Abstract
Mycoplasma pneumoniae is one of the main pathogens causing community-acquired respiratory tract infections in children and adults. Macrolide (ML) antibiotics are recognized generally as first-choice agents for M. pneumoniae infections, and these antibiotics were thought to have excellent effectiveness against M. pneumoniae for many years. In 2000, however, M. pneumoniae showing resistance to macrolides was isolated from clinical samples obtained from Japanese pediatric patients with community-acquired pneumonia (CAP). Since then, prevalence of ML-resistant M. pneumoniae isolates in pediatric patients has increased rapidly. In 2007, ML-resistant M. pneumoniae isolates were obtained from Japanese adults with CAP; numbers of such isolates also have gradually increased in Japan. Recently, similar antimicrobial resistance in M. pneumoniae has begun to emerge worldwide. In this review, we focus on changes of ML-resistant M. pneumoniae from year to year and consider resistance mechanisms as well as clinical features of patients with resistant M. pneumoniae infection.
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References
Waites KB, Rikihisa Y, Taylor-Robinson D. Mycoplasma, Ureaplasma. In: Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH, eds. Manual of clinical microbiology. 8th edn. Washington: American Society for Microbiology; 2003. p. 972–90.
Hammerschlag MR. Mycoplasma pneumoniae infections. Curr Opin Infect Dis. 2001;14:181–6.
Heiskanen-Kosma T, Korppi M, Jokinen C, Kurki S, Heiskanen L, Juvonen H, et al. Etiology of childhood pneumonia: serologic results of a prospective, population-based study. Pediatr Infect Dis J. 1998;17:986–91.
Kashyap B, Kumar S, Sethi GR, Das BC, Saigal SR. Comparison of PCR, culture & serological tests for the diagnosis of Mycoplasma pneumoniae in community-acquired lower respiratory tract infections in children. Indian J Med Res. 2008;128:134–9.
McIntosh K. Community-acquired pneumonia in children. N Engl J Med. 2002;346:429–37.
Morozumi M, Hasegawa K, Chiba N, Iwata S, Kawamura N, Kuroki H, et al. Application of PCR for Mycoplasma pneumoniae detection in children with community-acquired pneumonia. J Infect Chemother. 2004;10:274–9.
Nakayama E, Hasegawa K, Morozumi M, Kobayashi R, Chiba N, Iitsuka T, et al. Rapid optimization of antimicrobial chemotherapy given to pediatric patients with community-acquired pneumonia using PCR techniques with serology and standard culture. J Infect Chemother. 2007;13:305–13.
Oguz F, Unuvar E, Aydin D, Yilmaz K, Sidal M. Frequency of Mycoplasma pneumoniae among atypical pneumonia of childhood. Turk J Pediatr. 2002;44:283–8.
Defilippi A, Silvestri M, Tacchella A, Giacchino R, Melioli G, Di Marco E, et al. Epidemiology and clinical features of Mycoplasma pneumoniae infection in children. Respir Med. 2008;102:1762–8.
Howard LS, Sillis M, Pasteur MC, Kamath AV, Harrison BD. Microbiological profile of community-acquired pneumonia in adults over the last 20 years. J Infect. 2005;50:107–13.
Ishida T, Hashimoto T, Arita M, Ito I, Osawa M. Etiology of community-acquired pneumonia in hospitalized patients: a 3-year prospective study in Japan. Chest. 1998;114:1588–93.
Martínez MA, Ruiz M, Zunino E, Luchsinger V, Avendaño LF. Detection of Mycoplasma pneumoniae in adult community-acquired pneumonia by PCR and serology. J Med Microbiol. 2008;57:1491–5.
Miyashita N, Ouchi K, Kawasaki K, Oda K, Kawai Y, Shimizu H, et al. Mycoplasma pneumoniae pneumonia in the elderly. Med Sci Monit. 2008;14:387–91.
Porath A, Schlaeffer F, Lieberman D. The epidemiology of community-acquired pneumonia among hospitalized adults. J Infect. 1997;34:41–8.
Takahashi T, Morozumi M, Chiba N, Asami R, Okada T, Murayama SY, et al. Prolonged Mycoplasma pneumoniae infection in an elderly patient with community-acquired pneumonia. J Infect Chemother. 2009;15:243–7.
Abele-Horn M, Busch U, Nitschko H, Jacobs E, Bax R, Pfaff F, et al. Molecular approaches to diagnosis of pulmonary diseases due to Mycoplasma pneumoniae. J Clin Microbiol. 1998;36:548–51.
Dorjgo-Zetsma JW, Verkooyen RP, Van Helden HP, Van der Nat H, Van den Bosch JM. Molecular detection of Mycoplasma pneumoniae in adults with community-acquired pneumonia requiring Hospitalization. J Clin Microbiol. 2001;39:1184–6.
Dorigo-Zetsma JW, Zaat SA, Wertheim-van Dillen PM, Spanjaard L, Rijntjes J, van Waveren G, et al. Comparison of PCR, culture, and serological tests for diagnosis of Mycoplasma pneumoniae respiratory tract infection in children. J Clin Microbiol. 1999;37:14–7.
Hardegger D, Nadal D, Bossart W, Altwegg M, Dutly F. Rapid detection of Mycoplasma pneumoniae in clinical samples by real-time PCR. J Microbiol Methods. 2000;41:45–51.
Ieven M, Ursi D, Van Bever H, Quint W, Niesters HG, Goossens H. Detection of Mycoplasma pneumoniae by two polymerase chain reactions and role of M. pneumoniae in acute respiratory tract infections in pediatric patients. J Infect Dis. 1996;173:1445–52.
Khanna M, Fan J, Pehler-Harrington K, Waters C, Douglass P, Stallock J, et al. The pneumoplex assays, a multiplex PCR-enzyme hybridization assay that allows simultaneous detection of five organisms, Mycoplasma pneumoniae, Chlamydia (Chlamydophila) pneumoniae, Legionella pneumophila, Legionella micdadei, and Bordetella pertussis, and its real-time counterpart. J Clin Microbiol. 2005;43:565–71.
Morozumi M, Nakayama E, Iwata S, Aoki Y, Hasegawa K, Kobayashi R, et al. Simultaneous detection of pathogens in clinical samples from patients with community-acquired pneumonia by real-time PCR with pathogen-specific molecular beacon probes. J Clin Microbiol. 2006;44:1440–6.
Nadala D, Bossart W, Zucol F, Steiner F, Berger C, Lips U, et al. Community-acquired pneumonia in children due to Mycoplasma pneumoniae: diagnostic performance of a seminested 16S rDNA-PCR. Diagn Microbiol Infect Dis. 2001;39:15–9.
Otomo S, Yamamura J, Hayashi E, Nakamura T, Kakinuma H, Nakamoto Y, et al. Analysis of children with Chlamydophila (Chlamydia) pneumoniae and Mycoplasma pneumoniae respiratoryinfections by real-time PCR assay and serological tests. APMIS. 2008;116:477–83.
Pitcher D, Chalker VJ, Sheppard C, George RC, Harrison TG. Real-time detection of Mycoplasma pneumoniae in respiratory samples with an internal processing control. J Med Microbiol. 2006;55:149–55.
Templeton KE, Scheltinga SA, Graffelman AW, van Schie JM, Crielaard JW, Sillekens P, et al. Comparison and evaluation of real-time PCR, real-time nucleic acid sequence-based amplification, conventional PCR, and serology for diagnosis of Mycoplasma pneumoniae. J Clin Microbiol. 2003;41:4366–71.
Tjhie JH, van Kuppeveld FJ, Roosendaal R, Melchers WJ, Gordijn R, MacLaren DM, et al. Direct PCR enables detection of Mycoplasma pneumoniae in patients with respiratory tract infections. J Clin Microbiol. 1994;32:11–6.
Welti M, Jaton K, Altwegg M, Sahli R, Wenger A, Bille J. Development of a multiplex real-time quantitative PCR assay to detect Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae in respiratory tract secretions. Diagn Microbiol Infect Dis. 2003;45:85–95.
Felmingham D, Robbins MJ, Sanghrajka M, Leakey A, Ridgway GL. The in vitro activity of some 14-, 15- and 16-membered macrolides against Staphylococcus spp., Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum. Drugs Exp Clin Res. 1991;17:91–9.
Ishida K, Kaku M, Irifune K, Mizukane R, Takemura H, Yoshida R, et al. In vitro and in vivo activities of macrolides against Mycoplasma pneumoniae. Antimicrob Agents Chemother. 1994;38:790–8.
Morozumi M, Hasegawa K, Kobayashi R, Inoue N, Iwata S, Kuroki H, et al. Emergence of macrolide-resistant Mycoplasma pneumoniae with a 23S rRNA gene mutation. Antimicrob Agents Chemother. 2005;49:2302–6.
Rennie KA, Prasad ES, Wenman WM. In vitro activity of dirithromycin, a new macrolide antibiotic, against Mycoplasma species. Diagn Microbiol Infect Dis. 1994;20:57–9.
Waites KB, Cassell GH, Canupp KC, Fernandes PB. In vitro susceptibilities of mycoplasmas and ureaplasmas to new macrolides and aryl-fluoroquinolones. Antimicrob Agents Chemother. 1988;32:1500–2.
Okazaki N, Narita M, Yamada S, Izumikawa K, Umetsu M, Kenri T, et al. Characteristics of macrolide-resistant Mycoplasma pneumoniae strains isolated from patients and induced with erythromycin in vitro. Microbiol Immunol. 2001;45:617–20.
Okazaki N, Ohya H, Sasaki T. Mycoplasma pneumoniae isolated from patients with respiratory infection in Kanagawa Prefecture in 1976–2006: emergence of macrolide-resistant strains. Jpn J Infect Dis. 2007;60:325–6.
Morozumi M, Iwata S, Hasegawa K, Chiba N, Takayanagi R, Matsubara K, et al. Increased macrolide resistance of Mycoplasma pneumoniae in pediatric patients with community-acquired pneumonia. Antimicrob Agents Chemother. 2008;52:348–50.
Li X, Atkinson TP, Hagood J, Makris C, Duffy LB, Waites KB. Emerging macrolide resistance in Mycoplasma pneumoniae in children: detection and characterization of resistant isolates. Pediatr Infect Dis J. 2009;28:693–6.
Liu Y, Ye X, Zhang H, Xu X, Li W, Zhu D, et al. Antimicrobial susceptibility of Mycoplasma pneumoniae isolates and molecular analysis of macrolide-resistant strains from Shanghai, China. Antimicrob Agents Chemother. 2009;53:2160–2.
Pereyre S, Charron A, Renaudin H, Bébéar C, Bébéar CM. First report of macrolide-resistant strains and description of a novel nucleotide sequence variation in the P1 adhesin gene in Mycoplasma pneumoniae clinical strains isolated in France over 12 years. J Clin Microbiol. 2007;45:3534–9.
Xin D, Mi Z, Han X, Qin L, Li J, Wei T, et al. Molecular mechanisms of macrolide resistance in clinical isolates of Mycoplasma pneumoniae from China. Antimicrob Agents Chemother. 2009;53:2158–9.
Wolff BJ, Thacker WL, Schwartz SB, Winchell JM. Detection of macrolide resistance in Mycoplasma pneumoniae by real-time PCR and high-resolution melt analysis. Antimicrob Agents Chemother. 2008;52:3542–9.
Alexander ER, Foy HM, Kenny GE, Kronmal RA, McMahan R, Clarke ER, et al. Pneumonia due to Mycoplasma pneumoniae. Its incidence in the membership of a co-operative medical group. N Engl J Med. 1966;275:131–6.
Eun BW, Kim NH, Choi EH, Lee HJ. Mycoplasma pneumoniae in Korean children: the epidemiology of pneumonia over an 18-year period. J Infect. 2008;56:326–31.
Feikin DR, Moroney JF, Talkington DF, Thacker WL, Code JE, Schwartz LA, et al. An outbreak of acute respiratory disease caused by Mycoplasma pneumoniae and adenovirus at a federal service training academy: new implications from an old scenario. Clin Infect Dis. 1999;29:1545–50.
Hauksdóttir GS, Jónsson T, Sigurdardóttir V, Löve A. Seroepidemiology of Mycoplasma pneumoniae infections in Iceland 1987–96. Scand J Infect Dis. 1998;30:177–80.
Lind K, Benzon MW, Jensen JS, Clyde WA Jr. A seroepidemiological study of Mycoplasma pneumoniae infections in Denmark over the 50-year period 1946–1995. Eur J Epidemiol. 1997;13:581–6.
Beersma MF, Dirven K, van Dam AP, Templeton KE, Claas EC, Goossens H. Evaluation of 12 commercial tests and the complement fixation test for Mycoplasma pneumoniae-specific immunoglobulin G (IgG) and IgM antibodies, with PCR used as the “gold standard”. J Clin Microbiol. 2005;43:2277–85.
Narita M, Togashi T. Evaluation of a rapid IgM antibody detection kit for diagnosis of Mycoplasma pneumoniae infection during childhood. Kansenshogaku Zasshi. 2003;77:310–5.
Daxboeck F, Kircher K, Krause R, Heinzl H, Wenisch C, Stanek G. Effect of age on antibody titer to Mycoplasma pneumoniae. Scand J Infect Dis. 2002;34:577–9.
Sillis M. The limitations of IgM assays in the serological diagnosis of Mycoplasma pneumoniae infections. J Med Microbiol. 1990;33:253–8.
Hansen LH, Mauvais P, Douthwaite S. The macrolide-ketolide antibiotic binding site is formed by structures in domain II and V of 23S ribosomal RNA. Mol Microbiol. 1999;31:623–31.
Poehlsgaard J, Douthwaite S. Macrolide antibiotic interaction and resistance on the bacterial ribosome. Curr Opin Investig Drugs. 2003;4:140–8.
Vester B, Douthwaite S. Macrolide resistance conferred by base substitutions in 23S rRNA. Antimicrob Agents Chemother. 2001;45:1–12.
Bryskier A, Agouridas C, Chantot JF. Ketolides: new semisynthetic 14-membered-ring macrolides. In: Zinner SH, Young LS, Acar JF, Neu HC, editors. Expanding indications for the new macrolides, azalides, and streptogramins. New York: Marcel Dekker Inc; 1997. p. 39–50.
Lucier TS, Heitzman K, Liu SK, Hu PC. Trasition mutations in the 23S rRNA of erythromycin-resistant isolates of Mycoplasma pneumoniae. Antimicrob Agents Chemother. 1995;39:2770–3.
Pereyre S, Guyot C, Renaudin H, Charron A, Bébéar C, Bébéar CM. In vitro selection and characterization of resistance to macrolides and related antibiotics in Mycoplasma pneumoniae. Antimicrob Agents Chemother. 2004;48:460–5.
Ubukata K, Iwata S, Sunakawa K. In vitro activities of new ketolide, telithromycin, and eight other macrolide antibiotics against Strptococcus pneumoniae having mefA and ermB genes that mediate macrolide resistance. J Infect Chemother. 2003;9:221–6.
Cattoir V, Merabet L, Legrand P, Soussy CJ, Leclercq R. Emergence of a Streptococcus pneumoniae isolate resistant to streptogramins by mutation in ribosomal protein L22 during pristinamycin therapy of pneumococcal pneumonia. J Antimicrob Chemother. 2007;59:1010–2.
Reinert RR, Al-Lahham A. Time-kill study of the activity of telithromycin against macrolide-resistant Streptococcus pneumoniae isolates with 23S rRNA mutations and changes in ribosomal proteins L4 and L22. Antimicrob Agents Chemother. 2005;49:3011–3.
Bébéar CM, Pereyre S. Mechanisms of drug resistance in Mycoplasma pneumoniae. Curr Drug Targets Infect Disord. 2005;5:263–71.
Gruson D, Pereyre S, Renaudin H, Charron A, Bébéar C, Bébéar CM. In vitro development of resistance to six and four FQ in Mycoplasma pneumoniae and, respectively. Antimicrob Agents Chemother. 2005;49:1190–3.
Anokhina MM, Barta A, Nierhaus KH, Spiridonova VA, Kopylov AM. Mapping of the second tetracycline binding site on the ribosomal small subunit of E. coli. Nucleic Acids Res. 2004;32:2594–7.
Brodersen DE, Clemons WM Jr, Carter AP, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell. 2000;103:1143–54.
Roberts MC, Koutsky LA, Holmes KK, LeBlanc DJ, Kenny GE. Tetracycline-resistant Mycoplasma hominis strains contain streptococcal tetM sequences. Antimicrob Agents Chemother. 1985;28:141–3.
Matsuoka M, Narita M, Okazaki N, Ohya H, Yamazaki T, Ouchi K, et al. Characterization and molecular analysis of macrolide-resistant Mycoplasma pneumoniae clinical isolates obtained in Japan. Antimicrob Agents Chemother. 2004;48:4624–30.
Isozumi R, Yoshimine H, Morozumi M, Ubukata K, Ariyoshi K. Adult case of community-acquired pneumonia caused by macrolide-resistant Mycoplasma pneumoniae. Respirology. 2009; 14(8):1206–8.
Peuchant O, Ménard A, Renaudin H, Morozumi M, Ubukata K, Bébéar CM, et al. Increased macrolide resistance of Mycoplasma pneumoniae in France directly detected in clinical specimens by real-time PCR and melting curve analysis. J Antimicrob Chemother. 2009;64:52–8.
Cousin-Allery A, Charron A, Barbeyrac BD, Fremy G, Jensen JS, Renaudin H, et al. Molecular typing of Mycoplasma pneumoniae strains by PCR-based methods and pulsed-field gel electrophoresis. Application to French and Danish isolates. Epidemiol Infect. 2000;124:103–11.
Numazaki K, Umetsu M, Adachi N. Mycoplasma pneumoniae infection and its genotypical characterization in children of Hokkaido, Japan. In Vivo. 2003;17:421–4.
Schwartz SB, Thurman KA, Mitchell SL, Wolff BJ, Winchell JM. Genotyping of Mycoplasma pneumoniae isolates using real-time PCR and high-resolution melt analysis. Clin Microbiol Infect. 2009;15:756–62.
Suzuki S, Yamazaki T, Narita M, Okazaki N, Suzuki I, Andoh T, et al. Clinical evaluation of macrolide-resistant Mycoplasma pneumoniae. Antimicrob Agents Chemother. 2006;50:709–12.
Matsubara K, Morozumi M, Okada T, Matsushima T, Komiyama O, Shoji M, et al. A comparative clinical study of macrolide-sensitive and macrolide-resistant Mycoplasma pneumoniae infections in pediatric patients. J Infect Chemother. 2009; 15(6):380–3.
Denny FW, Clyde WA Jr, Glezen WP. Mycoplasma pneumoniae disease: clinical spectrum, pathophysiology, epidemiology, and control. J Infect Dis. 1971;123:74–92.
Smith CB, Friedewald WT, Chanock RM. Shedding of Mycoplasma pneumoniae after tetracycline and erythromycin therapy. N Engl J Med. 1967;276:1172–5.
Lu YJ, Chen TH, Lin LH, Shen CM, Huang CH. Macrolide use shortens fever duration in Mycoplasma pneumoniae infection in children: a 2-year experience. J Microbiol Immunol Infect. 2008;41:307–10.
John SD, Ramanathan J, Swischuk LE. Spectrum of clinical and radiographic findings in pediatric mycoplasma pneumonia. Radiographics. 2001;21:121–31.
Wieslander A, Boyer MJ, Wroblewski H. Membrane protein structure. In: Maniloff J, McElhaney RN, Finch LR, Baseman JB, editors. Mycoplasmas: molecular biology, pathogenesis. Washington: American Society for Microbiology; 1992. p. 93–112.
Chmura K, Bai X, Nakamura M, Kandasamy P, McGibney M, Kuronuma K, et al. Induction of IL-8 by Mycoplasma pneumoniae membrane in BEAS-2B cells. Am J Physiol Lung Cell Mol Physiol. 2008;295:220–30.
Broaders SA, Hooper WC, Phillips DJ, Talkington DF. Mycoplasma pneumoniae subtype-independent induction of proinflammatory cytokines in THP-1 cells. Microb Pathog. 2006;40:286–92.
Chaudhry R, Varshney AK, Malhotra P. Adhesion proteins of Mycoplasma pneumoniae. Front Biosci. 2007;12:690–9.
Layh-Schmitt G, Podtelejnikov A, Mann M. Proteins complexed to the P1 adhesin of Mycoplasma pneumoniae. Microbiology. 2000;146:741–7.
Seto S, Miyata M. Attachment organelle formation represented by localization of cytadherence proteins and formation of the electron-dense core in wild-type and mutant strains of Mycoplasma pneumoniae. J Bacteriol. 2003;185:1082–91.
Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev. 2004;17:697–728.
Yang J, Hooper WC, Phillips DJ, Talkington DF. Regulation of proinflammatory cytokines in human lung epithelial cells infected with Mycoplasma pneumoniae. Infect Immun. 2002;70:3649–55.
Yang J, Hooper WC, Phillips DJ, Talkington DF. Cytokines in Mycoplasma pneumoniae infections. Cytokine Growth Factor Rev. 2004;15:157–68.
Narita M, Tanaka H, Yamada S, Abe S, Ariga T, Sakiyama Y. Significant role of interleukin-8 in pathogenesis of pulmonary disease due to Mycoplasma pneumoniae infection. Clin Diagn Lab Immunol. 2001;8:1028–30.
Narita M, Tanaka H, Abe S, Yamada S, Kubota M, Togashi T. Close association between pulmonary disease manifestation in Mycoplasma pneumoniae infection and enhanced local production of interleukin-18 in the lung, independent of gamma interferon. Clin Diagn Lab Immunol. 2000;7:909–14.
Narita M, Tanaka H. Cytokines involved in the severe manifestations of pulmonary diseases caused by Mycoplasma pneumoniae. Pediatr Pulmonol. 2007;42:397.
Tanaka H, Narita M, Teramoto S, Saikai T, Oashi K, Igarashi T, et al. Role of interleukin-18 and T-helper type 1 cytokines in the development of Mycoplasma pneumoniae pneumonia in adults. Chest. 2002;121:1493–7.
Abe S, Nakamura H, Inoue S, Takeda H, Saito H, Kato S, et al. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;22:51–60.
Beović B, Bonac B, Kese D, Avsic-Zupanc T, Kreft S, Lesnicar G, et al. Aetiology and clinical presentation of mild community-acquired bacterial pneumonia. Eur J Clin Microbiol Infect Dis. 2003;22:584–91.
Marrie TJ. Epidemiology of mild pneumonia. Semin Respir Infect. 1998;13:3–7.
Waites KB. New concepts of Mycoplasma pneumoniae infections in children. Pediatr Pulmonol. 2003;36:267–78.
Miyashita N, Obase Y, Ouchi K, Kawasaki K, Kawai Y, Kobashi Y, et al. Clinical features of severe Mycoplasma pneumoniae pneumonia in adults admitted to an intensive care unit. J Med Microbiol. 2007;56:1625–9.
Kim DH, Lee KY, Kim MS, Youn YS, Hwang JY, Rhim JW, et al. Corticosteroid treatment in siblings affected with severe Mycoplasma pneumoniae pneumonia. Infect Chemother. 2009;41(3):190–5.
Tagliabue C, Salvatore CM, Techasaensiri C, Mejias A, Torres JP, Katz K, et al. The impact of steroids given with macrolide therapy on experimental Mycoplasma pneumoniae respiratory infection. J Infect Dis. 2008;198:1180–8.
Radisic M, Torn A, Gutierrez P, Defranchi HA, Pardo P. Severe acute lung injury caused by Mycoplasma pneumoniae: potential role for steroid pulses in treatment. Clin Infect Dis. 2000;31:1507–11.
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Morozumi, M., Takahashi, T. & Ubukata, K. Macrolide-resistant Mycoplasma pneumoniae: characteristics of isolates and clinical aspects of community-acquired pneumonia. J Infect Chemother 16, 78–86 (2010). https://doi.org/10.1007/s10156-009-0021-4
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DOI: https://doi.org/10.1007/s10156-009-0021-4