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Giménez MJ, Aguilar L, Granizo JJ. Revisiting cefditoren for the treatment of community-acquired infections caused by human-adapted respiratory pathogens in adults. Multidiscip Respir Med 2018; 13:40. [PMID: 30410757 PMCID: PMC6214181 DOI: 10.1186/s40248-018-0152-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 09/24/2018] [Indexed: 11/13/2022] Open
Abstract
Fifteen years after its licensure, this revision assesses the role of cefditoren facing the current pharmacoepidemiology of resistances in respiratory human-adapted pathogens (Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis). In the era of post- pneumococcal conjugate vaccines and in an environment of increasing diffusion of the ftsI gene among H. influenzae isolates, published studies on the cefditoren in vitro microbiological activity, pharmacokinetic/pharmcodynamic (PK/PD) activity and clinical efficacy are reviewed. Based on published data, an overall analysis is performed for PK/PD susceptibility interpretation. Further translation of PK/PD data into clinical/microbiological outcomes obtained in clinical trials carried out in the respiratory indications approved for cefditoren in adults (tonsillitis, sinusitis, acute exacerbation of chronic bronchitis and community-acquired pneumonia) is commented. Finally, the role of cefditoren within the current antibiotic armamentarium for the treatment of community respiratory tract infections in adults is discussed based on the revised information on its intrinsic activity, pharmacodynamic adequacy and clinical/bacteriological efficacy. Cefditoren remains an option to be taken into account when selecting an oral antibiotic for the empirical treatment of respiratory infections in the community caused by human-adapted pathogens, even when considering changes in the pharmacoepidemiology of resistances over the last two decades.
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Affiliation(s)
- María-José Giménez
- Research Department, PRISM-AG, Don Ramón de la Cruz 72, 28006 Madrid, Spain
| | - Lorenzo Aguilar
- Research Department, PRISM-AG, Don Ramón de la Cruz 72, 28006 Madrid, Spain
| | - Juan José Granizo
- Preventive Medicine Department, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain
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Baquero-Artigao F, Michavila A, Suárez-Rodriguez Á, Hernandez A, Martínez-Campos L, Calvo C. Spanish Society of Paediatric Infectious Diseases, Spanish Society of Paediatric Clinical Immunology and Allergy, Spanish Association of Paediatric Primary Care, and the Spanish Society of Extra-hospital Paediatrics and Primary Health Care consensus document on antibiotic treatment in penicillin or amoxicillin allergy. An Pediatr (Barc) 2017. [DOI: 10.1016/j.anpede.2016.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Yoon YK, Park CS, Kim JW, Hwang K, Lee SY, Kim TH, Park DY, Kim HJ, Kim DY, Lee HJ, Shin HY, You YK, Park DA, Kim SW. Guidelines for the Antibiotic Use in Adults with Acute Upper Respiratory Tract Infections. Infect Chemother 2017; 49:326-352. [PMID: 29299900 PMCID: PMC5754344 DOI: 10.3947/ic.2017.49.4.326] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Indexed: 12/20/2022] Open
Abstract
These guidelines were developed as part of the 2016 Policy Research Servicing Project by the Korea Centers for Disease Control and Prevention. A multidisciplinary approach was taken to formulate this guideline to provide practical information about the diagnosis and treatment of adults with acute upper respiratory tract infection, with the ultimate aim to promote the appropriate use of antibiotics. The formulation of this guideline was based on a systematic literature review and analysis of the latest research findings to facilitate evidence-based practice, and focused on key questions to help clinicians obtain solutions to clinical questions that may arise during the care of a patient. These guidelines mainly cover the subjects on the assessment of antibiotic indications and appropriate selection of antibiotics for adult patients with acute pharyngotonsillitis or acute sinusitis.
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Affiliation(s)
- Young Kyung Yoon
- Korean Society of Infectious Diseases, Seoul, Korea.,Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chan Soon Park
- Korean Society of Otorhinolaryngology-Head and Neck Surgery, Seoul, Korea.,Department of Otolaryngology-Head and Neck Surgery, The Catholic University of Korea, College of Medicine, Seoul, Korea
| | - Jae Wook Kim
- Korean Society of Otorhinolaryngology-Head and Neck Surgery, Seoul, Korea.,Department of Otolaryngology-Head and Neck Surgery, Soonchunhyang University hospital Seoul, Seoul, Korea
| | - Kyurin Hwang
- Korean Society of Otorhinolaryngology-Head and Neck Surgery, Seoul, Korea.,Department of Otolaryngology-Head and Neck Surgery, Soonchunhyang University hospital Seoul, Seoul, Korea
| | - Sei Young Lee
- Korean Society of Otorhinolaryngology-Head and Neck Surgery, Seoul, Korea.,Department of Otorhinolaryngology-Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, Korea
| | - Tae Hoon Kim
- Korean Society of Otorhinolaryngology-Head and Neck Surgery, Seoul, Korea.,Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea
| | - Do Yang Park
- Korean Society of Otorhinolaryngology-Head and Neck Surgery, Seoul, Korea.,Department of Otorhinolaryngology, Ajou University, School of Medicine, Suwon, Korea
| | - Hyun Jun Kim
- Korean Society of Otorhinolaryngology-Head and Neck Surgery, Seoul, Korea.,Department of Otorhinolaryngology, Ajou University, School of Medicine, Suwon, Korea
| | - Dong Young Kim
- Korean Society of Otorhinolaryngology-Head and Neck Surgery, Seoul, Korea.,Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University, College of Medicine, Seoul, Korea
| | - Hyun Jong Lee
- Korean Association of Otorhinolaryngologists, Seoul, Korea
| | - Hyun Young Shin
- Korean Association of Family Medicine, Seoul, Korea.,Department of Family Medicine, Myongji Hospital, Seonam University, College of Medicine, Goyang, Korea
| | - Yong Kyu You
- Korean Medical Practitioners Association, Seoul, Korea.,Department of Internal Medicine, Nammoon Medical Clinic, Seoul, Korea
| | - Dong Ah Park
- Division of Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Korea
| | - Shin Woo Kim
- Korean Society of Infectious Diseases, Seoul, Korea.,Korean Society for Chemotherapy, Seoul, Korea.,Department of Internal Medicine, Kungpook National University, School of Medicine, Daegu, Korea.
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Baquero-Artigao F, Michavila A, Suárez-Rodriguez Á, Hernandez A, Martínez-Campos L, Calvo C. [Spanish Society of Pediatric Infectious Diseases, Spanish Society of Paediatric Clinical Immunology and Allergy, Spanish Association of Paediatric Primary Care, and the Spanish Society of Extra-hospital Paediatrics and Primary Health Care consensus document on antibiotic treatment in penicillin or amoxicillin allergy]. An Pediatr (Barc) 2016; 86:99.e1-99.e9. [PMID: 27427544 DOI: 10.1016/j.anpedi.2016.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 06/06/2016] [Indexed: 11/26/2022] Open
Abstract
The suspected allergy to beta-lactam antibiotics, especially penicillin and amoxicillin, is the most frequent reason for consultation in Child Allergy Units. In this consensus document, the clinical and diagnostic criteria of allergic reactions are described, as well as alternative antibiotic treatment for the most common infections diagnosed in paediatrics for patients with known or suspected allergy.
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Affiliation(s)
| | | | | | - Anselmo Hernandez
- Sociedad Española de Pediatría Extrahospitalaria y Atención Primaria
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A Comparison of Cefditoren Pivoxil 8-12 mg/kg/day and Cefditoren Pivoxil 16-20 mg/kg/day in Treatment of Children With Acute Presumed Bacterial Rhinosinusitis: A Prospective, Randomized, Investigator-Blinded, Parallel-Group Study. Clin Exp Otorhinolaryngol 2015; 8:129-35. [PMID: 26045911 PMCID: PMC4451537 DOI: 10.3342/ceo.2015.8.2.129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Revised: 11/14/2013] [Accepted: 11/22/2013] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVES Cefditoren pivoxil (CDT) has been used in the treatment of rhinosinusitis. However, little is known about the efficacy of this drug at low and high doses. This study was to compare the efficacy and safety of low dose (8-12 mg/kg/day) and high dose (16-20 mg/kg/day) CDT in the treatment of children with uncomplicated acute rhinosinusitis (ARS). METHODS This investigation was a randomized, investigator-blinded, and parallel study, conducted in patients (aged 1-15 years) with a clinical diagnosis of uncomplicated ARS. Two groups of patients randomly received low dose or high dose CDT for 14 days. Patients' symptoms were assessed quantitatively using a quantitative symptom score (the S5 score). The changes in sinus symptoms and adverse events were provided by patients and their parents/caregivers. The response rate and adverse effects were evaluated at days 7 and 14. The relapse rate was recorded at days 21 and 28. The recurrences of sinus symptoms at day 60 were also assessed. RESULTS One hundred forty patients were recruited and randomized; 72 received low dose CDT (group I) and 68 received high dose CDT (group II). There were no significant differences in demographic data including sex, age, presenting symptoms, medical history, and X-ray findings between two groups. The responses rate at day 14 in groups I and II were 95.5% and 95.4%, respectively (P>0.99). There were no significant differences between groups in relapse rate at day 28 and no recurrence at day 60 in either group. The most common treatment-related adverse events were diarrhea (4.2% in group I vs. 2.9% in group II) and vomiting (2.8% in group I vs. 10.3% in group II). There was no statistically significant difference in adverse events between groups. CONCLUSION Both low and high doses regimens of CDT appeared a similar clinical outcome for treatment in uncomplicated ARS in pediatric patients.
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Ulloa C, Guevara S, Soley C, Abdelnour A, Arguedas A. In vitro Activity of Cefditoren against Middle Ear Fluid Isolates from Costa Rican Children with Otitis Media. Chemotherapy 2015; 60:211-8. [PMID: 25871785 DOI: 10.1159/000371836] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 01/05/2015] [Indexed: 11/19/2022]
Abstract
Otitis media (OM) is one of the most common infections in children, Streptococcus pneumoniae and nontypable Haemophilus influenzae being the two most common pathogens isolated in the middle ear fluid (MEF) of children with OM. Cefditoren is a third-generation cephalosporin with broad-spectrum antibacterial activity, including activity against those pathogens commonly causing OM, with enhanced stability against common β-lactamases. The main objective of this study was to evaluate the in vitro activity of cefditoren against pathogens collected from the MEF of Costa Rican children with OM between 2006 and 2011. A total of 715 samples were analyzed. Among the 89 S. pneumoniae strains that were penicillin-nonsusceptible, only 7% were cefditoren-resistant according to Spanish Regulatory Agency criteria; among the H. influenza and M. catarrhalis isolates obtained, 100 and 90% of the isolates, respectively, were cefditoren-susceptible. MIC50/90 against the 207 PCV-13 S. pneumoniae serotyped strains and the 79 serotypes not covered by PCV-13 for cefditoren were 0.03/1 and 0.03/0.12 mg/l, respectively. For both amoxicillin-susceptible and resistant H. influenzae strains, the MIC range against cefditoren was from ≤0.015 to 0.06 mg/l as well. In conclusion, the confirmation of the wide spectrum of activity of cefditoren and its intrinsic strength against resistant strains allows us to suggest that cefditoren might be included as one of the best choices among antibiotics that are widely used in empiric therapy for OM in pediatric patients.
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Kempf M, Varon E, Lepoutre A, Gravet A, Baraduc R, Brun M, Chardon H, Cremniter J, Croizé J, Dalmay F, Demachy MC, Fosse T, Grelaud C, Hadou T, Hamdad F, Koeck JL, Luce S, Mermond S, Patry I, Péchinot A, Raymond J, Ros A, Segonds C, Soullié B, Tandé D, Vergnaud M, Vernet-Garnier V, Wallet F, Gutmann L, Ploy MC, Lanotte P. Decline in antibiotic resistance and changes in the serotype distribution of Streptococcus pneumoniae isolates from children with acute otitis media; a 2001-2011 survey by the French Pneumococcal Network. Clin Microbiol Infect 2014; 21:35-42. [PMID: 25636925 DOI: 10.1016/j.cmi.2014.08.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 07/25/2014] [Accepted: 08/06/2014] [Indexed: 11/19/2022]
Abstract
Streptococcus pneumoniae is an important cause of acute otitis media (AOM). The aim of this study was to evaluate trends in antibiotic resistance and circulating serotypes of pneumococci isolated from middle ear fluid of French children with AOM during the period 2001-2011, before and after the introduction of the PCV-7 (2003) and PCV-13 (2010) vaccines. Between 2001 and 2011 the French pneumococcal surveillance network analysed the antibiotic susceptibility of 6683 S. pneumoniae isolated from children with AOM, of which 1569 were serotyped. We observed a significant overall increase in antibiotic susceptibility. Respective resistance (I+R) rates in 2001 and 2011 were 76.9% and 57.3% for penicillin, 43.0% and 29.8% for amoxicillin, and 28.6% and 13.0% for cefotaxime. We also found a marked reduction in vaccine serotypes after PCV-7 implementation, from 63.0% in 2001 to 13.2% in 2011, while the incidence of the additional six serotypes included in PCV-13 increased during the same period, with a particularly high proportion of 19A isolates. The proportion of some non-PCV-13 serotypes also increased between 2001 and 2011, especially 15A and 23A. Before PCV-7 implementation, most (70.8%) penicillin non-susceptible pneumococci belonged to PCV-7 serotypes, whereas in 2011, 56.8% of penicillin non-susceptible pneumococci belonged to serotype 19A. Between 2001 and 2011, antibiotic resistance among pneumococci responsible for AOM in France fell markedly, and PCV-7 serotypes were replaced by non-PCV-7 serotypes, especially 19A. We are continuing to assess the impact of PCV-13, introduced in France in 2010, on pneumococcal serotype circulation and antibiotic resistance.
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Affiliation(s)
- M Kempf
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - E Varon
- Centre National de Référence des Pneumocoques (CNRP), AP-HP HEGP, Paris, France
| | - A Lepoutre
- Institut de Veille Sanitaire (InVS), Saint Maurice, France
| | - A Gravet
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - R Baraduc
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - M Brun
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - H Chardon
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - J Cremniter
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - J Croizé
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - F Dalmay
- CHU Limoges, UFRCB, Limoges, France
| | - M-C Demachy
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - T Fosse
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - C Grelaud
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - T Hadou
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - F Hamdad
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - J-L Koeck
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - S Luce
- CHU Limoges, UFRCB, Limoges, France
| | - S Mermond
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - I Patry
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - A Péchinot
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - J Raymond
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - A Ros
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - C Segonds
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - B Soullié
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - D Tandé
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - M Vergnaud
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - V Vernet-Garnier
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - F Wallet
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - L Gutmann
- Centre National de Référence des Pneumocoques (CNRP), AP-HP HEGP, Paris, France
| | - M-C Ploy
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France
| | - P Lanotte
- French pneumococcal surveillance network 'Observatoires Régionaux du Pneumocoque', CHU Limoges, Limoges, France.
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Soriano F, Giménez MJ, Aguilar L. Pharmacodynamics for predicting therapeutic outcome and countering resistance spread: The cefditoren case. World J Clin Infect Dis 2012; 2:28-38. [DOI: 10.5495/wjcid.v2.i3.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The relationship between pharmacokinetics and pharmacodynamics is a key instrument to improve antimicrobial stewardship and should be aimed to identification of the drug exposure measure that is closely associated not only with the ability to kill organisms but also to suppress the emergence of resistant subpopulations. This article reviews published studies for efficacy prediction with cefditoren and those aimed to explore its potential for countering resistance spread, focusing on the three most prevalent community-acquired isolates from respiratory infections: Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae) and Streptococcus pyogenes (S. pyogenes). Studies for efficacy prediction include in vitro pharmacodynamic simulations (using physiological concentrations of human albumin) and mice models (taking advantage of the same protein binding rate in mice and humans) to determine the value of the pharmacodynamic indices predicting efficacy, and Monte Carlo simulations to explore population pharmacodynamic coverage, as weapons for establishing breakpoints. Studies exploring the potential of cefditoren (free concentrations obtained with 400 mg cefditoren bid administration) for countering spread of resistance showed its capability for countering (1) intra-strain spread of resistance linked to ftsI gene mutations in H. influenzae; (2) the spread of H. influenzae resistant strains (with ftsI gene mutations) in multi-strain H. influenzae niches or of S. pneumoniae strains with multiple resistance traits in multi-strain S. pneumoniae niches; and (3) for overcoming indirect pathogenicity linked to β-lactamase production by H. influenzae that protects S. pyogenes in multibacterial niches. This revision evidences the ecological potential for cefditoren (countering resistance spread among human-adapted commensals) and its adequate pharmacodynamic coverage of respiratory pathogens (including those resistant to previous oral compounds) producing community-acquired infections.
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Barberán J, Aguilar L, Giménez MJ. Update on the clinical utility and optimal use of cefditoren. Int J Gen Med 2012; 5:455-64. [PMID: 22675264 PMCID: PMC3367410 DOI: 10.2147/ijgm.s25989] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
This article reviews and updates published data on cefditoren. The in vitro activity of cefditoren and its potential pharmacokinetic/pharmacodynamic adequacy to cover emerging resistance phenotypes in the present decade is reviewed. Cefditoren’s in vitro activity against most prevalent bacterial respiratory pathogens in the community and its pharmacokinetic/pharmacodynamic profile suggests a significant role for cefditoren in the treatment of respiratory tract infections. Clinical trials (in acute exacerbations of chronic bronchitis, community-acquired pneumonia, pharyngotonsillitis, and sinusitis) performed during clinical development outside Japan, mainly in adults, are reviewed, together with new clinical studies in the treatment of pharyngotonsillitis, sinusitis, and otitis media in children, mainly in Japan, for efficacy and safety assessment. The results of these studies support the adequacy of cefditoren for the treatment of community-acquired respiratory tract infections with a safety profile similar to previous oral antibiotics. From the data reviewed, it is concluded that cefditoren is an adequate option for the treatment of mild-to-moderate community-acquired respiratory infections, especially in geographical areas with a reported prevalence of phenotypes exhibiting nonsusceptibility to common oral antibiotics.
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Affiliation(s)
- José Barberán
- Infectious Diseases Department, Hospital Central de la Defensa Gomez Ulla, Madrid, Spain
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Fenoll A, Aguilar L, Vicioso MD, Gimenez MJ, Robledo O, Granizo JJ. Increase in serotype 19A prevalence and amoxicillin non-susceptibility among paediatric Streptococcus pneumoniae isolates from middle ear fluid in a passive laboratory-based surveillance in Spain, 1997-2009. BMC Infect Dis 2011; 11:239. [PMID: 21910891 PMCID: PMC3180674 DOI: 10.1186/1471-2334-11-239] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Accepted: 09/12/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Conjugate vaccines, such as the 7-valent conjugate vaccine (PCV7), alter serotype nasopharyngeal carriage, potentially increasing cases of otitis media by non-vaccine serotypes. METHODS All paediatric middle ear fluid (MEF) isolates received in the Spanish Reference Laboratory for Pneumococci through a passive, laboratory-based surveillance system from January 1997 to June 2009 were analysed. Data from 1997 to 2000 were pooled as pre-vaccination period. Trends over time were explored by linear regression analysis. RESULTS A total of 2,077 isolates were analysed: 855 belonging to PCV7 serotypes, 466 to serotype 19A, 215 to serotype 3, 89 to serotype 6A and 452 to other serotypes (< 40 isolates each). Over time, there has been a decreasing trend for PCV7 serotypes (R(2) = 0.944; p < 0.001, with significant decreasing trends for serotypes 19F, 14, 23F and 9V), and increasing trends for serotype 19A (R(2) = 0.901; p < 0.001), serotype 3 (R(2) = 0.463; p = 0.030) and other non-PCV7 serotypes (R(2) = 0.877; p < 0.001), but not for serotype 6A (R(2) = 0.311; p = 0.094). Considering all isolates, amoxicillin non-susceptibility showed an increasing trend (R(2) = 0.528; p = 0.017). Regarding serotype 19A, increasing trends in non-susceptibility to penicillin (R(2) = 0.726; p = 0.001), amoxicillin (R(2) = 0.804; p < 0.001), cefotaxime (R(2) = 0.546; p = 0.005) and erythromycin (R(2) = 0.546; p = 0.009) were found, with amoxicillin non-susceptibility firstly detected in 2003 (7.4%) and increasing up to 38.0% in 2009. In PCV7 serotypes (which prevalence decreased from 70.7% during 1997-2000 to 10.6% in 2009) amoxicillin non-susceptibility rates showed an increasing trend (R(2) = 0.702; p = 0.002). However, overall, amoxicillin non-susceptibility (≈25% in 2008-9) could be mainly attributed to serotype 19A (> 35% isolates) since PCV7 strains represented < 11% of total clinical isolates. CONCLUSIONS In contrast to reports on invasive pneumococcal strains, in MEF isolates the reduction in the prevalence of PCV7 serotypes was not associated with decreases in penicillin/erythromycin non-susceptibility. The high prevalence of serotype 19A among paediatric MEF isolates and the amoxicillin non-susceptibility found in this serotype are worrisome since amoxicillin is the most common antibiotic used in the treatment of acute otitis media. These data suggest that non-PCV7 serotypes (mainly serotype 19A followed by serotypes 3 and 6A) are important etiological agents of acute otitis media and support the added value of the broader coverage of the new 13-valent conjugate vaccine.
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Affiliation(s)
- Asunción Fenoll
- Spanish Reference Pneumococcal Laboratory, Inst. Salud Carlos III, ctra. Majadahonda-Pozuelo Km. 2, 28220 Majadahonda, Madrid, Spain
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11
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Evolution of clonal and susceptibility profiles of serotype 19A Streptococcus pneumoniae among invasive isolates from children in Spain, 1990 to 2008. Antimicrob Agents Chemother 2011; 55:2297-302. [PMID: 21343456 DOI: 10.1128/aac.01494-10] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The genetic structure and antibiotic nonsusceptibility of all serotype 19A Streptococcus pneumoniae pediatric pneumococcal isolates received at the Spanish Pneumococcal Reference Laboratory (1990 to 2008) were analyzed. Of them, 410 (79.8%) isolates belonged to 14 sequence types (STs) with >10 isolates each, and 104 to 73 STs (with 21 new STs, ST5141 to ST5161, with one isolate each). Time trends in 2000 to 2008 (n=471) were explored by lineal regression. Serotype 19A increased from 5.7% in 2000 to 16.8% in 2008 (R2=0.872; P=0.001). Decreasing trends (P<0.03) were found for ST202 (R2=0.774) and ST81 (R2=0.559), and increasing trends (P<0.03) for ST878 (R2=0.544) and ST320 (R2=0.530), both belonging to the clonal complex (CC) Denmark(14)-32 and first detected in 2003 and 2007, respectively, and ST2013 (R2=0.704) and ST4461 (R2=0.707), both appearing in 2004. Penicillin nonsusceptibility was clustered in ST81, ST276, ST320, ST878, ST2013, and ST4461 (>90% nonsusceptibility), and amoxicillin and cefotaxime nonsusceptibility in ST320: 87% amoxicillin (MIC50/MIC90=8/8 μg/ml) and 43.5% cefotaxime (MIC50/MIC90=1/2 μg/ml) nonsusceptibility. No trends were found for erythromycin nonsusceptibility (ranging from 38.5% to 66.7%) and cefotaxime nonsusceptibility (ranging from 0.0% to 7.8%), but increasing trends (P<0.02) were found for oral penicillin (from 16.7% in 2000 to 56.3% in 2008; R2=0.628) and amoxicillin (from 0.0% before 2007 to 13.8% in 2008; R2=0.628) nonsusceptibility. This study warns about the emergence of serotype 19A STs associated with high-level antibiotic nonsusceptibility, with a role for ST320 and ST878 occupying the niche left by some pneumococcal 7-valent conjugate vaccine (PCV7)-related resistant STs. The rapid expansion of serotype 19A and STs related to antibiotic resistance indicates that vaccines covering serotype 19A present advantages in countering invasive disease.
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Cafini F, Yuste J, Giménez MJ, Sevillano D, Aguilar L, Alou L, Ramos-Sevillano E, Torrico M, González N, García E, Coronel P, Prieto J. Enhanced in vivo activity of cefditoren in pre-immunized mice against penicillin-resistant S. pneumoniae (serotypes 6B, 19F and 23F) in a sepsis model. PLoS One 2010; 5:e12041. [PMID: 20706584 PMCID: PMC2919394 DOI: 10.1371/journal.pone.0012041] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2010] [Accepted: 07/09/2010] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Specific antibodies are likely to be present before S. pneumoniae infection. We explored cefditoren (CDN) total and free values of serum concentrations exceeding the MIC (t>MIC) related to efficacy in a mice sepsis model, and the effect of specific gammaglobulins on in-vitro phagocytosis and in-vivo efficacy. METHODOLOGY/PRINCIPAL FINDINGS We used three pneumococcal isolates (serotype, MIC OF CDN): Strain 1 (6B, 1 microg/ml), Strain 2 (19F, 2 microg/ml) and Strain 3 (23F, 4 microg/ml). Hyperimmune serum (HS) was obtained from mice immunized with heat-inactivated strains. In-vitro, phagocytosis by HS diluted 1/10 in presence/absence of sub-inhibitory concentrations was measured by flow cytometry including fluorescent bacteria and a neutrophil cell line. In-vivo dose-ranging experiments with HS (dilutions 1/2-1/16) and CDN (6.25 mg/kg-100 mg/kg tid for 48 h) were performed to determine the minimal protective dilution/dose (highest survival) and the non-protective highest dilution/dose (highest mortality: HS-np dilution and CDN-np dose) over 7 days. Efficacy of CDN-np in animals pre-immunized with HS-np (combined strategy) was explored and blood bacterial clearance determined. The CDN measured protein binding was 86.9%. In-vitro, CDN significantly increased phagocytosis (vs. HS 1/10). In non pre-immunized animals, t>MIC values for CDN of approximately 35% (total) and approximately 19% (free) were associated with 100% survival. Significant differences in survival were found between HS-np alone (< or = 20%) or CDN-np alone (< or = 20%) vs. the combined strategy (90%, 60% and 60% for Stains 1, 2 and 3), with t>MIC (total/free) of 22.8%/14.3%, 26.8%/16.0%, and 22.4%/12.7% for Strains 1, 2 and 3, respectively. Prior to the second dose (8 h), median bacterial counts were significantly lower in animals surviving vs. dead at day 7. CONCLUSIONS/SIGNIFICANCE In mice (CDN protein binding similar to humans) total t>MIC values of approximately 35% (approximately 19% free) were efficacious, with a decrease in the required values in pre-immunized animals. This reinforces that immunoprotection to overcome resistance may provide lifesaving strategies.
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Affiliation(s)
- Fabio Cafini
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Jose Yuste
- Centro de Investigaciones Biológicas (CSIC) and CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Maria-Jose Giménez
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - David Sevillano
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Lorenzo Aguilar
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
- * E-mail:
| | - Luis Alou
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Elisa Ramos-Sevillano
- Centro de Investigaciones Biológicas (CSIC) and CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Martha Torrico
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Natalia González
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Ernesto García
- Centro de Investigaciones Biológicas (CSIC) and CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Pilar Coronel
- Scientific Department, Tedec-Meiji Farma S.A., Madrid, Spain
| | - Jose Prieto
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
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Hupková H, Urbancíková I, Bazárová K, Szovenyová Z, Fandáková V, Bukovský M. Two cases of severe invasive infections in children caused by Streptococcus pneumoniae serotype 14--case report. Folia Microbiol (Praha) 2010; 54:563-5. [PMID: 20140728 DOI: 10.1007/s12223-009-0083-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2009] [Revised: 10/22/2009] [Indexed: 11/26/2022]
Abstract
Two cases are presented of severe pneumococcal infections in infants caused by serotype 14 Streptococcus pneumoniae. The first case--meningitis--caused by S. pneumoniae (pneumococcus) with low-level penicillin susceptibility has developed from acute otitis media and resulted in fatal outcome. The second one--an immunocompromised child presenting recurrent otitis and chronic mastoiditis--developed into pneumococcal pneumonia. Both cases demonstrate the extreme importance of a relevant initial treatment of localized pneumococcal infections, preventing the development of generalized infection. Amoxicillin (an oral treatment option in both upper and lower respiratory tract infections caused also by Pneumococcus strains with low-level penicillin susceptibility due to its beneficial pharmacokinetics and pharmacodynamics) was not used in either case.
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Affiliation(s)
- H Hupková
- Institute of Microbiology, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovak Republic.
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Takano M, Ozaki K, Nitahara Y, Higuchi W, Takano T, Nishiyama A, Yamamoto T. Streptococcus pneumoniae and Haemophilus influenzae at the initial stage of influenza. Pediatr Int 2009; 51:687-95. [PMID: 19419515 DOI: 10.1111/j.1442-200x.2009.02861.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Streptococcus pneumoniae and Haemophilus influenzae infections in children with influenza have been noted because of the severity of co-infection. In Japan, vaccination against S. pneumoniae and H. influenzae infections has been listed in the vaccine program in 2008, but the characteristics of the two organisms, colonizing at the initial stage of influenza infection, have not been investigated in detail. METHODS Nasopharyngeal swabs from children with influenza (flu(+)) (n= 236; mean age, 6.2 years) were examined for bacterial pathogens, including S. pneumoniae and H. influenzae. They were then examined for serotypes, drug susceptibilities, and resistance genes (or gene mutations). As a reference, children with upper respiratory tract infection (URTI(+), flu(-); n = 189; mean age, 6.2 years) were also examined. RESULTS S. pneumoniae, beta-streptococci (groups A, B, and G), methicillin-susceptible and -resistant S. aureus, Moraxella catarrhalis, and H. influenzae were isolated. For S. pneumoniae, nine serotypes were detected with prevalent types of 3, 6, 19 and 23. Penicillin resistance was detected in types 19 and 23, while resistance to macrolide and clindamycin was found in various types. For H. influenzae, only b serotype was detected, with marked ampicillin resistance. The majority was non-typeable. Very similar results were obtained even in URTI(+) (flu(-)) cases. CONCLUSION Multiple drug-resistant S. pneumoniae with major serotypes, for example, 19 and 23 and H. influenzae with serotype b were already present at the initial stage of influenza infection, similar to URTI(+) flu(-) cases. They could be prevented by current vaccines, but drug-resistant non-typeable H. influenzae is troubling.
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Affiliation(s)
- Misao Takano
- Department of Infectious Disease Control and International Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Biedenbach DJ, Jones RN. Update of cefditoren activity tested against community-acquired pathogens associated with infections of the respiratory tract and skin and skin structures, including recent pharmacodynamic considerations. Diagn Microbiol Infect Dis 2009; 64:202-12. [PMID: 19321284 DOI: 10.1016/j.diagmicrobio.2009.01.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2008] [Accepted: 01/21/2009] [Indexed: 01/28/2023]
Abstract
Antimicrobial resistance rates have noticeably increased among commonly isolated species associated with respiratory tract infections and skin and skin structure infections, particularly Streptococcus pneumoniae and Staphylococcus aureus. Cefditoren, an oral 3rd-generation-like cephalosporin, has been shown to be very active against many Gram-positive and Gram-negative species with favorable attributes including bactericidal activity and stability against many beta-lactamase enzymes. Clinical trial data worldwide support the use of cefditoren for infections and species that have been approved by the US Food and Drug Administration (US-FDA). This review and a contemporary study report provide an update of clinical trial and in vitro data for cefditoren especially against pathogens within the spectrum of activity since 2002. A large collection of 7279 clinical isolates collected during 2002 and 2003 from medical centers in North and Latin America and Europe were tested to confirm cefditoren potency and spectrum compared with other oral cephalosporins and other class agents. Isolates were tested at a reference laboratory using reference broth microdilution methods. Cefditoren was shown to be active against nearly all (>99%) isolates of penicillin-susceptible S. pneumoniae isolates (MIC(90), < or = 0.03 microg/mL) and was the most potent orally administered cephalosporin against this organism. Cefditoren was the most active oral cephem tested against Haemophilus influenzae (MIC(90), < or = 0.03 microg/mL) and had >99% activity versus both beta-lactamase-positive and beta-lactamase-negative isolates. The potency of cefditoren (MIC(90), 0.5 microg/mL) was similar to that of amoxicillin/clavulanate and cefdinir (MIC(90), 0.25 microg/mL) when tested against Moraxella catarrhalis. Cefditoren was the most potent cephalosporin tested against oxacillin-susceptible S. aureus with an MIC(90) value of only 1 microg/mL, and it was 100% active against the tested beta-hemolytic streptococci. Using the data generated from the large collection of isolates tested in this global surveillance collection, as well as other summarized supporting studies and clinical trial information, we show that cefditoren has sustained in vitro activity and documented clinical efficacy for indications that have been approved by regulators (US-FDA).
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Seral C, Suárez L, Rubio-Calvo C, Gómez-Lus R, Gimeno M, Coronel P, Durán E, Becerril R, Oca M, Castillo FJ. In vitro activity of cefditoren and other antimicrobial agents against 288 Streptococcus pneumoniae and 220 Haemophilus influenzae clinical strains isolated in Zaragoza, Spain. Diagn Microbiol Infect Dis 2008; 62:210-5. [PMID: 18715733 DOI: 10.1016/j.diagmicrobio.2008.06.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2008] [Revised: 06/11/2008] [Accepted: 06/25/2008] [Indexed: 10/21/2022]
Abstract
In vitro cefditoren antimicrobial activity was tested against 288 Streptococcus pneumoniae and 220 Haemophilus influenzae clinical strains isolated in our hospital from January 2005 to May 2006 by agar dilution and broth microdilution method, respectively. MICs were also determined for 13 and 10 comparison drugs, respectively. The pneumococci tested comprised 113 (39.2%) penicillin susceptible, 91 (31.6%) penicillin intermediate, and 84 (29.2%) penicillin resistant. Cefditoren was the most active drug on the basis of the MICs (MIC(90)=0.5 microg/mL), followed by ceftriaxone and levofloxacin (MIC(90)=1 microg/mL). Cefditoren MICs ranged from 0.25 to 1 microg/mL for ceftriaxone-resistant isolates, with a modal MIC of 0.5 microg/mL and an MIC(90) of 1.0 microg/mL. No S. pneumoniae isolates evaluated in this study showed MICs to cefditoren higher than 1 microg/mL (MIC range, <or=0.015 to 1 microg/mL). Against penicillin-resistant pneumococci, the rank order of intrinsic activity (MIC(90), microg/mL) was cefditoren (0.5)<ceftriaxone (2.0)=cefotaxime (2.0)<amoxicillin/clavulanate (8.0)=amoxicillin (8.0)=cefuroxime (8.0). Among the 220 strains of H. influenzae, 42 (19.09%) produced a beta-lactamase (Hi beta+) and 3 (1.1%) were beta-lactamase (Hi beta-) negative but have reduced susceptibility to ampicillin (BLNAR). The most active drugs on the basis of MICs were cefditoren and levofloxacin, showing MIC(50) and MIC(90) values of 0.015/0.06 microg/mL. Cefditoren at concentration of 0.06 microg/mL inhibited all 3 BLNAR (ampicillin MICs >4 microg/mL). Against H. influenzae (Hi beta+), the rank order of intrinsic activity (MIC(90), microg/mL) was cefditoren (0.03) < cefixime (0.06)<ceftriaxone (0.12)=cefotaxime (0.12)<cefuroxime (1.0)<amoxicillin/clavulanate (2.0)<ampicillin (>8.0).
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Affiliation(s)
- Cristina Seral
- Department of Microbiology, Hospital Clinico Lozano Blesa, 50009 Zaragoza, Spain.
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Sevillano D, Aguilar L, Alou L, Giménez MJ, González N, Torrico M, Cafini F, Fenoll A, Coronel P, Prieto J. High protein binding and cidal activity against penicillin-resistant S. pneumoniae: a cefditoren in vitro pharmacodynamic simulation. PLoS One 2008; 3:e2717. [PMID: 18648650 PMCID: PMC2453320 DOI: 10.1371/journal.pone.0002717] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2008] [Accepted: 06/20/2008] [Indexed: 11/30/2022] Open
Abstract
Background Although protein binding is a reversible phenomenon, it is assumed that antibacterial activity is exclusively exerted by the free (unbound) fraction of antibiotics. Methodology/Principal Findings Activity of cefditoren, a highly protein bound 3rd generation cephalosporin, over 24h after an oral 400 mg cefditoren-pivoxil bid regimen was studied against six S. pneumoniae strains (penicillin/cefditoren MICs; µg/ml): S1 (0.12/0.25), S2 (0.25/0.25), S3 and S4 (0.5/0.5), S5 (1/0.5) and S6 (4/0.5). A computerized pharmacodynamic simulation with media consisting in 75% human serum and 25% broth (mean albumin concentrations = 4.85±0.12 g/dL) was performed. Protein binding was measured. The cumulative percentage of a 24h-period that drug concentrations exceeded the MIC for total (T>MIC) and unbound concentrations (fT>MIC), expressed as percentage of the dosing interval, were determined. Protein binding was 87.1%. Bactericidal activity (≥99.9% initial inocula reduction) was obtained against strains S1 and S2 at 24h (T>MIC = 77.6%, fT>MIC = 23.7%). With T>MIC of 61.6% (fT>MIC = 1.7%), reductions against S3 and S4 ranged from 90% to 97% at 12h and 24h; against S5, reduction was 45.1% at 12h and up to 85.0% at 24h; and against S6, reduction was 91.8% at 12h, but due to regrowth of 52.9% at 24h. Cefditoren physiological concentrations exerted antibacterial activity against strains exhibiting MICs of 0.25 and 0.5 µg/ml under protein binding conditions similar to those in humans. Conclusions/Significance The results of this study suggest that, from the pharmacodynamic perspective, the presence of physiological albumin concentrations may not preclude antipneumococcal activity of highly bound cephalosporins as cefditoren.
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Affiliation(s)
- David Sevillano
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Lorenzo Aguilar
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
- * E-mail:
| | - Luis Alou
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - María-José Giménez
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Natalia González
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Martha Torrico
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Fabio Cafini
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Asunción Fenoll
- Spanish National Reference Pneumococcal Laboratory, Instituto de Salud Carlos III, Madrid, Spain
| | - Pilar Coronel
- Scientific Department, Tedec-Meiji Farma SA, Madrid, Spain
| | - José Prieto
- Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain
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Torrico M, Aguilar L, González N, Giménez MJ, Echeverría O, Cafini F, Sevillano D, Alou L, Coronel P, Prieto J. influence of TEM-1 beta-lactamase on the pharmacodynamic activity of simulated total versus free-drug serum concentrations of cefditoren (400 milligrams) versus amoxicillin-clavulanic acid (2,000/125 milligrams) against Haemophilus influenzae strains exhibiting an N526K mutation in the ftsI gene. Antimicrob Agents Chemother 2007; 51:3699-706. [PMID: 17664320 PMCID: PMC2043252 DOI: 10.1128/aac.01530-06] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The aim of this study was to explore bactericidal activity of total and free serum simulated concentrations after the oral administration of cefditoren (400 mg, twice daily [bid]) versus the oral administration of amoxicillin-clavulanic acid extended release formulation (2,000/125 mg bid) against Haemophilus influenzae. A computerized pharmacodynamic simulation was performed, and colony counts and beta-lactamase activity were determined over 48 h. Three strains were used: ampicillin-susceptible, beta-lactamase-negative ampicillin-resistant (BLNAR) (also resistant to amoxicillin-clavulanic acid) and beta-lactamase-positive amoxicillin-clavulanic acid-resistant (BLPACR) strains, with cefditoren MICs of < or =0.12 microg/ml and amoxicillin-clavulanic acid MICs of 2, 8, and 8 microg/ml, respectively. Against the ampicillin-susceptible and BLNAR strains, bactericidal activity (> or =3 log(10) reduction) was obtained from 6 h on with either total and free cefditoren or amoxicillin-clavulanic acid. Against the BLPACR strain, free cefditoren showed bactericidal activity from 8 h on. In amoxicillin-clavulanic acid simulations the increase in colony counts from 4 h on occurred in parallel with the increase in beta-lactamase activity for the BLPACR strain. Since both BLNAR and BLPACR strains exhibited the same MIC, this was due to the significantly lower (P < or = 0.012) amoxicillin concentrations from 4 h on in simulations with beta-lactamase positive versus negative strains, thus decreasing the time above MIC (T>MIC). From a pharmacodynamic point of view, the theoretical amoxicillin T>MIC against strains with elevated ampicillin/amoxicillin-clavulanic acid MICs should be considered with caution since the presence of beta-lactamase inactivates the antibiotic, thus rendering inaccurate theoretical calculations. The experimental bactericidal activity of cefditoren is maintained over the dosing interval regardless of the presence of a mutation in the ftsI gene or beta-lactamase production.
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Affiliation(s)
- M Torrico
- Microbiology Department, School of Medicine, University Complutense, Avda Complutense s/n, 28040, Madrid, Spain
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