The clinical significance of Streptococcus pneumoniae resistance in community-acquired pneumonia
More details
Hide details
Lecturer in Pneumonology Medicine, Respiratory Medicine Clinic, Aristotle University of Thessaloniki
Assistant Professor in Pneumonology Medicine and Infectious Diseases, Respiratory Medicine Clinic, Aristotle University of Thessaloniki Respiratory Infections Unit, Respiratory Medicine Clinic, Aristotle University of Thessaloniki, “G. Papanikolaou” Hospital, Exohi, Thessaloniki
Ioannis Kioumis   

Respiratory Medicine Clinic Aristotle University of Thessaloniki G. Papanicolaou Hospital, Exohi, 57010 Thessaloniki, Greece
Pneumon 2011;24(4):376–388
As resistance to Streptococcus pneumoniae has escalated dramatically over the past decades, the efficacy of the three major classes of antibiotics most commonly used for the empirical treatment of community-acquired pneumonia (CAP), (i.e., β-lactams, macrolides and respiratory quinolones) is under investigation. According to recently published international data 21.8% of strains of S. pneumoniae are penicillin non-susceptible and 36.3% are resistant to azithromycin. Rates of quinolone resistance remain low, but clonal spread of resistant strains has been reported in closed communities. The precise clinical impact of antimicrobial resistance is difficult to assess, but treatment failures due to antibiotic-resistant S. pneumoniae have been documented. Comparison of the relatively small number of failures with the magnitude of confirmed resistance reveals a paradox that has not been clarified and possibly involves both pharmacokinetic and pharmacodynamic parameters. It is evident that the final outcome of CAP depends not only on the therapeutic regime but also on a variety of factors including the genetic characteristics of the bacterial strain and the background of the patient. Knowledge of the mechanisms of the emergence and spread of resistance is necessary for the rational selection of appropriate antibiotics. Current data suggest that the possibility of penicillin resistance should not be a leading factor for the choice of the therapeutic regime in CAP. In Greece, monotherapy of CAP with a macrolide poses clinical risks, while quinolones should be used with caution. In the setting of increasing resistance the administration of the appropriate antimicrobial therapy is essential for the prevention of emerging infections due to resistant S. pneumoniae strains, which apart from the increased cost of treatment may lead to an unfavourable outcome. 
Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents 2010;36:197-204.
Van der Poll T, Opal SM. Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet 2009;374:1543-56.
Muster DM. Streptococcus pneumoniae. In: Mandell, Douglas, and Bennett’s (editors) Principle and Practice of Infectious Diseases, Churchill Livingstone, 7th ed, 2010, pp2626-42.
Donowitz GR. Acute pneumonia. In: Mandell, Douglas, and Bennett’s (eds) Principle and Practice of Infectious Diseases, Churchill Livingstone, 7th ed, 2010, pp 891-916.
Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ, Johannes RS. Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia. Chest 2005;128:3854–62.
Jacobs MR. Antimicrobial-resistant Streptococcus pneumoniae: trends and management. Expert Rev Anti Infect Ther 2008;6:619–35.
Mandell LA, Wunderink RG, Anzueto A; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community acquired pneumonia in adults. Clin Infect Dis 2007;44(Suppl. 2):S27–72.
File TM. Clinical implications and treatment of multiresistant Streptococcus pneumoniae pneumonia. Clin Microbiol Infect 2006; 12 (Suppl. 3): 31–41.
Lynch JP III, Zhanel GG. Streptococcus Pneumoniae: Does Antimicrobial Resistance Matter? Semin Respir Crit Care Med 2009;30:210-238.
Καράμπελα Σ, Καναβάκη Σ, Κουμαντάκης Π, Μακαρώνα Μ, Μωραΐτου Ε, Πεφάνης Α. Η τρέχουσα αντοχή του πνευμονιοκόκκου στα αντιβιοτικά. Πνεύμων 2005; 18:263-274.
Bryan CS, Talwani R, Stinson MS. Penicillin Dosing for Pneumococcal Pneumonia. Chest 1997; 112:1657-64.
Hansman D, Bullen M. A resistant pneumococcus. Lancet 1967; ii: 264–265.
Jacobs MR, Koornhof HJ, Robins-Browne RM, et al. Emergence of multiply resistant pneumococci. New Engl J Med 1978; 299: 735–740.
Appelbaum PC, Bhamjee A, Scragg JN, Hallett AF, Bowen AJ, Cooper RC. Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet 1977; 2: 995–997.
Syrogiannopoulos GA, Grivea IN, Davies TA, Katopodis GD, Appelbaum PC, Beratis NG. Antimicrobial use and colonization with erythromycin-resistant Streptococcus pneumoniae in Greece during the first 2 years of life. Clin Infect Dis 2000; 31: 887–893.
Bedos JP, Chevret S, Chastang C, Geslin P, Regnier B. Epidemiological features of and risk factors for infection by Streptococcus pneumoniae strains with diminished susceptibility to penicillin: findings of a French survey. Clin Infect Dis 1996; 22: 63–72.
Kam KM, Luey KY, Fung SM, Yiu PP, Harden TJ, Cheung MM. Emergence of multiple-antibiotic-resistant Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 1995; 39: 2667–2670.
Lee HJ, Park JY, Jang SH, Kim JH, Kim EC, Choi KW. High incidence of resistance to multiple antimicrobials in clinical isolates of Streptococcus pneumoniae from a university hospital in Korea. Clin Infect Dis 1995; 20: 826–835.
Song JH, Lee NY, Ichiyama S. Spread of drug-resistant Streptococcus pneumoniae in Asian countries: Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study. Clin Infect Dis 1999; 28: 1206–1211.
Doern GV, Brueggemann A, Holley HPJr, Rauch AM. Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996; 40: 1208–1213.
Doern GV, Brueggemann AB, Blocker M. Clonal relationships among high-level penicillin-resistant Streptococcus pneumoniae in the United States. Clin Infect Dis 1998; 27: 757–761.
Doern GV, Brueggemann AB, Huynh H, Wingert E. Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997 98. Emerg Infect Dis 1999; 5: 757–765.
Whitney CG, Farley MM, Hadler J. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000; 343: 1917–1924.
Deeks SL, Palacio R, Ruvinsky R. Risk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae. The Streptococcus pneumoniae Working Group. Pediatrics 1999; 103: 409–413.
Schito GC, Felmingham D. Susceptibility of Streptococcus pneumoniae to penicillin, azithromycin and telithromycin (PROTEKT 1999-2003). Int J Antimicrob Agents 2005;26:479-85.
Richter SS, Heilmann KP, Dohrn CL, Riahi F, Beekmann SE, Doern GV. Changing Epidemiology of Antimicrobial-Resistant Streptococcus pneumoniae in the United States, 2004–2005. Clinical Infectious Diseases 2009; 48:e23–33.
Valles X, Marcos A, Pinart M et al. Hospitalized communityacquired pneumonia due to Streptococcus pneumoniae: Has resistance to antibiotics decreased? Chest 2006;130:800-806.
Maraki S, Mantadakis E, Samonis G. Serotype distribution and antimicrobial resistance of adult Streptococcus pneumoniae clinical isolates over the period 2001-2008 in Crete, Greece. Chemotherapy 2010;56:325-32.
Paraskakis I, Kafetzis DA, Chrisakis A et al; National Surveillance Network for Pneumococcal Resistance. Serotypes and antimicrobial susceptibilities of 1033 pneumococci isolated from children in Greece during 2001-2004. Clin Microbiol Infect 2006;12:490-3.
Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Twentieth informational supplement. Document M100-S20. Wayne, PA: Clinical and Laboratory Standards Institute, 2010.
Weinstein MP, Klugman KP, Jones RN. Rationale for revised penicillin susceptibility breakpoints versus Streptococcus pneumoniae: coping with antimicrobial susceptibility in an era of resistance. Clin Infect Dis 2009;48:1596–600.
Kosowska K, Jacobs MR, Bajaksouzian S, Koeth L, Appelbaum PC. Alterations of penicillin-binding proteins 1A, 2X, and 2B in Streptococcus pneumoniae isolates for which amoxicillin MICs are higher than penicillin MICs. Antimicrob Agents Chemother 2004; 48: 4020–4022.
Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg RN. The Alexander Project 1998–2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother 2003; 52: 229–246.
Sahm DF, Thornsberry C, Mayfield DC, Jones ME, Karlowsky JA. In vitro activities of broad-spectrum cephalosporins against nonmeningeal isolates of Streptococcus pneumoniae: MIC interpretation using NCCLS M100-S12 recommendations. J Clin Microbiol 2002; 40: 669–674.
Klugman KP, Lonks JR. Hidden epidemic of macrolide-resistant pneumococci. Emerg Infect Dis 2005 Jun;11(6):802-7.
Riedel S, Beekmann SE, Heilmann KP. Antimicrobial use in Europe and antimicrobial resistance in Streptococcus pneumoniae. Eur J Clin Microbiol Infect Dis 2007; 26: 485–490.
Doern GV, Richter SS, Miller A et al. Antimicrobial resistance among Streptococcus pneumoniae in the United States: have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis 2005;15:139-48.
Johnson DM, Stilwell MG, Fritsche TR, Jones RN. Emergence of multidrug-resistant Streptococcus pneumoniae: report from the SENTRY Antimicrobial Surveillance Program (1999–2003). Diagn Microbiol Infect Dis 2006; 56: 69–74.
Ho PI, Yung RWH, Tsang DNC et al. Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicenter study in 2000. J Antimicrob Chemother 2001;48:659-665.
Von Gottberg A, Klugman KP, Cohen C. Emergence of levofloxacin-non-susceptible Streptococcus pneumoniae and treatment for multidrug-resistant tuberculosis in children in South Africa: a cohort observational surveillance study. Lancet 2008; 371: 1108–1113.
Poulakou G, Katsarolis I, Matthaiopoulou I. Nationwide surveillance of Streptococcus pneumoniae in Greece: patterns of resistance and serotype epidemiology. Int J Antimicrob Agents 2007; 30: 87–92.
Rice LB. Bacterial monopolists: the bundling and dissemination of antimicrobial resistance genes in gram-positive bacteria. Clin Infect Dis 2000;31:762-9.
Gay K, Baughman W, Miller Y. The emergence of Streptococcus pneumoniae resistant to macrolide antimicrobial agents: a 6-year population-based assessment. J Infect Dis 2000; 182: 1417–1424.
Avery OT, Macleod CM, McCarty M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med 1944;79:137-58.
Pletz MW, McGee L, Jorgensen J et al. Levofloxacin-resistant invasive Streptococcus pneumoniae in the United States: evidence for clonal spread and the impact of conjugate pneumococcal vaccine. Antimicrob Agents Chemother 2004;48:3491-7.
Μανίκα Κ, Κιουμής Ι. Ο ρόλος των φθοριοκινολονών στη θεραπεία της Φυματίωσης. Πνεύμων 2008; 21:388-394.
Brown SD, Farrell DJ, Morrissey I. Prevalence and molecular analysis of macrolide and fluoroquinolone resistance among isolates of Streptococcus pneumoniae collected during the 2000-2001 PROTEKT US Study. J Clin Microbiol 2004;42:4980-7.
El Garch F, Lismond A, Piddock LJ, Courvalin P, Tulkens PM, Van Bambeke F. Fluoroquinolones induce the expression of patA and patB, which encode ABC efflux pumps in Streptococcus pneumoniae. J Antimicrob Chemother 2010;65:2076-82.
Zhanel GG, Palatnick L, Nichol KA, Bellyou T, Low DE, Hoban DJ. Antimicrobial resistance in respiratory tract Streptococcus pneumoniae isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob Agents Chemother 2003; 47: 1867–1874.
Doern GV, Pfaller MA, Kugler K, Freeman J, Jones RN. Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program. Clin Infect Dis 1998; 27: 764–770.
Lynch JPIII, Zhanel GG. Escalation of antimicrobial resistance among Streptococcus pneumoniae: implications for therapy. Semin Respir Crit Care Med 2005; 26: 575–616.
Jones ME, Blosser-Middleton RS, Thornsberry C, Karlowsky JA, Sahm DF. The activity of levofloxacin and other antimicrobials against clinical isolates of Streptococcus pneumoniae collected worldwide during 1999–2002. Diagn Microbiol Infect Dis 2003; 47: 579–586.
Macgowan AP; BSAC Working Parties on Resistance Surveillance. Clinical implications of antimicrobial resistance for therapy. J Antimicrob Chemother 2008;62(Suppl 2):ii105-14.
Metlay JP, Singer DE. Outcomes in lower respiratory tract infections and the impact of antimicrobial drug resistance. Clin Microbiol Infect 2002;8(Suppl 2):1-11.
Austrian R, Gold J. Pneumococal Bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964;60:759-76.
Fine MJ, Smith MA, Carson CA et al. Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. JAMA 1996;275:134-41.
Feikin DR, Schuchat A, Kolczak M et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. Am J Public Health 2000;90:223-9.
Centers for Disease Control and Prevention (CDC). Emergence of antimicrobial-resistant serotype 19A Streptococcus pneumoniae--Massachusetts, 2001-2006. MMWR Morb Mortal Wkly Rep 2007;56:1077-80.
Lode H, Grossman C, Choudhri S et al. Sequential IV/PO moxifloxacin treatment of patients with severe community-acquired pneumonia. Respir Med 2003;97:1134-42.
Choi EH, Lee HJ. Clinical outcome of invasive infections by penicillin-resistant Streptococcus pneumoniae in Korean children. Clin Infect Dis 1998;26:1346-54.
Turett GS, Blum S, Fazal BA, Justman JE, Telzak EE. Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high human immunodeficiency virus seroprevalence. Clin Infect Dis 1999;29:321-7.
Gómez-Barreto D, Calderón-Jaimes E, Rodríguez RS, de los Monteros LE. Clinical outcome of invasive infections in children caused by highly penicillin-resistant Streptococcus pneumoniae compared with infections caused by penicillin-susceptible strains. Arch Med Res 2000;31:592-8.
Castillo EM, Rickman LS, Brodine SK, Ledbetter EK, Kelly C. Streptococcus pneumoniae: bacteremia in an era of penicillin resistance. Am J Infect Control 2000;28:239-43.
Pallares R, Capdevila O, Liñares J et al. The effect of cephalosporin resistance on mortality in adult patients with nonmeningeal systemic pneumococcal infections. Am J Med 2002;113:120-6.
Maugein J, Guillemot D, Dupont MJ et al. Clinical and microbiological epidemiology of Streptococcus pneumoniae bacteremia in eight French counties. Clin Microbiol Infect 2003;9:280-8.
Fernández Guerrero ML, Ramos JM, Marrero J, Cuenca M, Fernández Roblas R, de Górgolas M. Bacteremic pneumococcal infections in immunocompromised patients without AIDS: the impact of beta-lactam resistance on mortality. Int J Infect Dis 2003;7:46-52.
Aspa J, Rajas O, Rodríguez de Castro F et al. Pneumococcal Pneumonia in Spain Study GroupDrug-resistant pneumococcal pneumonia: clinical relevance and related factors. Clin Infect Dis 2004;38:787-98. Epub 2004 Mar 1.
Lujan M, Gallego M, Fontanals D, Mariscal D, Rello J. Prospective observational study of bacteremic pneumococcal pneumonia: Effect of discordant therapy on mortality. Crit Care Med 2004;32:625-31.
Wunderink RG, Waterer GW. Community-acquired pneumonia: pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections. Infect Dis Clin North Am 2004;18:743-59.
Andersson DI, Levin BR. The biological cost of antibiotic resistance. Curr Opin Microbiol 1999;2:489-93.
Martínez JL, Baquero F. Interactions among strategies associated with bacterial infection: pathogenicity, epidemicity, and antibiotic resistance. Clin Microbiol Rev 2002 Oct;15(4):647-79.
Einarsson S, Kristjansson M, Kristinsson KG, Kjartansson G, Jonsson S. Pneumonia caused by penicillin-non-susceptible and penicillin-susceptible pneumococci in adults: a case-control study. Scand J Infect Dis 1998;30:253-6.
Tleyjeh IM, Tlaygeh HM, Hejal R, Montori VM, Baddour LM. The impact of penicillin resistance on short-term mortality in hospitalized adults with pneumococcal pneumonia: a systematic review and meta-analysis. Clin Infect Dis 2006;42:788-97. Epub 2006 Feb 8.
Reechaipichitkul W, Assawasanti K, Chaimanee P. Risk factors and clinical outcomes of penicillin resistant S. pneumoniae community-acquired pneumonia in Khon Kaen, Thailand. Southeast Asian J Trop Med Public Health 2006;37:320-6.
Ewig S, Ruiz M, Torres A et al. Pneumonia acquired in the community through drug-resistant Streptococcus pneumoniae. Am J Respir Crit Care Med 1999;159:1835-42.
Mufson MA, Chan G, Stanek RJ. Penicillin resistance not a factor in outcome from invasive Streptococcus pneumoniae community-acquired pneumonia in adults when appropriate empiric therapy is started. Am J Med Sci 2007;333:161-7.
Falcó V, Almirante B, Jordano Q et al. Influence of penicillin resistance on outcome in adult patients with invasive pneumococcal pneumonia: is penicillin useful against intermediately resistant strains? J Antimicrob Chemother 2004;54:481-8. Epub 2004 Jun 23.
Yu VL, Chiou CC, Feldman C et al; International Pneumococcal Study Group. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 2003;37:230-7. Epub 2003 Jul 7.
Silverstein M, Bachur R, Harper MB. Clinical implications of penicillin and ceftriaxone resistance among children with pneumococcal bacteremia. Pediatr Infect Dis J 1999;18:35-41.
Frankel RE, Virata M, Hardalo C, Altice FL, Friedland G. Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection. Clin Infect Dis 1996;23:577-84.
Deeks SL, Palacio R, Ruvinsky R et al. Risk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae. The Streptococcus pneumoniae Working Group. Pediatrics 1999;103:409-13.
Chen CJ, Lin CL, Chen YC et al. Host and microbiologic factors associated with mortality in Taiwanese children with invasive pneumococcal diseases, 2001 to 2006. Diagn Microbiol Infect Dis 2009;63:194-200.
Gómez-Barreto D, Espinosa-Monteros LE, López-Enríquez C, Jiménez-Rojas V, Rodríguez-Suárez R. Invasive pneumococcal disease in a third level pediatric hospital in Mexico City: epidemiology and mortality risk factors. Salud Publica Mex 2010;52:391 7.
Klugman KP. Bacteriological evidence of antibiotic failure in pneumococcal lower respiratory tract infections. Eur Respir J Suppl 2002;36:3s-8s.
Schrag SJ, McGee L, Whitney CG et al; Active Bacterial Core Surveillance Team. Emergence of Streptococcus pneumoniae with very-high-level resistance to penicillin. Antimicrob Agents Chemother 2004;48:3016-23.
Andes D, Craig WA. In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations. Antimicrob Agents Chemother 1998;42:2375-9.
Menendez R, Torres A. Treatment failure in community-acquired pneumonia. Chest 2007;132:1348-55.
Ομάδα Εργασίας της Ελληνικής Εταιρείας Λοιμώξεων, της Ελληνικής Εταιρείας Χημειοθεραπείας και της Ελληνικής Πνευμονολογικής Εταιρείας. Κατευθυντήριες οδηγίες για τη διάγνωση και την εμπειρική θεραπεία της πνευμονίας της κοινότητας. Στο: Κατευθυντήριες Οδηγίες για τη Διάγνωση και την Εμπειρική Θεραπεία των Λοιμώξεων από: Κέντρο Ελέγχου και Πρόληψης Νοσημάτων, Επιστημονική Επιτροπή Νοσοκομειακών Λοιμώξεων, Υπεύθυνος έκδοσης: Ελληνική Εταιρεία Λοιμώξεων. Αθήνα 2007 σελ: 33-46.
Metlay JP. Antibacterial drug resistance: implications for the treatment of patients with community-acquired pneumonia. Infect Dis Clin North Am 2004;18:777-90.
Dagan R, Abramson O, Leibovitz E et al. Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pediatr Infect Dis J 1996;15:980-5.
Dagan R, Leibovitz E, Fliss DM et al. Bacteriologic efficacies of oral azithromycin and oral cefaclor in treatment of acute otitis media in infants and young children. Antimicrob Agents Chemother 2000;44:43-50.
Hameed N, Tunkel AR. Treatment of Drug-resistant Pneumococcal Meningitis. Curr Infect Dis Rep 2010;12:274-81.
Morand B, Mühlemann K. Heteroresistance to penicillin in Streptococcus pneumoniae. Proc Natl Acad Sci U S A 2007;104:14098- 103. Epub 2007 Aug 17.
Azoulay-Dupuis, E, Moine P, Bedos JP, Rieux V, Vallee E. Amoxicillin dose-effect relationship with Streptococcus pneumoniae in a mouse pneumonia model and roles of in vitro penicillin susceptibilities, autolysis, and tolerance properties of the strains. Antimicrob Agents Chemother 1996; 40:941–946.
Abgueguen P, Azoulay-Dupuis E, Noel Vet al. Amoxicillin Is Effective against Penicillin-Resistant Streptococcus pneumoniae strains in a mouse pneumonia model simulating human pharmacokinetics. Antimicrob Agents Chemother 2007;51:208-214.
Pallares R, Gudiol F, Liñares J et al. Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med 1987;317:18-22.
Vanderkooi OG, Low DE, Green K, Powis JE, McGeer A; Toronto Invasive Bacterial Disease Network. Predicting antimicrobial resistance in invasive pneumococcal infections. Clin Infect Dis 2005;40:1288-97. Epub 2005 Mar 31.
Sacho H, Klugman KP, Koornhof HJ, Ruff P. Community-acquired pneumonia in an adult due to a multiply-resistant pneumococcus. J Infect 1987; 14: 188–189.
Buckingham SC, Brown SP, Joaquin VH. Breakthrough bacteremia and meningitis during treatment with cephalosporins parenterally for pneumococcal pneumonia. J Pediatr 1998; 132: 174–176.
Rzeszutek M, Wierzbowski A, Hoban DJ, Conly J, Bishai W, Zhanel GG. A review of clinical failures associated with macrolideresistant Streptococcus pneumoniae. Int J Antimicrob Agents 2004;24:95-104.
Kelley MA, Weber DJ, Gilligan P, Cohen MS. Breakthrough pneumococcal bacteremia in patients being treated with azithromycin and clarithromycin. Clin Infect Dis 2000;31:1008- 11. Epub 2000 Oct 13.
Fogarty C, Goldschmidt R, Bush K. Bacteremic pneumonia due to multidrug-resistant pneumococci in 3 patients treated unsuccessfully with azithromycin and successfully with levofloxacin. Clin Infect Dis 2000;31:613-5.
Lonks JR, Garau J, Medeiros AA. Implications of antimicrobial resistance in the empirical treatment of community-acquired respiratory tract infections: the case of macrolides. J Antimicrob Chemother 2002;50(Suppl S2):87-92.
Van Kerkhoven D, Peetermans WE, Verbist L, Verhaegen J. Breakthrough pneumococcal bacteraemia in patients treated with clarithromycin or oral beta-lactams. J Antimicrob Chemother 2003;51:691-6.
Lonks JR. What Is the Clinical Impact of Macrolide Resistance? Curr Infect Dis Rep 2004;6:7-12.
Yanagihara K, Izumikawa K, Higa F et al. Efficacy of azithromycin in the treatment of community-acquired pneumonia, including patients with macrolide-resistant Streptococcus pneumoniae infection. Intern Med 2009;48:527-35. Epub 2009 Apr 1.
Nuermberger E, Bishai WR. The clinical significance of macrolideresistant Streptococcus pneumoniae: it’s all relative. Clin Infect Dis 2004;38:99-103. Epub 2003 Dec 8.
Panteix G, Guillomond B, Harf R et al. In vitro concentration of azithromycin in human phagocytic cells. J Antimicrob Chemother 1993;31S:1-4.
Patel KB, Xuan D, Tessier PR, Russomanno JH, Quintiliani R, Nightingale CH. Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin. Antimicrob Agent Chemother 1996;40:2375-2379.
Johnson JD, Hand WL, Francis LB, King-Thompson N, Corwin RW. Antibiotic intake by alveolar macrophages. J Lab Clin Med 1980;95:429-439.
Lonks JR, Garau J, Gomez L, et al. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycinresistant Streptococcus pneumoniae. Clin Infect Dis 2002; 35:556–64.
Baquero F. Evolving resistance patterns of Streptococcus pneumoniae: a link with long-acting macrolide consumption? J Chemother 1999; 11(Suppl 1):35-43.
Nicolau D. Clinical and economic implications of antimicrobial resistance for the management of community-acquired respiratory infections. J Antimicrob Chemother 2002;S1:61-70.
Fukuda Y, Yanagihara K, Higashiyama Y et al. Effects of macrolides on pneumolysin of macrolide-resistant Streptococcus pneumoniae. Eur Respir J 2006;27:1020-5. Epub 2006 Feb 2.
Yasuda Y, Kasahara K, Mizuno F, Nishi K, Mikasa K, Kita E. Roxithromycin favorably modifies the initial phase of resistance against infection with macrolide-resistant Streptococcus pneumoniae in a murine pneumonia model. Antimicrob Agents Chemother 2007;51:1741-52. Epub 2007 Mar 12.
Friedlander AL, Albert RK. Chronic macrolide therapy in inflammatory airways diseases. Chest 2010 Nov;138(5):1202-12.
Bell SC, Senini SL, McCormack JG. Macrolides in cystic fibrosis. Chron Respir Dis 2005;2:85-98.
Woodroffe R, Yao GL, Meads C et al. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess 2005;9:1-179, iii-iv.
Tamaoki J. The effects of macrolides on inflammatory cells. Chest 2004;125(2 Suppl):41S-50S; quiz 51S.
Healy DP. Macrolide immunomodulation of chronic respiratory diseases. Curr Infect Dis Rep 2007;9:7-13.
Geissler EK. Can immunosuppressive strategies be used to reduce cancer risk in renal transplant patients? Transplant Proc 2010;42(9 Suppl):S32-5.
Čulić O, Erakovic V, Cepelak I et al. Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy subjects. Eur J Pharmacol 2002;30:277-89.
Davidson R, Cavalcanti R, Brunton JL et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:747-50.
Ross JJ, Worthington MG, Gorbach SL. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;347:65-7; author reply 65-7.
Low DE. Quinolone resistance among pneumococci: therapeutic and diagnostic implications. Clin Infect Dis 2004;38(Suppl 4):S357-62.
Pletz MW, van der Linden M, von Baum H, Duesberg CB, Klugman KP, Welte T; CAPNETZ study group. Low prevalence of fluoroquinolone resistant strains and resistance precursor strains in Streptococcus pneumoniae from patients with community-acquired pneumonia despite high fluoroquinolone usage. Int J Med Microbiol 2011;301:53-7. Epub 2010 Aug 7.
Lim S, Bast D, McGeer A, de Azavedo J, Low DE. Antimicrobial susceptibility breakpoints and first-step parC mutations in Streptococcus pneumoniae: redefining fluoroquinolone resistance. Emerg Infect Dis 2003; 9:833–7.
Low DE. Fluoroquinolone-resistant pneumococci: maybe resistance isn’t futile? Clin Infect Dis 2005;40:236-8. Epub 2004 Dec 21.
Allen GP, Kaatz GW, Rybak MJ. Activities of mutant prevention concentration-targeted moxifloxacin and levofloxacin against Streptococcus pneumoniae in an in vitro pharmacodynamic model. Antimicrob Agents Chemother 2003;47:2606-14.
Riedel S, Beekmann SE, Heilmann KP et al. Antimicrobial use in Europe and antimicrobial resistance in Streptococcus pneumoniae. Eur J Clin Microbiol Infect Dis. 2007;26:485-90. Eur J Clin Microbiol Infect Dis 2007;26:485-90.
Μπαρτζιώκας Κ, Κωστίκας Κ, Παπαδόπουλος Α. Ο ρόλος της προκαλσιτονίνης στην αντιμετώπιση των ασθενών με σήψη και λοιμώξεις του αναπνευστικού: Από την έρευνα στην κλινική πράξη. Πνεύμων 2010; 23:363-368.