Second Meeting of the Subcommittee of the Expert Committee on... Selection and Use of Essential Medicines

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 cephalosporins 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 cephalosporin 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 cefradine and cefodroxil, also have similar activity but are more
expensive. The antibacterial spectrum of second generation oral cephalosporins,
cefaclor and cefprozil, 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. Cefuroxime axetil,
another second generation oral cephalosporin is poorly absorbed and needs to be given
with food. Third generation oral cephalosporins cefdinir and cefpodoxime 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 bacteria, UTI caused by susceptible bacteria and Streptococcal pharyngitis.
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 otitis
media or for its prophylactic use to prevent skin and soft tissue infections. Prevalence
of SSTI and UTI caused by bacteria resistant to this antibiotic is increasing. Its efficacy
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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
General
• Good spectrum
Concern
• Likely to be misused and so
• Formulations
chance of driving resistance rates
• Palatability
high
• Few adverse events
• Less expensive
• International availability
Skin and soft
tissue
infections
• Clinically not inferior to other
oral and topical treatment
• Recommended in guidelines
• Increasing resistance (>50%
MRSA in some areas)
• Other inexpensive oral therapies
available
UTI
• E coli are susceptible
• Clinical efficacy
• > 25% in vitro resistance in some
areas preventing empirical use
• No recent clinical trials
Respiratory
infection
• Proven effective for
Streptococcal pharyngitis
• No evidence on ability to prevent
rheumatic fever
• No evidence for utility in other
lower and upper respiratory
infections
Prophylactic
use
• Limited use for UTI
• No evidence for skin and
superficial infections
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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.
Cellulitis 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 methicillin 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 penicillin, 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
Streptococcus 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 tonsillitis. 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/cefalexin 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.
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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 dicloxacillin (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 cefazolin 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 penicillins [38].
For sinusitis, antibiotics have only a limited role [39]. Cephalosporins have no proven
efficacy over aminopenicillins 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.
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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 hypersensitivity, but is very rare. About 5 10% of individuals hypersensitive to penicillin can have hypersensitivity to
cephalosporins [6, 29, 42]. Anaphylaxis 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
hepatitis 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 excretion is inhibited by
probenecid
Cephalosporin use can cause false positive Coombs test. 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
Cefadroxil
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 erythromycin
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 carbapenems.
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., Antifungal susceptibilities of Cryptococcus neoformans
cerebrospinal fluid isolates and clinical outcomes of cryptococcal meningitis
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 vancomycin 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.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
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.
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.
Prais, D., et al., Bacterial susceptibility to oral antibiotics in community
acquired urinary tract infection. Arch Dis Child, 2003. 88(3): p. 215-8.
Diagnosis and treatment of respiratory illness in children and adults. Institute
for Clinical Systems Improvement (ICSI). 1994 Jun (revised 2007 Jan).
Acute pharyngitis in children. Michigan Quality Improvement Consortium.,
2007.
Sore throat and tonsillitis. Finnish Medical Society Duodecim.EvidenceBased Medicine [Internet]. Helsinki, Finland:, 2007(Wiley Interscience. John
Wiley & Sons).
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.
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.
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.
British National Formulary for Children. 2006.
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.
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.
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.
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.
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.
Khangura, S., et al., Management of cellulitis in a pediatric emergency
department. Pediatr Emerg Care, 2007. 23(11): p. 805-11.
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.
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.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
Casey, J.R. and M.E. Pichichero, Symptomatic relapse of group A betahemolytic streptococcal tonsillopharyngitis in children. Clin Pediatr (Phila),
2007. 46(4): p. 307-10.
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.
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.
Helin, I., Three-day therapy with cephalexin for lower urinary tract infections
in children. Scand J Infect Dis, 1984. 16(3): p. 305-7.
Mitropoulos, I.F., J.C. Rotschafer, and K.A. Rodvold, Adverse events
associated with the use of oral cephalosporins/cephems. Diagn Microbiol
Infect Dis, 2007. 57(3 Suppl): p. 67S-76S.
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. 115116.
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.
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.
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.
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.
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.
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.
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.
Mouallem, R., Comparative efficacy and safety of cephradine and cephalexin
in children. J Int Med Res, 1976. 4(4): p. 265-71.
Stechenberg, B.W., et al., Cephalexin compared to ampicillin treatment of
otitis media. Pediatrics, 1976. 58(4): p. 532-6.
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)
Bass 1997
Hawaii
Allocation
concealment - B
Demidovich
1990 Hawaii
Allocation
concealment - B
Dillon 1983
USA
Allocation
concealment - B
Fujita 1984
Japan
Allocation
concealment - B
Hains 1989
USA
Allocation
concealment - B
Kiani 1991
multicentre USA
Participants
Outpatients
only impetigo
av age 3.8 yrs,
S. aureus 41/48
Outpatients, only
impetigo
5 m-15 yrs (av 3 yrs)
S. aureus 45/73,
GABHS 6/73, both
14/73,
only impetigo
(bullous 57/70)
av age 3.2 yrs, MF 41/37,
S. aureus: 64/70
outpatients
Age 16-84 yrs
M/F 120/84
outpatients child hospital
only impetigo
1-18 yrs, S. aureus 35%,
GABHS 12% both 54%
admitted + outpatients
S. aureus 152/179,
Interventions
1. cephalexin 50 mg/kg/day in 3 dd + placebo
ointment, 10 days
2.mupirocin ointment 2%, 3td + liquid oral placebo
3.bacitracin ointment 500 units/g, 3td + liquid oral
placebo
1.penicillin V 40-50 mg/kg/day in 3 dd, 10 days
2.cephalexin 40-50 mg/kg/day in 3 dd, 10 days
3.erythromycin 30-40 mg/kg/day in 3 dd, 10 days
Outcomes Notes
8-10 days, Lost to follow up
cure
(LTFU) 6/32, (5
mupirocin)
Side effects- not
reported
8-10 days, LTFU: 2/ 75
failed
SE: nil reported
1. cephalexin 50 mg/kg/day in 2 dd (>20 kg: 500mg
2td)
2. dicloxacillin 15 mg/kg/day in 4 dd (>40 kg: 125
mg 4td)
1.enoxacin 500 mg, 3td
2. cephalexin 500 mg 2td
(double dummy)
Prompt
cure
LTFU: C: 5/40,
D: 3/38
cured/imp
roved
1.cefadroxil 30 mg/kg/day, max 1 g., in 1 dd, 10
days
2.cephalexin 30 mg/kg/day, max 1 g., in 2 dd, 10
days
1. azithromycin 500 mg day 1, 250 mg, day 2-5, 5
days
14 days,
cured
LTFU 20/224
SE: E 11 of 113,
C 4 of 110
(mainly GI)
SE none reported
11 days,
cured/imp
253 entered, 179
evaluable (41
14
Allocation B
Tack 1997
multicentre US
Allocation - C
Tack 1998
multicenter USA
Allocation
concealment - B
Participants
S. pyogones 29/179
0-13 yrs (median 5.4)
M/F 217/197
S. aureus 284/394
13-88 yrs, M/F 564/388
(all participants), S.
aureus 308/382 (all
participants)
Interventions
2. cephalexin 500 mg twice daily, 10 days
1.cefdinir 7 mg/kg , twice a day 10 days
2.cephalexin 10 mg/kg four times a day 10 days
Outcomes Notes
roved
LTFU, 21 R bact)
7-14 day,
cure
1. cefdinir caps 300 mg, 2 times a day, 10 days
2. cephalexin caps 500 mg, 4times a day, 10 days
7-16 days,
cure/impr
oved
included only
those with
pathogen S to
both study drugs
15
Table 2Trials using cephalexin in children
Study
Methods
Tonsillopharyngitis
Disney
Randomized, doubleFA[36],
blind, crossover study
1992, USA Multicentric
Participants
Interventions
Outcome
Tonsillitis or
pharyngitis and
throat cultures
with GABHS
Children and
adolescents
(525)
Children with
acute tonsillopharyngitis with
laboratory
confirmed
GABHS
1.cephalexin
2. penicillin (27 mg/kg
per day) Four doses for
10 days.
Clinical failure penicillin-8%
cephalexin 3%
Bacteriologic failure penicillin 11%,
cephalexin 7%
clinical relapse plus asymptomatic
bacteriologic failure penicillin 19%,
cephalexin 10%
at 21 +/- 4 days
Bacteriologic cure:
cephalexin twice -87%, 3 times daily81%, cefadroxil - 81% (p=0.61).
Clinical cure:
cephalexin twice- 91%; 3 times daily 86%; cefadroxil - 84% (p=0.56).
Follow-up cultures - 2 to 6 and 12 to
16 days after treatment
Failure
bid 7.3 percent, qid 5.3 percent
Curtin C,
2003[37]
Prospective openlabel, observational
cohort study
Intention to treat
Stillerman
M[44] ,
1984,
Pediatrics
Double-blind,
randomized
Multicenter
GABHS
pharyngitis
1.Cephalexin 1.0/ 0.5 g
daily bid (82)
2. qid (75)
for 10 to 14 days
Tarpay
MM [45],
1984 USA
Double-blind
controlled study
GABHS
pharyngitis in
65 children
1.cephalexin b.i.d.
2.q.i.d.
1.Cephalexin twice (54)
2. three times daily (94)
3. Cefadroxil once daily
(70)
Adverse events
Younger age was
significantly
associated with
bacteriologic
(p=0.04) and
clinical (p=0.01)
failure
Clinical improvement - 98%
bacteriologic cure - 92%.
3 bacteriologic failures in the q.i.d.,
and 2 in the b.i.d. treatment groups.
16
Study
Matsen JM
[46]
1974
Methods
Skin related infections
Tack
Multicenter
KJ[47],
Randomized
1997 USA Controlled Trial
investigator-blind
Linder[48]
1993, USA
Randomized,
Multicenter
Mallory
SB[49]
1991,USA
childrens
Randomized
Controlled
third-party-blinded
Multicentric
Participants
Children with
streptococcal
pharyngitis. All
but six had
GABHS
isolated from
throat cultures
(128).
Interventions
1. cephalexin for10 days
(66)
2. phenoxymethyl
penicillin for 10 days
(34)
3. a single injection of
benzathine penicillin (28)
Children with
1.Cefdinir, 7 mg/kg twice
impetigo and
a day (165)
secondary
2.Cephalexin, 10 mg/kg
infection of
four times a day (156),
preexisting
each for 10 days. The
dermatitis.(394) most common pathogens
were S aureus and Strept
pyogenes
Pyoderma
1.Cefadroxil single oral
children and
daily dose 30 mg/kg,
adolescents (1- (156)
18 years).
2. Cephalexin 30
S aureus (56%) mg/kg/day in 2 divided
Strept pyogenes doses.(133)
(39%).
for 10 days
Skin and skin
1. Azithromycin (500 mg
structure infn
on day 1, 250 mg/day on
(148). Mainly S days 2-5)
aureus and
2. Cephalexin (500 mg
Outcome
Adverse events
Similar cure rates - 96.7, 97.1, and
96.4%
Bacteriological failures - cephalexin 2,
one each with oral penicillin and IM
penicillin.
Microbiologic eradication
Cefdinir 99.4% , Cephalexin 97.4% (P
= 0.14).
Clinical cure rates Cefdinir 98.3%,
Cephalexin 93.8% (P = 0.056).
16% cefdinir,11%
cephalexin (P =
0.11)
diarrhea most
common 8% cefdinir 4%
cephalexin
Bacteriologic response
Statistically greater in the patients
treated with cefadroxil (96% versus
89%; P = 0.042).
Clinical response
cefadroxil-94%, cephalexin 92% - (P
= 0.476).
Clinical cure
azithromycin - 99%, cephalexin 96%
On completion of therapy, both
treatments had eradicated
Compliance 95%
cefadroxil, 65%
cephalexin (P <
0.0001).
Adverse events
were infrequent
and mild
Both agents were
well-tolerated
17
Study
hospital
Demidovic
h[50],1990
Hawaii
Mouallem
R [51]
1976
Methods
Randomized
Controlled clinical
Trial
Follow up examiners
blinded
Randomized, doubleblind study
UTI and others
Helin I[41]
prospective
1984
Participants
Strept pyogenes
Children with
impetigo (73)
(62% - S aureus
only, 19% - S
aureus and
GABHS, 8%
GABHS only,
and 11% others)
Bacterial
infections (lobar
pneumonia or
skin infections)
in children 4
months – 11yrs
(162)
children with acute
lower urinary tract
infection
Russo RM
[40],
1977
Double
blind,
comparative
study
Children with initial
episodes of UTI(100)
Stechenberg
BW [52]
randomized
Children with otitis
media Bacteriologic
Interventions
twice daily for 10 days)
1.Penicillin V
2.Cephalexin 40 to 50
mg/kg per day
3. Erythromycin 30 to 40
mg/kg per day.
All were given in 3
divided doses for 10
days.
1.Cephradine - 25-110
mg/kg per day
2. Cephalexin - 25-150
mg/kg per day
for five to fifteen days.
1.Cephalexin, 25-50
mg/kg x 3-days (19)
2. Nitrofurantoin, 3-4
mg/kg/day x 10 days (24)
1. Cephalexin
2. Sulfisoxazole
1. Cephalexin
2. Ampicillin
Outcome
approximately 98% of pathogens
Treatment failure
penicillin V -24%, erythromycin -4%
and none with cephalexin
Adverse events
Clinical and bacteriologic responses
nearly identical in the two groups
Both equally safe
for use in
paediatric
practice.
Cure rates 90% and 96%, respectively.
Relapse – 2 and 1 respectively
Reinfection on follow-up 7-8 months - 2
cephalexin and 4 nitrofurantoin
Cephalexin - clinical cure rate 86%
bacterial cure rate 84%
Sulfisoxazole – 82% and 92% .
high rate of failure in Proteus mirabilis
infections (4/8)
No overall statistically significant
differences; Poor response in 20 on
No side effects
in either of the
treatment
groups.
Minimal
untoward effects
18
Study
1976, USA
Methods
Participants
diagnosis by needle
tympanocentesis (179)
Interventions
Outcome
cephalexin and 5 on ampicillin.
H influenzae as cause- 50% on
cephalexin and none on ampicillin had
poor response (P<.05)
Table 3 Recent trials using cephalexin
Adults with
1. Oral moxifloxacin Clinical outcome evaluated in 351
uncomplicated skin
400 mg OD for 7
Moxifloxacin as effective as
infections (401)
days
cephalexin
2. Cephalexin - 500 Clinically (90% and 91% respectively)
mg three times daily Bacteriologically eradicating
for 7 days
S aureus (92% and 93%, respectively).
Streptococcus spp. (90% and 82%,
respectively).
Parish, LC
[53] 2000
multicentre
Prospective,
randomised,
double-blind
trial.
Giordano PA
[31]2006
USA.
Randomized
Investigator
blinded
Adults and
adolescents (>13 yrs)
with mild to
moderate
uncomplicated skin
and skin structure
infections
1.cefdinir 300 mg
twice daily x 10
days
2. cephalexin 250 mg
four times daily x
10 days
(391 patients well
matched)
Free A [32],
2006, USA
Randomized
Controlled
Trial double
patients with
secondarily infected
traumatic lesions
1. topical retapamulin
1% twice daily x 5
days
Clinical response – 89% in both
groups – even those with MRSA
infections improved
Cefdinir - convenience higher
Enrollment probably skewed towards
those with abscesses. Incision and
drainage, spontaneous drainage, and
needle aspiration are likely to have
contributed to clinical response
Cure -89.5% in retapamulin; 91.9%
for cephalexin
Adverse events
Adverse events
comparable
Most frequent moxifloxacin- nausea
cephalexin- headache
Discontinued in 3%
moxifloxacin 4%
cephalexin treated
patients
Both well tolerated.
diarrhea (10% & 4%
p = 0.017),
nausea (3% & 6%, p
= 0.203), vaginal
mycosis (3% & 6% p
= 0.500).
Safety similar
Noncompliance 8.0%
with cephalexin,
19
blind
(1904 patients)
Parish
LC[33], 2006
USA
Randomized
Controlled
Trial
patients with
secondarily infected
dermatitis
Rajendran[34
]
Randomized,
double-blind,
placebocontrolled
trial
outpatients with skin
and soft tissue
abscesses
S. aureus 70.4%
(87.8% MRSA)
Casey[38]
Retrospective
GABHS
tonsillopharyngitis
1080 children (218yrs)
2. oral cephalexin,
500 mg twice daily x
10 days
1. topical retapamulin
1% twice daily x 5
days
2. oral cephalexin x
10 d
1.placebo (84)
2. cephalexin 500 mg
orally 4 times for 7
days (82)
after incision and
drainage
1. penicillin,
2. amoxicillin,
3. first-generation
Ceph
4. β lactamase stable
antibiotic all for 10 d
0.39% with
retapamulin
clinical success rates: 85.9% and
89.7%, respectively
Both safe and
tolerated
clinical cure 7 days
Placebo - 90.5% (95% CI 0.82 to
0.96)
Cephalexin 84.1% (95% CI, 0.74 to
0.91) (difference in the two
proportions, P = 0.25).
Frequency of symptomatic relapses
within 5 days of completing therapy
Rank-order for failures P, A, 1st Ceph,
β -lactamase stable ( P = .005).
Antibiotics may be
unnecessary after
drainage of
uncomplicated skin
and soft tissue
abscesses
Symptomatic relapse
after retreatment more
with P than ceph (P =
.02).
20