Clinical efficacy of cefpodoxime in respiratory tract infection

Journal of Antimicrobial Chemotherapy (2002) 50, Topic T1, 23 27 DOI: 10.1093/jac/dkf805 Clinical efficacy of cefpodoxime in respiratory tract infection Robert Cohen* Department of Microbiology, Intercommunal Hospital of Créteil, Créteil, France Acute otitis media (AOM), sinusitis and tonsillopharyngitis are respiratory tract infections frequently encountered by primary-care physicians. Increasing bacterial resistance, particularly in Streptococcus pneumoniae, which is one of the most important respiratory tract bacteria implicated in community-acquired respiratory tract infections, has led to concern about the current options for empirical antibiotic treatment and has prompted a search for effective alternative treatments. Data from in vitro studies show that cefpodoxime has good activity against the main respiratory tract pathogens, S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes. Clinical studies confirm the efficacy of cefpodoxime in AOM, sinusitis and tonsillopharyngitis. As with all broad-spectrum antibiotics, there is the risk of promotion of bacterial resistance associated with overuse. However, if used with care, cefpodoxime can be considered as an alternative for empirical treatment of bacterial respiratory tract infections encountered in general practice, particularly where penicillins and macrolides have reduced efficacy against the main bacterial pathogens. Introduction Community-acquired respiratory tract infections, in particular acute otitis media (AOM), sinusitis and tonsillopharyngitis, are among the most common reasons for general practice consultation, accounting for more than 50% of paediatric consultations and more than 75% of antibiotic prescriptions for out-patients. 1 The most important bacterial pathogens in AOM and sinusitis are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in tonsillopharyngitis, Streptococcus pyogenes. As the bacterial aetiology of infection is usually not confirmed prior to initiation of treatment, empirical antibiotic therapy needs to take account of the major causative bacteria. However, increasing bacterial resistance, particularly penicillin and macrolide resistance among S. pneumoniae isolates, 2 has led to growing concern about current options for empirical therapy and has prompted a search for other effective treatments. This article examines the clinical and bacteriological efficacy of the oral cephalosporin, cefpodoxime, for treatment of bacterial AOM, sinusitis and tonsillopharyngitis. Acute otitis media Acute otitis media is particularly distressing for children, and prompt effective treatment is required for symptom relief, as well as for prevention, as far as possible, of long-term sequelae, such as hearing loss and permanent middle-ear damage. Currently, S. pneumoniae is regarded as the principal clinically important bacterial cause of AOM, with amoxicillin indicated for first-line therapy. 3 The importance of H. influenzae as a cause of non-responsive AOM should also be borne in mind. 4 It is possible that preventative measures such as the implementation of vaccination programmes for pneumococcal infection may diminish the importance of S. pneumoniae, resulting in H. influenzae becoming the main pathogen in AOM. 5 An antibiotic with a spectrum of antibacterial activity covering both S. pneumoniae and H. influenzae and effective against penicillin-susceptible and penicillin-intermediate strains of S. pneumoniae is necessary to achieve good bacteriological and clinical efficacy and to help prevent the development of resistance. Data from in vitro studies indicate that cefpodoxime, an oral cephalosporin with a broad spectrum of antibacterial activity, may be an appropriate treatment choice in bacterial AOM, as well as in sinusitis, which shares a similar aetiology. Cefpodoxime is active against penicillin-susceptible S. pneumoniae, with MIC 90 values ranging from <0.06 mg/l to <0.25 mg/l, as well as against penicillin-intermediate strains of S. pneumoniae (MIC 90 1 2 mg/l). 6 It also shows good activity against H. influenzae (including β-lactamaseproducing strains), with MIC 90 values ranging from <0.03 mg/l to 0.13 mg/l. 6 In a study conducted in the USA, cefpodoxime... *Correspondence address. Centre Hospitalier de Créteil, 94010 Créteil Cedex, France. Tel: +33-1-43970297; Fax: +33-1-43970277; E-mail: robert.cohen@wanadoo.fr... 23 2002 The British Society for Antimicrobial Chemotherapy

R. Cohen Table 1. Summary of comparative clinical studies in paediatric patients with acute otitis media using cefpodoxime Study (no. of patients) Treatment regimen Mean age (years) Clinical endpoint Clinical efficacy at end of treatment [n/total cases (%)] Mendelman et al. (1992) 7 cefpodoxime 10 mg/kg/day, 10 days 3.4 cure + improvement 90/98 (92) (n = 229) co-amoxiclav 40/10 mg/kg/day, 10 days 3.4 42/48 (88) Cohen et al. (1994) 8 cefpodoxime 8 mg/kg/day, 8 days 1.9 cure + improvement 61/69 (88) a (n = 146) cefixime 8 mg/kg/day, 8 days 2.1 52/71 (73) Gehanno et al. (1994) 9 cefpodoxime 8 mg/kg/day, 8 days 2.8 cure + improvement 112/118 (95) (n = 262) cure 71/118 (60) b co-amoxiclav 40/10 mg/kg/day, 8 days 3.1 cure + improvement 100/105 (95) cure 42/105 (40) Fernández MacLoughlin et al. cefpodoxime 10 mg/kg/day, 5 days 3.5 cure + improvement 73/78 (94) (1996) 10 (n = 167) cefaclor 40 mg/kg/day, 5 days 3.6 76/83 (92) Cohen et al. (1997) 11 cefpodoxime 8 mg/kg/day, 5 days 1.6 cure + improvement 160/186 (86) (n = 398) co-amoxiclav 80/10 mg/kg/day, 8 days 1.4 153/184 (83) a Cefpodoxime versus cefixime, P <0.05 ; b cefpodoxime versus AMC, P <0.005 (χ 2 or Fisher s exact tests; 95% confidence intervals). exhibited greater in vitro activity against S. pneumoniae than did cefaclor, cefuroxime, cefprozil, cefixime or loracarbef. 6 Moreover, pharmacodynamic and pharmacokinetic properties of cefpodoxime are favourable, because effective concentrations of cefpodoxime in the middle-ear fluid of paediatric patients are achieved with recommended dosing schedules. 6 Clinical data show that cefpodoxime is an effective treatment for bacterial AOM in children. Table 1 shows the results of five multicentre, randomized trials comparing the clinical efficacy of cefpodoxime with co-amoxiclav, cefixime or cefaclor in a total of 1202 paediatric patients. 7 11 The duration of treatment with cefpodoxime ranged from 5 to 10 days. In three of these trials, cefpodoxime was clinically at least as effective as the treatment used for comparison. In the other two trials, treatment with cefpodoxime demonstrated significantly greater clinical efficacy and cure rates than either cefixime or co-amoxiclav, respectively. 8,9 Clinical trials often fail to show a difference in clinical efficacy between antibiotic treatments, and there are currently no definitive trials of bacteriological efficacy in childhood AOM. Alternative methods of assessing antibiotics, such as the in vivo sensitivity test to assess bacteriological efficacy by examining fluid acquired by a tympanocentesis before and a few days after the start of treatment, and retrospective analyses of treatment failures, have therefore been investigated. Such analyses show good bacteriological efficacy for cefpodoxime against H. influenzae and penicillin-susceptible S. pneumoniae (Figure 1). 12 20 Moreover, the less frequent dosing schedule of cefpodoxime (bd) compared with either co-amoxiclav or cefaclor (tds), would be an added advantage for treatment with cefpodoxime. Figure 1. Comparison of eradication rates for (a) H. influenzae and (b) penicillin-susceptible S. pneumoniae in acute otitis media using data from the in vivo sensitivity test to assess bacteriological efficacy and retrospective analyses of treatment failures. Filled bars, bacteriological failure; open bars, eradication. Data from Klein 17 except for: *Klein 17 and Dagan et al. 18 ; Dagan et al. 19,20. 24

Cefpodoxime in respiratory tract infection Acute sinusitis The treatment of acute sinusitis is complicated by a difficulty in establishing the causative bacteria. In AOM, sampling of ear fluid using tympanocentesis is a routine procedure in some countries, whereas in sinusitis, sampling of infected fluid using sinus puncture is a painful and rare procedure. Consequently, empirical treatment of acute sinusitis of suspected bacteriological aetiology is the approach usually adopted. Selection of appropriate antibiotic therapy should take account of the most likely causative bacteria, local patterns of bacterial resistance and the pharmacokinetic profile of the antibiotic. Co-amoxiclav is currently regarded as first-line therapy for acute bacterial sinusitis. 21 However, the increasing prevalence of resistant strains among the main pathogens of acute sinusitis does suggest the need for effective treatment alternatives. As the bacterial aetiology of acute sinusitis is similar to that observed with AOM, cefpodoxime, which shows good in vitro activity against both S. pneumoniae and H. influenzae, 6 may be an appropriate alternative. Data from clinical trials show that treatment with cefpodoxime is clinically at least as effective as amoxicillin or co-amoxiclav in both adults and children. 22 24 Moreover, clinical cure rates in adults with acute sinusitis are significantly better after a 10 day treatment course with cefpodoxime than with cefaclor (Table 2). 25 Tonsillopharyngitis Acute tonsillopharyngitis is one of the most common reasons for consultation in general practice. 26 In most countries, antibiotic treatment is definitely indicated for treatment of group A β-haemolytic streptococci (GABHS), the most common bacterial cause of acute tonsillopharyngitis, to prevent suppurative complications and serious sequelae such as acute rheumatic fever or glomerulonephritis. Clinical diagnosis of GABHS infection is, however, difficult, because many of the signs and symptoms of GABHS tonsillopharyngitis are nonspecific and are indistinguishable from viral infections, even for experienced clinicians. Diagnosis of GABHS requires confirmation by either rapid antigen test or culture prior to initiation of antibiotic therapy. 26 Traditionally, oral penicillin therapy for 10 days has been regarded as the treatment of choice for GABHS tonsillopharyngitis because of its proven efficacy, narrow spectrum of antibacterial activity and tolerability. 27 Although effective in most patients, the treatment failure rates with penicillin are typically in the region of 10 30%, 28 while the causative pathogen remains susceptible to β-lactam therapy. Possible reasons for this observed failure rate include poor compliance and co-pathogen colonization with, for example, Staphylococcus aureus, H. influenzae or M. catarrhalis, which produce β-lactamase, thereby inactivating penicillin before it can exert any effect. Therefore, antibiotics that have high potency against GABHS are β-lactamase stable, and are effective in a shorter regimen, are preferred. Macrolide therapy is a possible alternative treatment. The increased prevalence of macrolide resistance, particularly in Italy and Spain, should, however, be considered. 2 Cefpodoxime has good in vitro activity against S. pyogenes, with an MIC 90 of <0.06 mg/l. 6 Clinical studies show that treatment with cefpodoxime 200 mg daily for 5 10 days is at least as effective in eradicating GABHS as a standard 10-day treatment course of penicillin in both adult and paediatric patients. 29 32 In studies in paediatric patients (Table 3), the rate of bacterial eradication following a 5 day or 10 day course of cefpodoxime was significantly higher than that observed following treatment with penicillin V for 10 days. 30,32 Table 2. Summary of comparative clinical trials in adult and paediatric patients with acute sinusitis Study (no. of patients) Treatment regimen Mean age (years) Clinical endpoint Clinical efficacy at end of treatment [n/total cases (%)] Gehanno et al. (1990) 25 cefpodoxime 400 mg/day, 10 days 41.3 cure + improvement 116/122 (95) (n = 267) cure 102/122 (84) a cefaclor 1500 mg/day, 10 days 42.1 cure + improvement 106/114 (93) cure 77/114 (68) Von Sydow et al. (1995) 22 cefpodoxime 400 mg/day, 10 days 33.0 cure + improvement 112/117 (96) (n = 286) amoxicillin 1500 mg, 10 days 33.0 103/113 (91) Autret et al. (1994) 23 cefpodoxime 8 mg/kg/day, 10 days 6.9 cure + improvement 42/44 (95) (n = 116) co-amoxiclav 40/10 mg/kg/day, 10 days 6.9 23/28 (82) Sabater et al. (1995) 24 cefpodoxime 400 mg/day, 5 days 35.5 cure + improvement 32/32 (100) (n = 66) co-amoxiclav 1500/375 mg/day, 8 days 36.6 32/33 (97) a Cefpodoxime versus cefaclor, P < 0.05. 25

R. Cohen Table 3. Summary of comparative clinical trials in adult and paediatric patients with group A β-haemolytic streptococcal tonsillopharyngitis Study (no. of patients) Treatment regimen Mean age (years) Bacteriological efficacy [eradication/total cases (% eradication)] Brown et al. (1991) 29 cefpodoxime 200 mg/day, 10 days 31.4 29/30 (97) (n = 93) penicillin V 1 g/day, 10 days 29.4 30/33 (91) Dajani et al. (1993) 30 cefpodoxime 10 mg/kg/day, 10 days 8.4 256/275 (93) c (n = 578) penicillin V 40 mg/kg/day, 10 days 8.3 112/138 (81) Portier et al. (1994) 31 cefpodoxime 200 mg/day, 5 days 30.4 79/82 (96) (n = 220) penicillin V 1800 mg/day, 10 days 28.6 64/68 (94) Pichichero et al. (1994) 32 cefpodoxime 10 mg/kg/day, 5 days 8.1 113/125 (90) a (n = 484) cefpodoxime 10 mg/kg/day, 10 days 7.4 112/118 (95) b penicillin V 40 mg/kg/day, 10 days 8.0 101/129 (78) χ 2 Or Fisher s exact test: a Cefpodoxime 5 days versus penicillin V, P <0.05; b cefpodoxime 10 days versus penicillin V, P <0.005; c cefpodoxime versus penicillin V, P <0.01. Given the fact that poor compliance is an important contributing factor to bacteriological treatment failure in GABHS tonsillopharyngitis, cefpodoxime, given over a 5 10 day period, may be a suitable treatment option. Discussion Cefpodoxime has good in vitro activity against the bacterial pathogens that are responsible for common respiratory tract infections such as AOM, acute sinusitis and tonsillopharyngitis. Clinical studies show that cefpodoxime is at least as effective as standard first-line antibiotic therapy for each of these indications. As with all broad-spectrum antibiotics, there is the risk of increased resistance if they are overused or used inappropriately. 33 However, if used with care, cefpodoxime can be considered as an appropriate choice for the empirical treatment of community-acquired respiratory tract infection caused by bacteria, particularly where there is emerging resistance to traditional antimicrobial chemotherapy. References 1. Shappert, S. M. (1992). Office visits for otitis media: United States, 1975 90. In Vital and Health Statistics of the Centers for Disease Control/National Center for Health Statistics No. 214, pp. 1 20. US Department of Health and Human Services, Hyattsville, MD. 2. Felmingham, D. & Gruneberg, R. N. (2000). The Alexander Project 1996 1997: latest susceptibility data from this international study of bacterial pathogens from community-acquired lower respiratory tract infections. Journal of Antimicrobial Chemotherapy 45, 191 203. 3. Olson, L. C. & Jackson, M. A. (1999). Only the pneumococcus. Pediatric Infectious Disease Journal 18, 849 50. 4. Musher, D. & Dagan, R. (2000). Is the pneumococcus the one and only in acute otitis media? Pediatric Infectious Disease Journal 19, 399 400. 5. Eskola, J., Kilpi, T., Palmu, A., Jokinen, J., Haapakoski, J., Herva, E. et al. (2001). Efficacy of a pneumococcal conjugate vaccine against acute otitis media. New England Journal of Medicine 344, 403 9. 6. Fulton, B. & Perry, C. M. (2001). Cefpodoxime proxetil. A review of its use in the management of bacterial infections in paediatric patients. Paediatric Drugs 3, 137 58. 7. Mendelman, P. M., Del Beccaro, M. A., McLinn, S. E. & Todd, W. M. (1992). Cefpodoxime proxetil compared with amoxicillinclavulanate for the treatment of otitis media. Journal of Pediatrics 121, 459 65. 8. Cohen, R., de La Rocque, F., Boucherat, M., Grandsenne, Ph., Corrard, F., Bouhanna, Ch. A. et al. (1994). Cefpodoxime proxetil vs cefixime for painful febrile acute otitis media in children. Médecine et Maladies Infectieuses 24, 844 51. 9. Gehanno, P., Barry, B., Bobin, S. & Safran, C. (1994). Twice daily cefpodoxime proxetil compared with thrice daily amoxicillin/ clavulanic acid for treatment of acute otitis media in children. Scandinavian Journal of Infectious Diseases 26, 577 84 10. Fernández MacLoughlin, G. J., F, Barreto, D. G., de la Torre, C., Pinetta, E. A., del Castillo, F. & Palma, L. (1996). Cefpodoxime proxetil suspension compared with cefaclor suspension for treatment of acute otitis media in paediatric patients. Journal of Antimicrobial Chemotherapy 37, 565 73. 26

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