective of the dose or route of administration or indication. (b) Control groups -Other antibiotic (irrespective of the dose or route of administration), placebo, or no drug. c) Participants: children (0-5 years) d) Type of study: RCTs and observational studies Any studies whose primary outcome measure was efficacy but contained safety data were included. PubMed: under therapy, broad sensitive search, 82 articles were retrieved 40 of which were relevant. Most of the studies had been appraised in the ICHRC review [6] .Eight recent and relevant studies were initially identified for inclusion after two reviewers independently reviewed the titles and abstracts of identified articles for relevance. However, three included adult patients as participants and were excluded leaving the ICHRC review and 5 further publications. In addition, some studies included in the review had data that the review did not capture and we felt it wise to include these additional data. Supplementary searches then carried out in pubmed related articles and the WHOLIS database reference lists of key articles retrieved 3 extra studies. The Cochrane Library was also searched using mesh terms ‘quinolones’, ‘ciprofloxacin’ and ‘safety’. No further studies were retrieved. The search process identified no clinical practice guideline on fluoroquinolone use in neonatal and young infant sepsis. Full texts of the eight articles not included in the prior review were sourced in addition to the ICHRC review itself. RESULTS Summary of the previous review Mitchell et al in her recent review on the safety of quinolones analysed a large number of studies. All the controlled trials included in the review included a total of 1349 participants while observational data were available on 4,343. The total additional participants within the included reviews was not clear. Most of the side effects reported in Mitchell et al’s review were found to be mild and transient. The rates of arthralgia reported in the review ranged from 0% in 4 cohort studies, 1.5% in the largest cohort (N=1795) and between 1% and 5% in the reviews .Arthropathy rates reported were < 1% in the reviews. All these episodes of arthropathy resolved with cessation of treatment. An exception were cohorts of children with cystic fibrosis, in Phillip et al and Salam et al (4% in children through to 7-8% in adolescents) who reported unusually high rates of arthralgia in both the treatment and control group (therefore implying no association with use of ciprofloxacin). The RCTs (arguably providing the best evidence) in general reported only few, mild arthropathies that resolved with cessation of treatment or no arthropathies at all. The most frequently reported adverse effects in the RCTs were gastrointestinal, and CNS related, (headache, dizziness.) with a frequency ranging from 2%-20%. All included reviews reported an overall adverse events rate in children between 13 – 20%, which is comparable to rates seen for many other antimicrobial agents. The range was however affected by the duration of treatment and the particular fluoroquinolone used. All the cohort studies included in the review had results consistent to those of RCTs and the reviews. Based on the above data , Mitchell et al considers the adverse effect profiles as acceptable when considered in light of the severity of the conditions for which the drugs are used in children. However, caution should still be exercised and continued adverse event surveillance carried out. New data The following results are findings of publications not previously included in the review as well as previously unreported neonatal data from two previously included neonatal studies to add to one new study reporting the safety and efficacy of fluoroquinolones when used among neonates. Included in this update are five prospective studies [3, 7-10],one retrospective study[11], one RCT [12] and one review. Ciprofloxacin in Paediatric patients (General) Leone et al [11] analyzed safety data on quinolones particularly and other antibacterial agents from the passive surveillance system database (that relies on clinicians spontaneously reporting adverse events) of three regions in Italy .The adverse effects being measured ranged from musculoskeletal, skin, CNS, and gastrointestinal. The reported musculoskeletal events ranged from 1.4% to 5.9 % for all the quinolones with an exception of levofloxacin and pefloxacin whose rates were 25.9% to 22.5% respectively. Age specific results indicated that use of fluoroquinolones in children was rare. Other limitations of such passive reporting are a bias towards reporting immediate and not long term adverse effects and the inadequacies of information concerning the fluoroquinolone prescription rates. However they concluded the safety profiles of fluoroquinolones differed and should be accounted for during prescription of the same. A more recent prospective multicentre study [10] carried out in 8 countries compared children taking levofloxacin with those taking other antibiotics and monitored them for adverse effects for 1 year . Safety assessment was based on the incidence of musculoskeletal disorders, relationship to therapy, and severity and on changes in physical exam. Levofloxacin was well tolerated during and for 1 month after therapy as evidenced by similar incidence and character of adverse events compared with other antibiotics. Differences between the incidences of reported adverse effects involving weight-bearing joints in levofloxacin group and control group were, however, statistically significant 2 months post therapy (P = 0.03) and 1 year post therapy (P= 0.047). Subsequently, evaluation of a larger experience that included this trial and 2 other prospective clinical trials demonstrated that incidence of one or more of these disorders is greater in levofloxacin-exposed children than in children treated with non fluoroquinolone antibiotics. Singh et al[3]carried out a prospective study of 219 children aged 5days -14 years admitted in paediatric wards, and receiving both oral and intravenous ciprofloxacin for various reasons. Radiographs and MRI of the joints of these children were taken during therapy and were repeated after 6 months, along with thorough physical examinations and lab investigations. The X-rays and MRI did not reveal any abnormalities. Adverse drug reactions were noted in 35/219 (15.98%) children with arthropathy rates being only (0.9%) (2/219 children). The results of this study also apply to neonates >5 day but the number of neonatal participants is not clear. Dolecek et al [12], in a multicentre open label RCT carried out in Vietnam assessed the efficacy and tolerability of gatifloxacin a third generation quinolone against azithromycin for treatment of uncomplicated typhoid fever. The results of this study indicate that gatifloxacin was well tolerated. No adverse effect related to gatifloxacin was observed. Gastrointestinal side effects that were probably typhoid related were relatively frequent in both treatment arms and they did not require interruption of therapy. This data adds to the evidence that fluoroquinolones are a safe class of antibiotics in paediatric populations. Ciprofloxacin for Neonates A prospective observational study carried out at a special care nursery in a children’s hospital in Bangladesh [7] administered ciprofloxacin to neonates with neonatal sepsis (n=48) and later enrolled a matched group of neonates with neonatal sepsis (N= 66) that had been treated with other antibiotics for comparison for follow up purposes. The neonates were then monitored for any adverse effects. Physical examination was normal in both groups during follow-up. No osteoarticular problems or joint deformities were observed in both groups. Treatment was not interrupted at any one time since no side effects were detected. Normal development was observed in 35.6%, mild impairments were found in 41.1% and serious impairments in 23.3%. No differences in development (physical and cognitive) were apparent between the groups. An additional prospective observational study that was carried out in India [8]involved thirty neonates with multi drug resistant septicaemia, who were treated with ciprofloxacin for a period of 14 days and another thirty with neonatal sepsis received other antibiotics formed the comparison group. Serial ultrasonographic measurements of the knee cartilage taken after one and six months indicated no difference in the two groups. The femoral cartilage showed an increase of 78.8% and 78.4% in the mean longitudinal area after 6 months in the study group and control group respectively indicating that growth and development rates were the same for the two groups. In a third prospective observational study neonates with sepsis [9] aged approximately 2-4 weeks received either ciprofloxacin (n=116) or other antibiotics (n=100) . The decision on the kind of antimicrobial to be used was left purely on the attending physician. The neonates were followed up for a period of one year and monitored for adverse effects. No clinical evidence of arthropathies was reported both during the hospitalization and follow-up period. No potential effects on growth were observed, although height may be totally independent of cartilage damage. Moreover, this study concluded that ciprofloxacin administration to neonates with sepsis is not associated with increased risk for hematologic, hepatic or renal dysfunction neither is it associated with clinical arthropathy or growth impairment of the treated infants during the first year of life. DISCUSSION The fluoroquinolone class of antimicrobials has been in clinical use for over 17 years now [14]. For a long time quinolones had not been approved for use in children, primarily because of concerns they could cause irreversible damage to growing cartilage in weight bearing joints, concerns resulting from effects in immature animals [15]. In some cases drugs in this class have been withdrawn for safety reasons (namely, trovafloxacin and grepafloxacin and temafloxacin) however other agents have been extensively prescribed, such as ciprofloxacin and levofloxacin. Most of the data present is on ciprofloxacin but in all it is clear that fluoroquinolones cannot be considered interchangeable in terms of efficacy or tolerability and safety [1]. A large recent study[10] on exposure to levofloxacin indicated it was associated with a small but statistically significant increased risk of developing a set of musculoskeletal disorders. These disorders however were typically transient and all resolved without apparent sequelae over the 1-year period of observation. Some caution must be used in interpreting these findings as are based on somewhat subjective observational data linking the drug administered 1 to 12 months before the side effect. Thus, although relatively reassuring, the limited ability to detect very rare events should also be considered in using these data to assess overall risk of using levofloxacin in children. Despite this, the results reported by Dolecek et al’s trial[12] on gatifloxacin a newer fluoroquinolone, are comparable to the excellent clinical outcomes achieved with ofloxacin in Vietnam in the early 1990s when S. typhi isolates were still susceptible to nalidixic acid [16]. No adverse effect related to gatifloxacin was observed. Another very large comprehensive review[17] including over 7000 children and adolescents who received ciprofloxacin, ofloxacin or nalidixic acid failed to show any association between quinolone use and arthropathy. Three prospective observational studies included in this review [3, 7, 8] suggest that ciprofloxacin may be a safe therapeutic option for newborns with sepsis produced by multiple resistant organisms...In view of this, there seems to be no reason to withhold short courses of ciprofloxacin from neonates when alternative unrestricted therapies are either unavailable or inappropriate.[7] A recent ICHRC review [6] -on which this update is based- indicated, on the basis of numerous paediatric studies worldwide, that fluoroquinolones, particularly ciprofloxacin are safe and they will therefore play an important role in the treatment of a variety of severe paediatric infections where any risk is outweighed by potential benefit. Ciprofloxacin is a particularly useful fluoroquinolone for dysentery and typhoid and a role may emerge for treatment of highly resistant infections in the neonatal period. There is less experience with other fluoroquinolones and in the case of levofloxacin a suggestion of marginally higher rates of arthropathy. Limitations. • The attrition levels of the studies included in this review was large, Ahmed et al reported a death rate of 57% of the neonates enrolled and a dropout level of 13% although the death rate was lower in the ciprofloxacin group. 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 absence of ultrasonographic evidence to support the clinically observed finding s in three of these studies warrants the need of larger and methodologically reliable studies for fluoroquinolone use in neonates • Overall, the validity of the findings of this review is limited by the small sample sizes in the included studies • Some of the studies [3, 8, 12] had a short follow up period compared to the rest and this complicates the comparability among them.. Conclusion There is no evidence that permanent arthritis is induced by quinolone use in humans. All studies utilizing radiographic techniques, or monitoring growth and joints over long time periods have noted only rare development of transient and mild arthralgia or arthritis. Most experience is with Ciprofloxacin which therefore appears safe for use in the paediatric age group. Some data indicate safety in the neonatal period too but more and better data are required for any definitive conclusion. SUMMARY WHAT THIS UPDATE ADDS WHAT IS KNOWN There is no evidence that permanent arthritis is induced by quinolone use in humans. Adverse effects rate for most fluoroquinolones is comparable to other antimicrobial agents, and that most they are mild and transient. This adverse effects profile is acceptable in light of severity of the conditions Most data refer to the safety of Ciprofloxacin in children Fluoroquinolones cannot be considered interchangeable in terms of efficacy or tolerability and safety; Safety data of each drug varies. Levofloxacin has the highest rates of adverse effects-particularly musculoskeletal and the probability of them developing increased with time-after exposure- within 1 year. However they are mild and transient and resolved without sequelae within a year. Ciprofloxacin may be a safe therapeutic option for newborns with sepsis produced by multiply resistant organisms especially where REFERENCES [1] Ball P. The quinolones: History and overview The Quinolones3rd ed San Diego, Calif: . 2000. [2] Dagan R. Fluoroquinolones in paediatrics‐‐1995. Drugs. 1995;49 Suppl 2:92‐9. [3] Singh UK, Sinha RK, Prasad B, Chakrabarti B, Sharma SK. Ciprofloxacin in children: is arthropathy a limitation? Indian J Pediatr. 2000 May; 67(5):386‐7. [4] Fish DN. Fluoroquinolone adverse effects and drug interactions. Pharmacotherapy. 2001 Oct;21(10 Pt 2):253S‐72S. [5] Congeni BL, Thomson RB, Jr. Fluoroquinolones: considerations for future use. Pediatr Infect Dis J. 2002 Apr;21(4):345‐6. [6] Mitchell R CN. Are quinolones safe to use in children? International child Health Review Collaboration. 2008. [7] Ahmed AS, Khan NZ, Saha SK, Chowdhury MA, Muslima H, Law P, et al. Ciprofloxacin treatment in preterm neonates in Bangladesh: lack of effects on growth and development. Pediatr Infect Dis J. 2006 Dec;25(12):1137‐41. [8] Chaudhari S, Suryawanshi P, Ambardekar S, Chinchwadkar M, Kinare A. Safety profile of ciprofloxacin used for neonatal septicemia. Indian Pediatr. 2004 Dec;41(12):1246‐51. [9] Drossou‐Agakidou V, Roilides E, Papakyriakidou‐Koliouska P, Agakidis C, Nikolaides N, Sarafidis K, et al. Use of ciprofloxacin in neonatal sepsis: lack of adverse effects up to one year. Pediatr Infect Dis J. 2004 Apr;23(4):346‐9. [10] Noel GJ, Bradley JS, Kauffman RE, Duffy CM, Gerbino PG, Arguedas A, et al. Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders. Pediatr Infect Dis J. 2007 Oct;26(10):879‐91. [11] Leone R, Venegoni M, Motola D, Moretti U, Piazzetta V, Cocci A, et al. Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three italian regions. Drug Saf. 2003;26(2):109‐20. [12] Dolecek C, Tran TP, Nguyen NR, Le TP, Ha V, Phung QT, et al. A multi‐center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PLoS ONE. 2008;3(5):e2188. [13] Forsythe CT, Ernst ME. Do fluoroquinolones commonly cause arthropathy in children? Cjem. 2007 Nov;9(6):459‐62. [14] Mandell L, Tillotson G. Safety of fluoroquinolones: An update. Can J Infect Dis. 2002 Jan;13(1):54‐61. [15] Krasula RW, Pernet AG. Comparison of organ‐specific toxicity of temafloxacin in animals and humans. Am J Med. 1991 Dec 30;91(6A):38S‐41S. [16] Vinh H, Wain J, Vo TN, Cao NN, Mai TC, Bethell D, et al. Two or three days of ofloxacin treatment for uncomplicated multidrug‐resistant typhoid fever in children. Antimicrob Agents Chemother. 1996 Apr;40(4):958‐61. [17] Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone arthropathy in animals versus children. Clin Infect Dis. 1997 Nov;25(5):1196‐204. [18] Childs S. Safety of the fluoroquinolone antibiotics; focus on the molecular structure. Infect Urol 2000;13::3‐10. SUMMARY OF EVIDENCE PAEDIATRIC POPULATION (GENERAL) STUDY DESIGN /SETTING SAMPLE SIZE Dolecek et al 2008 Multicentre open label RCT N = 358 No. of children <15yrs; 109 vs. 101 in treatment and control groups Vietnam 3 hospitals in the south of Vietnam. INCLUSION/EXCLUS ION CRITERIA Patients with clinically suspected or culture confirmed uncomplicated typhoid fever. (Median age =11years) INTERVENTION Oral treatment with either 20 mg/kg azithromycin (n=101) or 10 mg/kg gatifloxacin (n=109) once daily for seven days. Patients were followed up for six months Noel G et al 2007 Argentina , Brazil ,Chile CostaRica Israel ,Mexico Panama and USA Prospective study 87 centers in 8 countries from August ‘02 to May‘06 8 countries N=2233 children Children who took at least 1 dose of levofloxacin or comparator as part of any of the previous efficacy trials described above were eligible children randomized to receive levofloxacin versus nonfluoroquinolone antibiotics were compared and followed up 1 year post therapy. ADVERSE EFFECTS Both treatments were well tolerated. One adverse event related to azithromycin reported, a maculopapular rash. Gastrointestinal side-effects -probably typhoid related were relatively frequent in both treatment arms at the start of treatment. In the gatifloxacin group, one patient experienced vomiting on day 2 & 3 and one patient diarrhoea (4 episodes/day) on day 4 &5 of treatment. These episodes were self-limiting and did not require the interruption of therapy. Safety assessment was based on the incidence of musculoskeletal disorders, relationship to therapy, and severity and on changes in physical exam. Levofloxacin was well tolerated during and for 1 month after therapy but had higher rates of adverse events than other fluoroquinolones. Differences between the AE incidences of reported AE involving weight-bearing joints in levofloxacin group and control group were statistically significant 2 months post therapy (P = 0.03)&1 year post therapy (P= 0.047). Leone et al 2003 Retrospective study Italy Three northern Italian regions. 432 fluoroquinolone reports (all age groups) Spontaneous adverse effects reports collected between January 1999 and December 2001 were analyzed. Complete adverse effects reports between January 1999-December 2001 All ages. Children had lowest reporting rates , along with the lowest consumption, this could however be indicative of absence of adverse effects among children.22.5% involved fluoroquinolones. Most reactions involved the skin (25%) significantly lower (p < 0.01) than other systemic antimicrobials (58.5%). CNS reactions (12.2 vs. 3.6%) musculoskeletal (14.7 vs. 0.3%) & psychiatric (9.3 vs. 1.8%) were significantly higher (p< 0.01). All reports of ADRs occurring in association with fluoroquinolones during the study period were analyzed in detail. Individual safety profiles: ciprofloxacin-more skin reactions noted (p < 0.01), levofloxacin and pefloxacin - musculoskeletal (p < 0.01), Toxic epidermal necrolysis and Stevens-Johnson syndrome were seen only ciprofloxacin. Singh et al 2000 Observational prospective study N=219 Children admitted for a variety of infections Age range (5 -14 days) ciprofloxacin doses: 20 mg/kg/day and 10mg/kg/day orally and intravenously respectively in two divided doses. Physical &lab investigations & ultrasonography done to monitor adverse effects . ADR was observed in 15.98% of the children. and arthropathy observed in 0.9% of children only. The X-rays and M.R.I. of involved joints did not reveal any abnormality either during treatment or six months after discontinuation of therapy. Ciprofloxacin was completed successfully in all other children. PRETERMS AND NEONATES Study Design/ setting Ahmed et al 2006 Bangladesh Chaudhari S.et al 2004 prospective observational study. N = 492 Special Care Nursery, Dhaka (Children) Hospital Prospective observational study Neonatal ICU & follow-up Clinic, India Sample size N N=60 Inclusion/Exclusion criteria INTERVENTIONS ADVERSE EFFECTS Newborn infants <72 hours old and (preterm neonates; <33 weeks) Excluded: major congenital anomaly, generalized skin disease, ciprofloxacin for ≥ 5 days (n=92) Other antibiotics, mainly cefotaxime, gentamicin & ampicillin.(n=400) Physical examination normal in both groups during follow up. No evidence of acute joint toxicity in form of swelling, tenderness or restricted movement during or after treatment. No joint deformities noted. Similar weight, length or head circumference in both groups at any of the ages studied. Normal development was observed in 35.6%, mild impairments found in 41.1% and serious impairments in 23.3%. No differences in development (physical and cognitive) between the groups. Treatment with ciprofloxacin started between the 3rd &16th days of age. structural defect >5% BSA &admission for major surgery. Length of treatment (range, 5-17days). No side effects detected during treatment. Neonates with septicemia (Age not clear) Ciprofloxacin 20 mg/kg in 2 divided doses as a slow intravenous infusion over a period of 30 minutes, for 14 days (n=30) vs. Other antibiotics (cefotaxime, amikacin), enrolled for comparison (n = 30) Treatment with ciprofloxacin started on days 5-13 No difference noted in the mean serum electrolytes, hepatic, renal and hematologic parameters of the two groups. Serial ultrasonography of knee cartilage after 1 and 6 months showed no difference in the two groups. Increase in femoral cartilage-78.8% & 78.4% ( mean longitudinal area) after 6 months in the study group & control group respectively. Tibial cartilage - no difference in the % increase in size in both groups at the end of 6 months. After control for birth weight & gestation, cartilage size was not affected by ciprofloxacin. LO E Drossou et al 2004 Greece Prospective observational study Neonatal ICU N =216 Admitted neonates with proven/ probable sepsis; The age range 14±19 (range, 1 to 44) days and 12 ±8 (range, 1 to 31) Excluded : Any deaths ≥15th day after initiation or failure to complete the lab follow-up. Ciprofloxacin was administered in a dosage of 10 mg/ kg/day in 2 divided doses (N=116 [89 preterm; 27 term]) vs A broad range of antimicrobials (N=100 [88 preterm; 12 term]) [ampicillin penicillin gentamicin/amikacin imipenem,vancomycin amphotericin B metronidazole and rimethoprim-sulfamethoxazole] No significant differences in the hematologic indices and the biochemical markers of hepatic and renal function in the two groups Although no ultrasound and MRI of the joints was performed, no clinical evidence of arthropathy was observed during either the initial hospitalization or follow-up. One neonate from each group developed greenish discoloration of the teeth during 1st year of life. Growth rate was comparable in the two groups studied
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