Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines Geneva, 29 September to 3 October 2008

1. Summary statement of the proposal for inclusion, change or deletion

Currently there are no oral on the list of essential medicines for children, although these are widely used in community out patient practice. Hence the subcommittee on selection and use of essential medicines recommended that a full review and application be submitted for including an oral in the list. Accordingly, this application is to include cephalexin, a first generation cephalosporin. Cephalexin, active against Gram positive cocci like Staphylococcus aureus and Streptoccus pyogenes and a few gram negative bacilli, is useful in treating several common community acquired infections in children. Other oral first generation cephalosporins like and cefodroxil, also have similar activity but are more expensive. The antibacterial spectrum of second generation oral cephalosporins, and , is similar to that of the first generation drugs, but with lesser activity against S aureus and better activity against H influenzae and Moraxella. Their indications for use are limited compared to first generation cephalosporins. In addition, cefaclor can cause protracted skin reactions especially in children. axetil, another second generation oral cephalosporin is poorly absorbed and needs to be given with food. Third generation oral cephalosporins and proxetil are more recent introductions with extended spectrum of activity against most bacterial pathogens causing community acquired respiratory infections and skin and soft tissue infections (SSTI). These are however several times more expensive than cephalexin. International availability may also be an issue. Cephalexin has been in use for decades. Adverse events are rare. Formulations suitable for children are available. Palatability is also documented. Evidence based indications for cephalexin use include SSTI caused by susceptible , UTI caused by susceptible bacteria and Streptococcal . It can also be used to complete therapy following initial parenteral antibacterial therapy. There is no evidence to support its use in treating purulent rhinitis, sinusitis or or for its prophylactic use to prevent skin and soft tissue infections. Prevalence of SSTI and UTI caused by bacteria resistant to this is increasing. Its efficacy

1 for preventing sequel like rheumatic fever is not proven. For the three indications mentioned above, other oral medicines with equal or better clinical efficacy are presently listed. Cephalexin is widely used in paediatric out patient practice for non severe infections. In order to prevent rapid emergence of resistance to this and related drugs, it is important to restrict its use only to treatment of infections where antibacterial therapy is indicated and where cephalexin is the appropriate choice.

Summary of issues to be considered for including cephalexin in the EML for children In favour Concern General • Good spectrum • Likely to be misused and so • Formulations chance of driving resistance rates • Palatability high • Few adverse events • Less expensive • International availability Skin and soft • Clinically not inferior to other • Increasing resistance (>50% tissue oral and topical treatment MRSA in some areas) infections • Recommended in guidelines • Other inexpensive oral therapies available UTI • E coli are susceptible • > 25% in vitro resistance in some • Clinical efficacy areas preventing empirical use • No recent clinical trials Respiratory • Proven effective for • No evidence on ability to prevent infection Streptococcal pharyngitis rheumatic fever • No evidence for utility in other lower and upper respiratory infections Prophylactic • Limited use for UTI • No evidence for skin and use superficial infections

2 2. Name of the focal point in WHO submitting or supporting application

3. Names of organisations consulted and or supporting the application

4. International non-propriety name (INN generic name) of the medicine Cephalexin

5. Formulation proposed for inclusion – paediatric Capsules – 250mg tab-cap Suspension or powder to be reconstituted with water – 125mg/5ml or 125mg/ml

6. International availability – sources, if possible manufacturers 250 mg tab-cap – UNFPA, IMRES, MEDS, DURBIN, JMS, ORBI, ACTION 125mg/ml – MEDS 125mg/5ml - UNFPA

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group As individual drug (belonging to first generation cephalosporins)

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population Cephalexin is used for the treatment of skin and soft tissue infections, urinary tract infections (UTI) and different types of upper and lower respiratory infections in children. a. Skin and soft tissue infections A variety of SSTI affect children and include impetigo, cellulites, erysipelas, folliculitis and abscesses. Skin infections are the most common bacterial infections seen in children seeking primary care [1, 2]. Impetigo is a contagious infection affecting mostly 2-5yr old children [1]. Incidence is higher in areas with poor hygiene and overcrowding [1]. Data from the UK show that the annual incidence of impetigo in children seen in primary practice is 2.8% in < 4 yrs and 1.6% in those between 5-14yrs [3]. In a study done in children and

3 youths (median age 5.3 yrs) in Australian aboriginal communities, where skin infections are very common, impetigo accounted for 65% of skin infections[4]. Nonbullous impetigo is most common and accounts for about 70% of paediatric cases[5]. Diagnosis is usually made clinically [1]. Gram stain and culture help in identifying the causative organism [1]. While simple infections can be managed with topical therapy, more extensive infections require oral therapy. also occurs in children frequently, usually following a break in the skin. Prompt antibiotic therapy is required [5]. S aureus and S pyogenes are the most common causative agents of these infections [1, 2, 4, 5]. Cephalexin is active against susceptible S aureus (irrespective of penicillinase production) and streptococci [5-8] It is therefore recommended in children for the treatment of impetigo and cellulitis requiring systemic antimicrobial therapy and also for other skin and soft tissue infections caused by staphylococci or streptococci and surgical site infections following non intestinal surgeries and in areas away from perineum and axilla[9]. Cephalosporins have no action on methicillin resistant S aureus (MRSA). Prevalence of community acquired MRSA infections is increasing [10]. A study in the US shows that community acquired MRSA infection occurs in 18-25 individuals per 100000 population;.77% of these had SSTI [11]. The incidence is higher in children below 2 yrs of age [11]. Data from other areas also show that prevalence of MRSA in SSTI can be well above 50% [12, 13]. Although treatment failures can be expected in such cases, reports based on clinical observations from some centres show no adverse outcomes in patients treated with drugs not useful against MRSA [11, 14]. However, others recommend specific anti MRSA therapy in such cases [15]. Cephalexin was the most used oral antibiotic for non facial cellulitis in children in a study in a paediatric surgery emergency department [16]. For periorbital and orbital cellulitis following trauma also, first generation cephalosporins is recommended as one of the alternatives [17]. Cephalexin is not useful for treating necrotising infections and gas gangrene. It is not generally recommended for infections associated with bites. Other cutaneous infections like anthrax require specific therapies for the causative agents. b. UTI Cephalexin has action against Gram negative bacilli like E coli, and Klebsiella spp[6, 7], which are the most frequent causes of community acquired UTI. Therefore, it can be

4 used as one of the alternative antimicrobials in treating UTI in children usually those not requiring inpatient care [18, 19]. It is not a preferred option for prophyaxis of UTI in children but can be used if nitrofuantoin or cotrimoxazole cannot be tolerated [19]. Prevalence of bacterial resistance to cephalosporins is increasing and more than 25% of E coli causing UTI in children are resistant to first generation cephalosporins in many areas [20-22]. Hence cephalexin is better used for UTI only after culture and susceptibility testing. Cephalexin is not useful for UTI due to most other Gram negative bacilli and in nosocomial infections. Enterococci are also not susceptible. Data on proportion of children with UTI receiving this drug currently could not be obtained. c. Respiratory tract infections The only evidence based indication is tonsillopharyngitis caused by S pyogenes. It is recommended for use as an alternative in children allergic to , developing streptococcal sore throat [23-25] and is FDA approved for this indication [23]. It can also be used for persistent S pyogenes throat infections [23]. Although there is no evidence to recommend its use for other respiratory infections, it is used widely in community out patient practice for all types of upper and lower respiratory tract infections including those in children [26] since it has action on most agents causing community acquired lower and upper respiratory infections like pneumoinae (except penicillin resistant S pneumoniae), Haemophilus influenzae, Moraxella (Branhamella) catarrhalis and Streptococcus pyogenes [6, 7], It does not form part of currently accepted guidelines for the treatment of sinusitis, acute or chronic otitis media or lower respiratory infections. d. Other infections Cephalexin may be effective in treating infections associated with external pin fixation in children [27]. For uncomplicated osteomyelitis, it can be used for oral therapy following parenteral therapy in children [28].

9. Treatment details (dosage, regimen, duration, reference to existing WHO or other guidelines, need for special diagnostic or treatment facilities and skills) Cephalexin is administered orally without regard to meals, is acid-stable, and rapidly absorbed from the GI tract [6, 7]. Following a 250 or 500 mg oral dose of cephalexin, average peak serum concentrations of 9 or 15—18 mcg/ml, respectively, are achieved

5 within 1 hour and mean serum concentrations decline to 1.6 or 3.4 mcg/ml, respectively, at 3 hours post-dose. Cephalexin is distributed into most body tissues and fluids but does not reach therapeutic levels within the CSF. Cephalexin is largely excreted unchanged into the urine which leads to high urinary concentrations. Specific data related to children and neonates could not be obtained. The usual recommended dose for susceptible infections is 25 to 50mg/kg/day in divided doses. For streptococcal sore throat, twice daily dosing for 10 days is recommended [24]. For skin and soft tissue infections, four doses per day [9] for 3-14 days is required. For UTI, four doses per day for 7-14 days is recommended [19]. For UTI prophylaxis, 12.5 mg/kg as single dose at night [29] is used. Guidelines • Pocket book of hospital care for children. Guidelines for the management of common illnesses with limited resources, World Health Organisation, 2005[18] • Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Infectious Diseases Society of America - Medical Specialty Society. 2005 [9] • Diagnosis and treatment of respiratory illness in children and adults Institute for Clinical Systems Improvement (ICSI). 1994 Jun (revised 2007 Jan) [23] • Sore throat and . Finnish Medical Society Duodecim.Evidence-Based Medicine [Internet]. Helsinki, Finland: Wiley Interscience. John Wiley & Sons, 2007 [25] • Evidence-based care guideline for medical management of first urinary tract infection in children 12 years of age or less. Cincinnati Children's Hospital Medical Center. 2006 [19].

10. Summary of comparative effectiveness in a variety of clinical settings: Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data) The Cochrane library was searched for reviews and other clinical trials using cephalexin for various indications. A Medline search was also done for studies documenting clinical efficacy using cephalexin/ and trial as search terms. In general there was paucity of clinical trials, especially recent ones and those evaluating cephalexin in children. Most trials showed non inferiority as compared to other drugs.

6

SSTI A Cochrane review (2003) on impetigo showed that for non bullous impetigo, topical treatment with mupirocin brings about better cure rates as compared to placebo ( OR 6.49; 95% CI 3.93 – 10.73) [8]. There were no significant differences between mupirocin or oral therapy with cephalexn or other oral cephalosporins [8]. For bullous impetigo, there was no significant difference between cephalexin and (OR 3.39; 95 % CI 0.62 – 18.49) [8]. For secondary impetigo, there was no difference between cephalexin and enoxacin[8]. There was insufficient data to understand recurrence rates and development of bacterial resistance. Studies where cephalexin was used are shown in table 1. Although recent in vitro data suggest superiority of other oral cephalosporins [30] for this indication, clinical trials show that Cephalexin is still effective in treating uncomplicated skin and soft tissue infections [31] and secondary infections following trauma [32]and dermatitis [33]. The latter two trials however, show that topical therapy can be equally effective. A recent trial on management of abscesses shows that following incision and drainage cephalexin therapy and placebo had similar out comes [34] in a population with high incidence of MRSA. Treatment failure was recorded in 8.9% of children with cellulitis treated with cephalexin and was similar to those treated with and probenicid [35]. Tonsillopharyngitis Clinical trials show that cephalexin can eradicate S pyogenes from throat and can bring about clinical cure comparable to penicillin [36, 37]. However, evidence on its ability to prevent rheumatic fever is inadequate. Treatment failures can occur, but is less than that following treatment with [38]. For sinusitis, have only a limited role [39]. Cephalosporins have no proven efficacy over for this indication. Cephalexin is not FDA approved for this indication [23]. UTI Earlier studies showed that cephalexin is useful in treating UTI [40, 41]. However, prevalence of bacterial resistance to cephalexin has increased since then. Studies using cephalexin for treatment of infections in children are summarised in table 2 and other recent studies in table 3.

7 11. Summary of comparative evidence on safety Adverse reactions are rare with first generation cephalosporins [42]. Product literature on Keflex state that safety and effectiveness have been established in children using suspensions and capsules [7]. The important probable adverse reaction is , but is very rare. About 5 - 10% of individuals hypersensitive to penicillin can have hypersensitivity to cephalosporins [6, 29, 42]. can occur in 0.0001% to 0.1% of individuals. Rash is more common but occurs only in <2% [42]. Most common adverse effects are GI related and occur in about 5%[42]. Diarrhoea is most common. Nausea vomiting, dyspepsia and gastritis can occur. These events may be severe enough to discontinue therapy. Mild to severe antibiotic associated diarrhoea is reported [29]. Intestinal and vaginal candidiasis is also a possibility [42]. Cholestatic is also described. [29, 43] Since these drugs are primarily eliminated through kidneys, dosage needs to be modified in case of renal impairment [29]. Cephalosporins can cause a fall in prothrombin activity and so those at risk should be monitored [7]. These drugs are also reported to trigger seizures and cause sleep disturbances and hallucinations. Abnormalities like elevated bilirubin, elevated LDH, pancytopenia etc are also reported [7, 29]. Renal clearance of metfromin can be delayed. Cephalexin is inhibited by Cephalosporin use can cause false positive . This can also occur in new born babies of mothers on cephalosporins. It can also cause a false positive glucose in urine test [7].

12. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group As per International Drug Price Indicator Guide, a range of prices are there. Median prices in US $ is shown below. Cephalexin 250 mg capsule - 0.043/capsule 125mg/ml suspension – 0.0076/ml 125mg/5ml suspension– 0.0070/ml

8 Cefuroxime 250mg cap 0.2381/cap 250 mg/5ml 0.015/ml 125 mg/5ml 0.0127/ml 500 mg tab - cap 0.09/cap Cefradine is not listed in the drug price indicator guide Cefaclor is not listed in the drug price indicator guide Cefpodoxime is not listed in the drug price indicator guide According to BNF C, Cephalexin - 21 cap pack is approx £4, 125mg/5 ml 100 ml-£ 3 Cefradine – 250 mg 20 cap – £4.26, 250 mg/5ml 100 ml £4.22 Cefpodoxime - 10 tab pack £10, 100ml £12 Cefprozil. 20 tab – £14.95, 250mg/5 ml 100 ml – £15.22 Cefaclor -50 cap pack £26, 100 ml £7.5 Cefadroxil . 20 cap pack £5.64, 125mg/5ml 60 ml – £1.75

13. Comparative cost effectiveness presented as range of cost per routine out come (cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, cost per quality adjusted life years gained, if possible and relevant) Therapy for 10 days with Cephalexin 250 mg 4 times a day - Approximately $1 – 2 Using suspension – approx $ 3 This is the least expensive oral cephalosporin 14. Summary of regulatory status Cephalexin is FDA approved. The approved label recommends it for use in children BNF C recommends it for use in children 15. Availability of pharmacopoeial standards Reference standards and monographs are listed in European and US pharmacopoeia

9 16. Proposed text for the WHO Model Formulary Cephalexin Cephalexin is an oral first generation cephalosporin with good activity against methicillin susceptible S.aureus and streptococci. It also has activity against H influenzae, penicillin susceptible S pneumoniae and some E coli and Klebsiella spp Tablets/ capsules 250mg Oral suspensions 125mg/5ml and 125mg/ml Uses in children 1. Infections of skin and related structures caused by susceptible bacteria - in those requiring systemic antibiotics, as an alternative to penicillin group of drugs. 2. UTI caused by susceptible bacteria – to be used based on susceptibility data. 3. Streptococcal tonsillo pharyngitis in children allergic to penicillin, as an alternative to Caution

• To check emergence and spread of resistance, use only for infections strongly suspected or proven to benefit from cephalexin. Inform patients about appropriate use

• There is insufficient data on its ability to prevent rheumatic fever/carditis. Contraindications Proven immediate hypersensitivity to penicillin or . Precautions Hypersensitivity reactions can occur in individuals with penicillin hypersensitivity Super infection with non susceptible microorganisms can occur during therapy The dose has to be reduced in renal impairment. Can cause false positive Coombs test results and urine glucose results Dosage Children Dose Frequency Treatment of infection 25 -50 mg/kg/day 2-4 divided doses Prophylaxis for UTI 12.5 mg/kg (max 125mg) at night Adverse reactions Adverse reactions are rare. GI related symptoms like nausea, vomiting and diarrhoea are the commonest Allergic rash and anaphylaxis can occur. Confusion can follow large doses in patients with renal impairment

10

References

1. Cole, C. and J. Gazewood, Diagnosis and treatment of impetigo. Am Fam Physician, 2007. 75(6): p. 859-64. 2. Fleming, D.M., A.J. Elliot, and H. Kendall, Skin infections and antibiotic prescribing: a comparison of surveillance and prescribing data. Br J Gen Pract, 2007. 57(540): p. 569-73. 3. George, A. and G. Rubin, A systematic review and meta-analysis of treatments for impetigo. Br J Gen Pract, 2003. 53(491): p. 480-7. 4. Valery, P.C., et al., Skin infections among Indigenous Australians in an urban setting in Far North Queensland. Epidemiol Infect, 2007: p. 1-6. 5. Jacobs, M.R., R.N. Jones, and P.A. Giordano, Oral beta-lactams applied to uncomplicated infections of skin and skin structures. Diagn Microbiol Infect Dis, 2007. 57(3 Suppl): p. 55S-65S. 6. Manosuthi, W., et al., susceptibilities of Cryptococcus neoformans cerebrospinal fluid isolates and clinical outcomes of cryptococcal in HIV-infected patients with/without fluconazole prophylaxis. J Med Assoc Thai, 2006. 89(6): p. 795-802. 7. Keflex label. Advancis Pharmaceutical Corporation, USA, 2005. 8. Koning, S., et al., Interventions for impetigo. Cochrane Database of Systematic Reviews , Issue 2. Art. No.: CD003261., 2003. 9. Stevens DL, et al., Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis, 2005(41): p. 1373-406. 10. Cohen, P.R., Community-acquired methicillin-resistant Staphylococcus aureus skin infections: implications for patients and practitioners. Am J Clin Dermatol, 2007. 8(5): p. 259-70. 11. Fridkin, S.K., et al., Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med, 2005. 352(14): p. 1436-44. 12. Weigelt, J., et al., Linezolid versus in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother, 2005. 49(6): p. 2260-6. 13. Moran, G.J., et al., Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med, 2006. 355(7): p. 666-74. 14. Young, D.M., et al., An epidemic of methicillin-resistant Staphylococcus aureus soft tissue infections among medically underserved patients. Arch Surg, 2004. 139(9): p. 947-51; discussion 951-3. 15. Ruhe, J.J., et al., Community-onset methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: impact of antimicrobial therapy on outcome. Clin Infect Dis, 2007. 44(6): p. 777-84. 16. Khangura S, et al., Management of cellulitis in a pediatric emergency department. Pediatr Emerg Care, 2007. 23(11): p. 805-11. 17. Hennemann, S., et al., Clinical inquiries. What is the best initial treatment for orbital cellulitis in children? J Fam Pract, 2007. 56(8): p. 662-4. 18. WHO, Chapter 6. Fever. Pocket book of hospital care for children Guidelines for the management of common illnesses with limited resources, 2005. 19. Evidence-based care guideline for medical management of first urinary tract infection in children 12 years of age or less. Cincinnati Children's Hospital Medical Center., 2006.

11 20. Mehr, S.S., C.V. Powell, and N. Curtis, Cephalosporin resistant urinary tract infections in young children. J Paediatr Child Health, 2004. 40(1-2): p. 48-52. 21. Sakran, W., et al., [Community acquired urinary tract infection among hospitalized children in northern Israel: pathogens, susceptibility patterns and urinary tract anomalies]. Harefuah, 2003. 142(4): p. 249-52, 320, 319. 22. Prais, D., et al., Bacterial susceptibility to oral antibiotics in community acquired urinary tract infection. Arch Dis Child, 2003. 88(3): p. 215-8. 23. Diagnosis and treatment of respiratory illness in children and adults. Institute for Clinical Systems Improvement (ICSI). 1994 Jun (revised 2007 Jan). 24. Acute pharyngitis in children. Michigan Quality Improvement Consortium., 2007. 25. Sore throat and tonsillitis. Finnish Medical Society Duodecim.Evidence- Based Medicine [Internet]. Helsinki, Finland:, 2007(Wiley Interscience. John Wiley & Sons). 26. Beilby, J., et al., Effect of changes in antibiotic prescribing on patient outcomes in a community setting: a natural experiment in Australia. Clin Infect Dis, 2002. 34(1): p. 55-64. 27. Gordon, J.E., et al., Pin site care during external fixation in children: results of a nihilistic approach. J Pediatr Orthop, 2000. 20(2): p. 163-5. 28. Bachur, R. and Z. Pagon, Success of short-course parenteral antibiotic therapy for acute osteomyelitis of childhood. Clin Pediatr (Phila), 2007. 46(1): p. 30-5. 29. British National Formulary for Children. 2006. 30. Jones, R.N. and H.S. Sader, Update on the cefdinir spectrum and potency against pathogens isolated from uncomplicated skin and soft tissue infections in North America: are we evaluating the orally administered cephalosporins correctly? Diagn Microbiol Infect Dis, 2006. 55(4): p. 351-6. 31. Giordano, P.A., et al., Cefdinir vs. cephalexin for mild to moderate uncomplicated skin and skin structure infections in adolescents and adults. Curr Med Res Opin, 2006. 22(12): p. 2419-28. 32. Free, A., et al., Retapamulin ointment twice daily for 5 days vs oral cephalexin twice daily for 10 days for empiric treatment of secondarily infected traumatic lesions of the skin. Skinmed, 2006. 5(5): p. 224-32. 33. Parish, L.C., et al., Topical retapamulin ointment (1%, wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial. J Am Acad Dermatol, 2006. 55(6): p. 1003-13. 34. Rajendran, P.M., et al., randomized, double-blind, placebo-controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother, 2007. 51(11): p. 4044-8. 35. Khangura, S., et al., Management of cellulitis in a pediatric emergency department. Pediatr Emerg Care, 2007. 23(11): p. 805-11. 36. Disney, F.A., et al., Cephalexin and penicillin in the treatment of group A beta-hemolytic streptococcal throat infections. Am J Dis Child, 1992. 146(11): p. 1324-7. 37. Curtin, C.D., et al., Efficacy of cephalexin two vs. three times daily vs. cefadroxil once daily for streptococcal tonsillopharyngitis. Clin Pediatr (Phila), 2003. 42(6): p. 519-26.

12 38. Casey, J.R. and M.E. Pichichero, Symptomatic relapse of group A beta- hemolytic streptococcal tonsillopharyngitis in children. Clin Pediatr (Phila), 2007. 46(4): p. 307-10. 39. Arroll B and T. Kenealy., Antibiotics for the common cold and acute purulent rhinitis. Cochrane Database of Systematic Reviews , Issue 3. Art. No.: CD000247, 2005. 40. Russo, R.M., et al., The comparative efficacy of cephalexin and sulfisoxazole in acute urinary tract infection in children. Clin Pediatr (Phila), 1977. 16(1): p. 83-4, 89-91. 41. Helin, I., Three-day therapy with cephalexin for lower urinary tract infections in children. Scand J Infect Dis, 1984. 16(3): p. 305-7. 42. Mitropoulos, I.F., J.C. Rotschafer, and K.A. Rodvold, Adverse events associated with the use of oral cephalosporins/. Diagn Microbiol Infect Dis, 2007. 57(3 Suppl): p. 67S-76S. 43. Australian medicines hand book. 2006, The Royal Australian College of General Practitioners; Australasian Soceity of Clinical ans Experimental Pharmacologists and Toxicologists;Pharmaceutical Soceity of Australia. 115- 116. 44. Stillerman, M., et al., Comparison between cephalexin two- and four-time per day regimens in group A streptococcal pharyngitis. Clin Pediatr (Phila), 1984. 23(6): p. 348-51. 45. Tarpay, M.M., et al., The extended microbiology of group A streptococcal pharyngitis. Observations during a double-blind controlled study of cephalexin twice versus four-times daily. Infection, 1984. 12(3): p. 181-4. 46. Matsen, J.M., et al., Use of available dosage forms of cephalexin in clinical comparison with phenoxymethyl penicillin and benzathine penicillin in the treatment of streptococcal pharyngitis in children. Antimicrob Agents Chemother, 1974. 6(4): p. 501-6. 47. Tack, K.J., et al., Study of use of cefdinir versus cephalexin for treatment of skin infections in pediatric patients. The Cefdinir Pediatric Skin Infection Study Group. Antimicrob Agents Chemother, 1997. 41(4): p. 739-42. 48. Linder, C.W., et al., Comparative evaluation of cefadroxil and cephalexin in children and adolescents with pyodermas. Cefadroxil Once Daily Pyoderma Study Group. Clin Ther, 1993. 15(1): p. 46-56. 49. Mallory, S.B., Azithromycin compared with cephalexin in the treatment of skin and skin structure infections. Am J Med, 1991. 91(3A): p. 36S-39S. 50. Demidovich, C.W., et al., Impetigo. Current etiology and comparison of penicillin, erythromycin, and cephalexin therapies. Am J Dis Child, 1990. 144(12): p. 1313-5. 51. Mouallem, R., Comparative efficacy and safety of cephradine and cephalexin in children. J Int Med Res, 1976. 4(4): p. 265-71. 52. Stechenberg, B.W., et al., Cephalexin compared to treatment of otitis media. Pediatrics, 1976. 58(4): p. 532-6. 53. Parish, L.C., et al., Moxifloxacin versus cephalexin in the treatment of uncomplicated skin infections. Int J Clin Pract, 2000. 54(8): p. 497-503.

13 Table 1 Studies included in Cochrane review (3)

Participants Interventions Outcomes Notes Bass 1997 Outpatients 1. cephalexin 50 mg/kg/day in 3 dd + placebo 8-10 days, Lost to follow up Hawaii only impetigo ointment, 10 days cure (LTFU) 6/32, (5 Allocation av age 3.8 yrs, 2.mupirocin ointment 2%, 3td + liquid oral placebo mupirocin) concealment - B S. aureus 41/48 3. ointment 500 units/g, 3td + liquid oral Side effects- not placebo reported Demidovich Outpatients, only 1.penicillin V 40-50 mg/kg/day in 3 dd, 10 days 8-10 days, LTFU: 2/ 75 1990 Hawaii impetigo 2.cephalexin 40-50 mg/kg/day in 3 dd, 10 days failed SE: nil reported Allocation 5 m-15 yrs (av 3 yrs) 3.erythromycin 30-40 mg/kg/day in 3 dd, 10 days concealment - B S. aureus 45/73, GABHS 6/73, both 14/73, Dillon 1983 only impetigo 1. cephalexin 50 mg/kg/day in 2 dd (>20 kg: 500mg Prompt LTFU: C: 5/40, USA (bullous 57/70) 2td) cure D: 3/38 Allocation av age 3.2 yrs, MF 41/37, 2. dicloxacillin 15 mg/kg/day in 4 dd (>40 kg: 125 concealment - B S. aureus: 64/70 mg 4td) Fujita 1984 outpatients 1.enoxacin 500 mg, 3td cured/imp LTFU 20/224 Japan Age 16-84 yrs 2. cephalexin 500 mg 2td roved SE: E 11 of 113, Allocation M/F 120/84 (double dummy) C 4 of 110 concealment - B (mainly GI) Hains 1989 outpatients child hospital 1.cefadroxil 30 mg/kg/day, max 1 g., in 1 dd, 10 14 days, SE none reported USA only impetigo days cured Allocation 1-18 yrs, S. aureus 35%, 2.cephalexin 30 mg/kg/day, max 1 g., in 2 dd, 10 concealment - B GABHS 12% both 54% days Kiani 1991 admitted + outpatients 1. azithromycin 500 mg day 1, 250 mg, day 2-5, 5 11 days, 253 entered, 179 multicentre USA S. aureus 152/179, days cured/imp evaluable (41

14 Participants Interventions Outcomes Notes Allocation B S. pyogones 29/179 2. cephalexin 500 mg twice daily, 10 days roved LTFU, 21 R bact) Tack 1997 0-13 yrs (median 5.4) 1.cefdinir 7 mg/kg , twice a day 10 days 7-14 day, multicentre US M/F 217/197 2.cephalexin 10 mg/kg four times a day 10 days cure Allocation - C S. aureus 284/394 Tack 1998 13-88 yrs, M/F 564/388 1. cefdinir caps 300 mg, 2 times a day, 10 days 7-16 days, included only multicenter USA (all participants), S. 2. cephalexin caps 500 mg, 4times a day, 10 days cure/impr those with Allocation aureus 308/382 (all oved pathogen S to concealment - B participants) both study drugs

15

Table 2Trials using cephalexin in children

Study Methods Participants Interventions Outcome Adverse events Tonsillopharyngitis Disney Randomized, double- Tonsillitis or 1.cephalexin Clinical failure penicillin-8% FA[36], blind, crossover study pharyngitis and 2. penicillin (27 mg/kg cephalexin 3% 1992, USA Multicentric throat cultures per day) Four doses for Bacteriologic failure penicillin 11%, with GABHS 10 days. cephalexin 7% Children and clinical relapse plus asymptomatic adolescents bacteriologic failure penicillin 19%, (525) cephalexin 10% Curtin C, Prospective open- Children with 1.Cephalexin twice (54) at 21 +/- 4 days Younger age was 2003[37] label, observational acute tonsillo- 2. three times daily (94) Bacteriologic cure: significantly cohort study pharyngitis with 3. Cefadroxil once daily cephalexin twice -87%, 3 times daily- associated with Intention to treat laboratory (70) 81%, cefadroxil - 81% (p=0.61). bacteriologic confirmed Clinical cure: (p=0.04) and GABHS cephalexin twice- 91%; 3 times daily - clinical (p=0.01) 86%; cefadroxil - 84% (p=0.56). failure Stillerman Double-blind, GABHS 1.Cephalexin 1.0/ 0.5 g Follow-up cultures - 2 to 6 and 12 to M[44] , randomized pharyngitis daily bid (82) 16 days after treatment 1984, Multicenter 2. qid (75) Failure Pediatrics for 10 to 14 days bid 7.3 percent, qid 5.3 percent

Tarpay Double-blind GABHS 1.cephalexin b.i.d. Clinical improvement - 98% MM [45], controlled study pharyngitis in 2.q.i.d. bacteriologic cure - 92%. 1984 USA 65 children 3 bacteriologic failures in the q.i.d., and 2 in the b.i.d. treatment groups.

16 Study Methods Participants Interventions Outcome Adverse events Matsen JM Children with 1. cephalexin for10 days Similar cure rates - 96.7, 97.1, and [46] streptococcal (66) 96.4% 1974 pharyngitis. All 2. phenoxymethyl Bacteriological failures - cephalexin 2, but six had penicillin for 10 days one each with oral penicillin and IM GABHS (34) penicillin. isolated from 3. a single injection of throat cultures benzathine penicillin (28) (128). Skin related infections Tack Multicenter Children with 1.Cefdinir, 7 mg/kg twice Microbiologic eradication 16% cefdinir,11% KJ[47], Randomized impetigo and a day (165) Cefdinir 99.4% , Cephalexin 97.4% (P cephalexin (P = 1997 USA Controlled Trial secondary 2.Cephalexin, 10 mg/kg = 0.14). 0.11) investigator-blind infection of four times a day (156), Clinical cure rates Cefdinir 98.3%, diarrhea most preexisting each for 10 days. The Cephalexin 93.8% (P = 0.056). common - dermatitis.(394) most common pathogens 8% cefdinir 4% were S aureus and Strept cephalexin pyogenes Linder[48] Randomized, Pyoderma 1.Cefadroxil single oral Bacteriologic response Compliance 95% 1993, USA Multicenter children and daily dose 30 mg/kg, Statistically greater in the patients cefadroxil, 65% adolescents (1- (156) treated with cefadroxil (96% versus cephalexin (P < 18 years). 2. Cephalexin 30 89%; P = 0.042). 0.0001). S aureus (56%) mg/kg/day in 2 divided Clinical response Adverse events Strept pyogenes doses.(133) cefadroxil-94%, cephalexin 92% - (P were infrequent (39%). for 10 days = 0.476). and mild Mallory Randomized Skin and skin 1. Azithromycin (500 mg Clinical cure Both agents were SB[49] Controlled structure infn on day 1, 250 mg/day on azithromycin - 99%, cephalexin 96% well-tolerated 1991,USA third-party-blinded (148). Mainly S days 2-5) On completion of therapy, both childrens Multicentric aureus and 2. Cephalexin (500 mg treatments had eradicated

17 Study Methods Participants Interventions Outcome Adverse events hospital Strept pyogenes twice daily for 10 days) approximately 98% of pathogens Demidovic Randomized Children with 1.Penicillin V Treatment failure h[50],1990 Controlled clinical impetigo (73) 2.Cephalexin 40 to 50 penicillin V -24%, erythromycin -4% Hawaii Trial (62% - S aureus mg/kg per day and none with cephalexin Follow up examiners only, 19% - S 3. Erythromycin 30 to 40 blinded aureus and mg/kg per day. GABHS, 8% All were given in 3 GABHS only, divided doses for 10 and 11% others) days. Mouallem Randomized, double- Bacterial 1.Cephradine - 25-110 Clinical and bacteriologic responses Both equally safe R [51] blind study infections (lobar mg/kg per day nearly identical in the two groups for use in 1976 or 2. Cephalexin - 25-150 paediatric skin infections) mg/kg per day practice. in children 4 for five to fifteen days. months – 11yrs (162) UTI and others Helin I[41] prospective children with acute 1.Cephalexin, 25-50 Cure rates 90% and 96%, respectively. No side effects 1984 lower urinary tract mg/kg x 3-days (19) Relapse – 2 and 1 respectively in either of the infection 2. Nitrofurantoin, 3-4 Reinfection on follow-up 7-8 months - 2 treatment mg/kg/day x 10 days (24) cephalexin and 4 nitrofurantoin groups. Russo RM Double Children with initial 1. Cephalexin Cephalexin - clinical cure rate 86% Minimal [40], blind, episodes of UTI(100) 2. Sulfisoxazole bacterial cure rate 84% untoward effects 1977 comparative Sulfisoxazole – 82% and 92% . study high rate of failure in Proteus mirabilis infections (4/8) Stechenberg randomized Children with otitis 1. Cephalexin No overall statistically significant BW [52] media Bacteriologic 2. Ampicillin differences; Poor response in 20 on

18 Study Methods Participants Interventions Outcome Adverse events 1976, USA diagnosis by needle cephalexin and 5 on ampicillin. tympanocentesis (179) H influenzae as cause- 50% on cephalexin and none on ampicillin had poor response (P<.05)

Table 3 Recent trials using cephalexin Parish, LC Prospective, Adults with 1. Oral moxifloxacin Clinical outcome evaluated in 351 Adverse events [53] 2000 randomised, uncomplicated skin 400 mg OD for 7 Moxifloxacin as effective as comparable multicentre double-blind infections (401) days cephalexin Most frequent - trial. 2. Cephalexin - 500 Clinically (90% and 91% respectively) moxifloxacin- nausea mg three times daily Bacteriologically eradicating cephalexin- headache for 7 days S aureus (92% and 93%, respectively). Discontinued in 3% Streptococcus spp. (90% and 82%, moxifloxacin 4% respectively). cephalexin treated patients Giordano PA Randomized Adults and 1.cefdinir 300 mg Clinical response – 89% in both Both well tolerated. [31]2006 Investigator adolescents (>13 yrs) twice daily x 10 groups – even those with MRSA diarrhea (10% & 4% USA. blinded with mild to days infections improved p = 0.017), moderate 2. cephalexin 250 mg Cefdinir - convenience higher nausea (3% & 6%, p uncomplicated skin four times daily x Enrollment probably skewed towards = 0.203), vaginal and skin structure 10 days those with abscesses. Incision and mycosis (3% & 6% p infections (391 patients well drainage, spontaneous drainage, and = 0.500). matched) needle aspiration are likely to have contributed to clinical response Free A [32], Randomized patients with 1. topical retapamulin Cure -89.5% in retapamulin; 91.9% Safety similar 2006, USA Controlled secondarily infected 1% twice daily x 5 for cephalexin Noncompliance 8.0% Trial double traumatic lesions days with cephalexin,

19 blind (1904 patients) 2. oral cephalexin, 0.39% with 500 mg twice daily x retapamulin 10 days Parish Randomized patients with 1. topical retapamulin clinical success rates: 85.9% and Both safe and LC[33], 2006 Controlled secondarily infected 1% twice daily x 5 89.7%, respectively tolerated USA Trial dermatitis days 2. oral cephalexin x 10 d Rajendran[34 Randomized, outpatients with skin 1.placebo (84) clinical cure 7 days Antibiotics may be ] double-blind, and soft tissue 2. cephalexin 500 mg Placebo - 90.5% (95% CI 0.82 to unnecessary after placebo- abscesses orally 4 times for 7 0.96) drainage of controlled S. aureus 70.4% days (82) Cephalexin 84.1% (95% CI, 0.74 to uncomplicated skin trial (87.8% MRSA) after incision and 0.91) (difference in the two and soft tissue drainage proportions, P = 0.25). abscesses Casey[38] Retrospective GABHS 1. penicillin, Frequency of symptomatic relapses Symptomatic relapse tonsillopharyngitis 2. , within 5 days of completing therapy after retreatment more 1080 children (2- 3. first-generation Rank-order for failures P, A, 1st Ceph, with P than ceph (P = 18yrs) Ceph β -lactamase stable ( P = .005). .02). 4. β lactamase stable antibiotic all for 10 d

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