AiM  Vol.4 No.10 , August 2014
Insights into Pneumococcal Pathogenesis and Antibiotic Resistance

Since its discovery in 1891, the pneumococcus has been one of the most extensively studied microbes, and was involved in several historical findings such as the discovery of genetic material that was later shown to be DNA. The pneumococcus is part of the normal bacterial flora of the nasopharynx, but can on occasions progress to sterile sites of the body and cause invasive diseases. There are about one million new invasive pneumococcal infections every year, majority of which occur in the developing world where children <5 years are most affected. The burden of pneumococcal disease is further heightened by the increasing prevalence of multidrug resistance of the organism. The pneumococcus remains a pathogen of immense public health significance and understanding its biology, particularly the pathogenesis and antibiotic resistance is crucial to controlling pneumococcal disease.

Cite this paper
Donkor, E. and Badoe, E. (2014) Insights into Pneumococcal Pathogenesis and Antibiotic Resistance. Advances in Microbiology, 4, 627-643. doi: 10.4236/aim.2014.410069.
[1]   Black, R.E., Cousens, S., Johnson, H.L., Lawn, J.E., Rudan, I., Bassani, D.G., Jha, P., Campbell, H., Walker, C.F., Cibulskis, R., Eisele, T., Liu, L. and Mathers, C. (2010) Global, Regional, and National Causes of Child Mortality in 2008: A Systematic Analysis. The Lancet, 375, 1969-1987.

[2]   O’Brien, K.L., Wolfson, L.J, Watt, J.P., Henkle, E. and Deloria-Knoll, M. (2009) Burden of Disease Caused by Streptococcus pneumoniae in Children Younger than 5 Years: Global Estimates. The Lancet, 374, 893-902.

[3]   Selman, S., Hayes, D., Perin, L.A. and Hayes, W.S. (2000) Pneumococcal Conjugate Vaccine for Young Children. Managed Care, 9, 49-52.

[4]   Pelton, S.I., Huot, H., Finkelstein, J.A., Bishop, C.J., Hsu, K.K., Kellenberg, J., Huang, S.S., Goldstein, R. and Hanage, W.P. (2007) Emergence of 19A as Virulent and Multidrug Resistant Pneumococcus in Massachusetts Following Universal Immunization of Infants with Pneumococcal Conjugate Vaccine. Pediatric Infectious Disease Journal, 26, 468-472.

[5]   Singleton, R.J., Hennessy, T.W., Bulkow, L.R., Hammitt, L.L., Zulz, T., Hurlburt, D.A., Butler, J.C., Rudolph, K. and Parkinson, A. (2007) Invasive Pneumococcal Disease Caused by Nonvaccine Serotypes among Alaska Native Children with High Levels of 7-Valent Pneumococcal Conjugate Vaccine Coverage. JAMA, 297, 1784-1792.

[6]   Donkor, E.S., Dayie, N.T.K.D. and Badoe, E.V. (2013) Vaccination against Pneumococcus in West Africa: Perspectives and Prospects. International Journal of General Medicine, 6, 1-8.

[7]   White, B.A. (1938) The Biology of Pneumococcus. Harvard University Press, Cambridge.

[8]   Bergey, D.H., Buchanan, R.E. and Gibbons, N.E. (1974) Bergey’s Manual of Determinative Bacteriology. Williams & Wilkins Co., Baltimore.

[9]   Griffith, F. (1928) The Significance of Pneumococcal Types. Journal of Hygiene, 27, 113-159.

[10]   Steinman, R.M. and Moberg, C.L. (1994) A Triple Tribute to the Experiment That Transformed Biology. Journal of Experimental Medicine, 179, 379-384.

[11]   Avery, O.T., Macleod, C.M. and Mccarty, M. (1995) Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types. Induction of Transformation by a Deoxyribonucleic Acid Fraction Isolated from Pneumococcus Type III. 1944. Molecular Medicine, 1, 344-365.

[12]   Austrian, R. (1981) Some Observations on the Pneumococcus and on the Current Status of Pneumococcal Disease and Its Prevention. Clinical Infectious Diseases, 3, S1-S17.

[13]   Watson, D.A., Musher, D.M., Jacobson, J.W. and Verhoef, J. (1993) A Brief History of the Pneumococcus in Biomedical Research: A Panoply of Scientific Discovery. Clinical Infectious Diseases, 17, 913-924.

[14]   Henrichsen, J. (1995) Six Newly Recognized Types of Streptococcus pneumoniae. Journal of Clinical Microbiology, 33, 2759-2762.

[15]   Park, I.H., Pritchard, D.G., Cartee, R., Brandao, A., Brandileone, M.C.C. and Nahm, M.H. (2007) Discovery of a New Capsular Serotype (6C) within Serogroup 6 of Streptococcus pneumoniae. Journal of Clinical Microbiology, 45, 1225-1233.

[16]   Calix, J.J. and Nahm, M.H. (2010) A New Pneumococcal Serotype, 11E, Has a Variably Inactivated wcjE Gene. The Journal of Infectious Diseases, 202, 29-38.

[17]   Austrian, R. and Collins, P. (1966) Importance of Carbon Dioxide in the Isolation of Pneumococci. Journal of Bacteriology, 92, 1281-1284.

[18]   Werno A.M. and Murdoch, D.R. (2008) Laboratory Diagnosis of Invasive Pneumococcal Disease. Clinical Infectious Diseases, 46, 926-932.

[19]   Tettelin, H., Nelson, K.E., Paulsen, I.T., Eisen, J.A., Read, T.D., Peterson, S., Heidelberg, J., Deboy, R.T., Haft, D.H., Dodson, R.J., Durkin, A.S., Gwinn, M., Kolonay, J.F., Nelson, W.C., Peterson, J.D., Umayam, L.A., White, O., Salzberg, S.L., Lewis, M.R., Radune, D., Holtzapple, E., Khouri, H., Wolf, A.M., Utterback, T.R., Hansen, C.L., Mcdonald, L.A., Feldblyum, T.V., Angiuoli, S., Dickinson, T., Hickey, E.K., Holt, I.E., Loftus, B.J., Yang, F., Smith, H.O., Venter, J.C., Dougherty, B.A., Morrison, D.A., Hollingshead, S.K. and Fraser, C.M. (2001) Complete Genome Sequence of a Virulent Isolate of Streptococcus pneumoniae. Science, 293, 498-506.

[20]   Donati, C., Hiller, N.L., Tettelin, H., Muzzi, A., Croucher, N.J., Angiuoli, S.V., Oggioni, M., Hotopp, J.C.D., Hu, F.Z., Riley, D.R., Covacci, A., Mitchell, T.J., Bentley, S.D., Kilian, M., Ehrlich, G.D., Rappuoli, R., Moxon, E.R. and Masignani, V. (2010) Structure and Dynamics of the Pan-Genome of Streptococcus pneumoniae and Closely Related Species. Genome Biology, 11, R107.

[21]   Hoskins, J., Alborn, W.E., Arnold, J., Blaszczak, L.C., Burgett, S., Dehoff, B.S., Estrem, S.T., Fritz, L., Fu, D.J., Fuller, W., Geringer, C., Gilmour, R., Glass, J.S., Khoja, H., Kraft, A.R., Lagace, R.E., Leblanc, D.J., Lee, L.N., Lefkowitz, E.J., Lu, J., Matsushima, P., Mcahren, S.M., Mchenney, M., Mcleaster, K., Mundy, C.W., Nicas, T.I., Norris, F.H., O’gara, M., Peery, R.B., Robertson, G.T., Rockey, P., Sun, P.M., Winkler, M.E., Yang, Y., Young-Bellido, M., Zhao, G., Zook, C.A., Baltz, R.H., Jaskunas, S.R., Rosteck, P.R., Skatrud, P.L. and Glass, J.I. (2001) Genome of the Bacterium Streptococcus pneumoniae Strain R6. Journal of Bacteriology, 183, 5709-5717.

[22]   Hava, D.L. and Camilli, A. (2002) Large-Scale Identification of Serotype 4 Streptococcus pneumoniae Virulence Factors. Molecular Microbiology, 45, 1389-1406.

[23]   Silby, M.W. and Levy, S.B. (2004) Use of in Vivo Expression Technology to Identify Genes Important in Growth and Survival of Pseudomonas fluorescens Pf0-1 in Soil: Discovery of Expressed Sequences with Novel Genetic Organization. Journal of Bacteriology, 186, 7411-7419.

[24]   Obert, C., Sublett, J., Kaushal, D., Hinojosa, E., Barton, T., Tuomanen, E.I. and Orihuela, C.J. (2006) Identification of a Candidate Streptococcus pneumoniae Core Genome and Regions of Diversity Correlated with Invasive Pneumococcal Disease. Infection and Immunity, 74, 4766-4777.

[25]   Hensel, M., Shea, J.E., Gleeson, C., Jones, M.D., Dalton, E. and Holden, D.W. (1995) Simultaneous Identification of Bacterial Virulence Genes by Negative Selection. Science, 269, 400-403.

[26]   Autret, N. and Charbit, A. (2005) Lessons from Signature-Tagged Mutagenesis on the Infectious Mechanisms of Pathogenic Bacteria. FEMS Microbiology Reviews, 29, 703-717.

[27]   Choi, K.H. and Kim, K.J. (2009) Signature-Tagged Mutagenesis: Technical Advances in a Negative Selection Method for Virulence Gene Identification. The Journal of Microbiology and Biotechnology, 19, 217-228.

[28]   Meng, J.P., Yin, Y.B., Zhang, X.M., Huang, Y.S., Lan, K., Cui, F. and Xu, S.X. (2008) Identification of Streptococcus pneumoniae Genes Specifically Induced in Mouse Lung Tissues. Canadian Journal of Microbiology, 54, 58-65.

[29]   Karlin, S. (2001) Detecting Anomalous Gene Clusters and Pathogenicity Islands in Diverse Bacterial Genomes. Trends in Microbiology, 9, 335-343.

[30]   Van Passel, M.W., Bart, A., Thygesen, H.H., Luyf, A.C., Van Kampen, A.H. and van der Ende, A. (2005) An Acquisition Account of Genomic Islands Based on Genome Signature Comparisons. BMC Genomics, 6, 163.

[31]   Subramanian, G., Mural, R., Hoffman, S.L., Venter, J.C. and Broder, S. (2001) Microbial Disease in Humans: A Genomic Perspective. Journal of Molecular Diagnostics, 6, 243-252.

[32]   Avery, O.T. and Goebel, W.F. (1931) Chemo-Immunological Studies on Conjugated Carbohydrate-Proteins: The Immunological Specifity of an Antigen Prepared by Combining the Capsular Polysaccharide of Type III Pneumococcus with Foreign Protein. The Journal of Experimental Medicine, 54, 437-447.

[33]   De Velasco, E.A., Verheul, A.F., Verhoef, J. and Snippe, H. (1995) Streptococcus pneumoniae: Virulence Factors, Pathogenesis, and Vaccines. Microbiological Reviews, 59, 591-603.

[34]   Hammerschmidt, S., Wolff, S., Hocke, A., Rosseau, S., Müller, E. and Rohde, M. (2005) Illustration of Pneumococcal Polysaccharide Capsule during Adherence and Invasion of Epithelial Cells. Infection and Immunity, 73, 4653-4667.

[35]   Hyams, C., Camberlein, E., Cohen, J.M., Bax, K. and Brown J.S. (2010) The Streptococcus pneumoniae Capsule Inhibits Complement Activity and Neutrophil Phagocytosis by Multiple Mechanisms. Infection and Immunity, 78, 704-715.

[36]   Magee, A.D. and Yother, J. (2001) Requirement for Capsule in Colonization by Streptococcus pneumoniae. Infection and Immunity, 69, 3755-3761.

[37]   Kelly, T., Dillard, J.P. and Yother, J. (1994) Effect of Genetic Switching of Capsular Type on Virulence of Streptococcus pneumoniae. Infection and Immunity, 62, 1813-1819.

[38]   Barocchi, M.A., Ries, J., Zogaj, X., Hemsley, C., Albiger, B., Kanth, A., Dahlberg, S., Fernebro, J., Moschioni, M., Masignani, V., Hultenby, K., Taddei, A.R., Beiter, K., Wartha, F., Von Euler, A., Covacci, A., Holden, D.W., Normark, S., Rappuoli, R. and Henriques-Normark, B. (2006) A Pneumococcal Pilus Influences Virulence and Host Inflammatory Responses. Proceedings of the National Academy of Sciences of the United States of America, 103, 2857-2862.

[39]   Sjostrom, K., Blomberg, C., Fernebro, J., Dagerhamn, J., Morfeldt, E., Barocchi, M.A., Browall, S., Moschioni, M., Andersson, M., Henriques, F., Albiger, B., Rappuoli, R., Normark, S. and Henriques-Normark, B. (2007) Clonal Success of Piliated Penicillin Nonsusceptible Pneumococci. Proceedings of the National Academy of Sciences of the United States of America, 104, 12907-12912.

[40]   Moschioni, M., Donati, C., Muzzi, A., Masignani, V., Censini, S., Hanage, W.P., Bishop, C.J., Reis, J.N., Normark, S., Henriques-Normark, B., Covacci, A., Rappuoli, R. and Barocchi, M.A. (2008) Streptococcus pneumoniae Contains 3 rlrA Pilus Variants That Are Clonally Related. The Journal of Infectious Diseases, 197, 888-896.

[41]   Bagnoli, F., Moschioni, M., Donati, C., Dimitrovska, V., Ferlenghi, I., Facciotti, C., Muzzi, A., Giusti, F., Emolo, C., Sinisi, A., Hilleringmann, M., Pansegrau, W., Censini, S., Rappuoli, R., Covacci, A., Masignani, V. and Barocchi, M.A. (2008) A Second Pilus Type in Streptococcus pneumoniae Is Prevalent in Emerging Serotypes and Mediates Adhesion to Host Cells. Journal of Bacteriology, 190, 5480-5492.

[42]   Volkova, M.O., Kostiukova, N.N. and Kvetnaia, A.S. (1994) The Role of Hyaluronidase in the Occurrence of a Generalized Pneumococcal Infection. Zh Mikrobiol Epidemiol Immunobiol, 1, 118-122.

[43]   Kvetnaia, A.S., Kostiukova, N.N., Ivanova, V.V., Volkova, M.O. and Loskutova, N.G. (1995) Streptococcus pneumoniae Adhesion. Zh Mikrobiol Epidemiol Immunobiol, 5, 23-26.

[44]   Zwijnenburg, P.J., van der Poll, T., Florquin, S., van Deventer, S.J., Roord, J.J. and van Furth, A.M. (2001) Experimental Pneumococcal Meningitis in Mice: A Model of Intranasal Infection. The Journal of Infectious Diseases, 183, 1143-1146.

[45]   Kadioglu, A., Taylor, S., Iannelli, F., Pozzi, G., Mitchell, T.J. and Andrew, P.W. (2002) Upper and Lower Respiratory Tract Infection by Streptococcus pneumoniae Is Affected by Pneumolysin Deficiency and Differences in Capsule Type. Infection and Immunity, 70, 2886-2890.

[46]   Cockeran, R., Durandt, C., Feldman, C., Mitchell, T.J. and Anderson, R. (2002) Pneumolysin Activates the Synthesis and Release of Interleukin-8 by Human Neutrophils in Vitro. The Journal of Infectious Diseases, 186, 562-565.

[47]   Neeleman, C., Klaassen, C.H.W., Klomberg, D.M., de Valk, H.A. and Mouton, J.W. (2004) Pneumolysin Is a Key Factor in Misidentification of Macrolide-Resistant Streptococcus pneumoniae and Is a Putative Virulence Factor of S. mitis and Other Streptococci. Journal of Clinical Microbiology, 42, 4355-4357.

[48]   Lock, R.A., Hansman, D. and Paton, J.C. (1992) Comparative Efficacy of Autolysin and Pneumolysin as
Immunogens Protecting Mice against Infection by Streptococcus pneumoniae. Microbial Pathogene-
sis, 12, 137-143.

[49]   Gosink, K.K., Mann, E.R., Guglielmo, C., Tuomanen, E.I. and Masure, H.R. (2000) Role of Novel Choline Binding Proteins in Virulence of Streptococcus pneumoniae. Infection and Immunity, 68, 5690-5695.

[50]   Pettigrew, M.M., Fennie, K.P., York, M.P., Daniels, J. and Ghaffar, F. (2006) Variation in the Presence of Neuraminidase Genes among Streptococcus pneumoniae Isolates with Identical Sequence Types. Infection and Immunity, 74, 3360-3365.

[51]   Hammerschmidt, S., Bethe, G., Remane, P.H. and Chhatwal, G.S. (1992) Identification of Pneumococcal Surface Protein A as a Lactoferrin-Binding Protein of Streptococcus pneumoniae and Their Use in Functional Studies and Cloning of the pspA Gene. Journal of Bacteriology, 174, 610-618.

[52]   Fenno, J.C., Leblanc, D.J. and Fives-Taylor, P. (1989) Nucleotide Sequence Analysis of a Type 1 Fimbrial Gene of Streptococcus sanguis FW213. Infection and Immunity, 57, 3527-3533.

[53]   Briles, D.E., Hollingshead, S.K., Swiatlo, E., Brooks-Walter, A., Szalai, A., Virolainen, A., Mcdaniel, L.S., Benton, K. A., White, P., Prellner, K., Hermansson, A., Aerts, P.C., van Dijk, H. and Crain, M.J. (1997) PspA and PspC: Their Potential for Use as Pneumococcal Vaccines. Microbial Drug Resistance, 3, 401-408.

[54]   Gilliespie, S.H. and Balakrishnan, I. (2000) Pathogenesis of Pneumococcal Infection. Journal of Medical Microbiology, 49, 1057-1067.

[55]   Rosenow, C., Ryan, P., Weiser, J.N., Johnson, S., Fontan, P., Ortqvist, A. and Masure, H.R. (1997) Contribution of Novel Choline-Binding Proteins to Adherence, Colonization and Immunogenicity of Streptococcus pneumoniae. Molecular Microbiology, 25, 819-829.

[56]   Hammerschmidt, S., Talay, S.R., Brandtzaeg, P. and Chhatwal, G.S. (2001) SpsA, a Novel Pneumococcal Surface Protein with Specific Binding to Secretory Immunoglobulin A and Secretory Component. Molecular Microbiology, 40, 1273-1287.

[57]   Dave, S., Brooks-Walter, A., Pangburn, M.K. and McDaniel, L.S. (2001) PspC, a Pneumococcal Surface Protein, Binds Human Factor H. Infection and Immunity, 69, 3435-3437.

[58]   Berry, A.M. and Paton, J.C. (1996) Sequence Heterogeneity of PsaA, a 37-Kilodalton Putative Adhesin Essential for Virulence of Streptococcus pneumoniae. Infection and Immunity, 64, 5255-5262.

[59]   Anderton, J.M., Rajam, G., Romero-Steiner, S., Summer, S., Kowalczyk, A.P., Carlone, G.M., Sampson, J.S. and Ades, E.W. (2007) E-Cadherin Is a Receptor for the Common Protein Pneumococcal Surface
Adhesin A (PsaA) of Streptococcus pneumoniae. Microbial Pathogenesis, 42, 225-236.

[60]   Johnston, J.W., Myers, L.E., Ochs, M.M., Benjamin, W.H., Briles, D.E. and Hollingshead, S.K. (2004) Lipoprotein PsaA in Virulence of Streptococcus pneumoniae: Surface Accessibility and Role in Protection from Superoxide. Infection and Immunity, 72, 5858-5867.

[61]   Holmes, A.R., Mcnab, R., Millsap, K.W., Rohde, M., Hammerschmidt, S., Mawdsley, J.L. and Jenkinson, H.F. (2001) The pavA Gene of Streptococcus pneumoniae Encodes a Fibronectin-Binding Protein That Is Essential for Virulence. Molecular Microbiology, 41, 1395-1408.

[62]   Pracht, D., Elm, C., Gerber, J., Bergmann, S., Rohde, M., Seiler, M., Kim, K.S., Jenkinson, H.F., Nau, R. and Hammerschmidt, S. (2005) PavA of Streptococcus pneumoniae Modulates Adherence, Invasion,
and Meningeal Inflammation. Infection and Immunity, 73, 2680-2689.

[63]   Jensch, I., Gámez, G., Rothe, M., Ebert, S., Fulde, M., Somplatzki, D., Bergmann, S., Petruschka, L., Rohde, M., Nau, R. and Hammerschmidt, S. (2010) PavB Is a Surface-Exposed Adhesin of Streptococcus pneumoniae Contributing to Nasopharyngeal Colonization and Airways Infections. Molecular Microbiology, 77, 22-43.

[64]   Terra, V.S., Homer, K.A., Rao, S.G., Andrew, P.W. and Yesilkaya, H. (2010) Characterization of Novel β-Galactosidase Activity That Contributes to Glycoprotein Degradation and Virulence in Streptococcus pneumoniae. Infection and Immunity, 78, 348-357.

[65]   Bergmann, S., Rohde, M., Chhatwal, G.S. and Hammerschmidt, S. (2001) α-Enolase of Streptococcus pneumoniae Is a Plasmin(ogen)-Binding Protein Displayed on the Bacterial Cell Surface. Molecular Microbiology, 40, 1273-1287.

[66]   Bogaert, D., de Groot, R. and Hermans, P.W. (2004) Streptococcus pneumoniae Colonisation: The
Key to Pneumococcal Disease. The Lancet Infectious Diseases, 4, 144-154.

[67]   Opal, S.M. and van der Poll, T. (2009) Pathogenesis, Treatment, and Prevention of Pneumococcal Pneumonia. The Lancet, 374, 1543-1556.

[68]   Cundell, D.R., Pearce, B.J., Sandros, J., Naughton, A.M. and Masure, H.R. (1995) Peptide Permeases from Streptococcus pneumoniae Affect Adherence to Eucaryotic Cells. Infection and Immunity, 63, 2493-2498.

[69]   Moreillon, P. and Majcherczyk, P.A. (2003) Proinflammatory Activity of Cell-Wall Constituents from Gram-Positive Bacteria. Scandinavian Journal of Infectious Diseases, 35, 632-641.

[70]   Suresh, M.V., Singh, S.K., Ferguson Jr., D.A. and Agrawal, A. (2006) Role of the Property of C-Reactive Protein to Activate the Classical Pathway of Complement in Protecting Mice from Pneumococcal Infection. The Journal of Immunology, 176, 4369-4374.

[71]   Tuomanen, E.I., Austrian, R. and Masure, H.R. (1995) Pathogenesis of Pneumococcal Infection. The New England Journal of Medicine, 332, 1280-1284.

[72]   Van Bambeke, F., Reinert, R.R., Appelbaum, P.C., Tulkens, P.M. and Peetermans, W.E. (2007) Multidrug-Resistant Streptococcus pneumoniae Infections: Current and Future Therapeutic Options. Drugs, 67, 2355-2382.

[73]   Blossom, D.B., Cordeiro, S.M., Bajaksouzian, S., Joloba, M.L., Kityo, C., Whalen, C.C., Salata, R.A. and Jacobs, M.R. (2007) Characterization of Penicillin Intermediate Serotypes of Streptococcus pneumoniae Carried by Human Immunodeficiency Virus-Infected Adults and Healthy Children in Uganda. Microbial Drug Resistance, 13, 21-28.

[74]   Hanage, W.P. (2008) Serotype-Specific Problems Associated with Pneumococcal Conjugate Vaccination. Future Microbiology, 3, 23-30.

[75]   Paradiso, P.R. (2011) Advances in Pneumococcal Disease Prevention: 13-Valent Pneumococcal Conjugate Vaccine for Infants and Children. Clinical Infectious Diseases, 52, 1241-1247.

[76]   Klugman, K.P. (2002) The Successful Clone: The Vector of Dissemination of Resistance in Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy, 50, 1-6.

[77]   Smith, A.M. and Klugman, K.P. (1997) Three Predominant Clones Identified within Penicillin-Resistant South African Isolates of Streptococcus pneumoniae. Microbial Drug Resistance, 3, 385-389.

[78]   Paul, J., Bates, J., Kimari, J. and Gilks, C. (1996) Serotypes and Antibiotic Susceptibilities of Streptococcus pneumoniae in Nairobi, Kenya. Journal of Infection, 32, 139-142.

[79]   Abraham, E.P., Chain, E., Fletcher, C.M., Florey, H.W., Gardner, A.D., Heatley, N.G. and Jennings, M.A. (1992) Further Observations on Penicillin. 1941. European Journal of Clinical Pharmacology, 42, 3-9.

[80]   Skovbjerg, S., Soderstrom, A., Hynsjo, L., Normark, B.H., Ekdahl, K. and Ahrén, C. (2013) Low Rate of Pneumococci Non-Susceptible to Penicillin in Healthy Swedish Toddlers. Scandinavian Journal of Infectious Diseases, 45, 279-284.

[81]   Yocum, R.R., Rasmussen, J.R. and Strominger, J.L. (1980) The Mechanism of Action of Penicillin. Penicillin Acylates the Active Site of Bacillus stearothermophilus D-Alanine Carboxypeptidase. Journal of Biological Chemistry, 255, 3977-3986.

[82]   Hansman, D. and Bullen, M.M. (1967) A Resistant Pneumococcus. The Lancet, 2, 264-265.

[83]   Zerfass, I., Hakenbeck, R. and Denapaite, D. (2009) An Important Site in PBP2x of Penicillin-Resistant Clinical Isolates of Streptococcus pneumoniae: Mutational Analysis of Thr338. Antimicrobial Agents and Chemotherapy, 53, 1107-1115.

[84]   Grebe, T. and Hakenbeck, R. (1996) Penicillin-Binding Proteins 2b and 2x of Streptococcus pneumoniae Are Primary Resistance Determinants for Different Classes of Beta-Lactam Antibiotics. Antimicrobial Agents and Chemotherapy, 40, 829-834.

[85]   Coffey, T.J., Daniels, M., Mcdougal, L.K., Dowson, C.G., Tenover, F.C. and Spratt, B.G. (1995) Genetic Analysis of Clinical Isolates of Streptococcus pneumoniae with High-Level Resistance to Expanded-Spectrum Cephalosporins. Antimicrobial Agents and Chemotherapy, 39, 1306-1313.

[86]   Coffey, T.J., Dowson, C.G., Daniels, M. and Spratt, B.G. (1993) Horizontal Spread of an Altered Penicillin-Binding Protein 2B Gene between Streptococcus pneumoniae and Streptococcus oralis. FEMS Microbiology Letters, 110, 335-339.

[87]   Wise, R. (1999) A Review of the Mechanism of Action and Resistance of Antimicrobial Agents. Canadian Respiratory Journal, 6, 20-22.

[88]   Walker, C.B., Karpinia, K. and Baehni, P. (2004) Chemotherapeutics: Antibiotics and Other Antimicrobials. Periodontology 2000, 36, 146-165.

[89]   Newton, B.A. (1995) Mechanisms of Antibiotic Action. Ann Rev of Microbiol, 19, 209-240.

[90]   Leclercq, R. and Courvalin, P. (1991) Intrinsic and Unusual Resistance to Macrolide, Lincosamide, and Streptogramin Antibiotics in Bacteria. Antimicrobial Agents and Chemotherapy, 35, 1273-1276.

[91]   Sutcliffe, J., Grebe, T., Tait-Kamradt, A. and Wondrack, L. (1996) Detection of Erythromycin-Resistant Determinants by PCR. Antimicrobial Agents and Chemotherapy, 40, 2562-2566.

[92]   Amezaga, M.R., Carter, P.E., Cash, P. and McKenzie, H. (2002) Molecular Epidemiology of Erythromycin Resistance in Streptococcus pneumoniae Isolates from Blood and Noninvasive Sites. Journal of Clinical Microbiology, 40, 3313-3318.

[93]   Doern, G.V., Heilmann, K.P., Huynh, H.K., Rhomberg, P.R., Coffman, S.L. and Brueggemann, A.B. (2001) Antimicrobial Resistance among Clinical Isolates of Streptococcus pneumoniae in the United States during 1999-2000, Including a Comparison of Resistance Rates Since 1994-1995. Antimicrobial Agents and Chemotherapy, 45, 1721-1729.

[94]   Oster, P., Zanchi, A., Cresti, S., Lattanzi, M., Montagnani, F., Cellesi, C. and Rossolini, G.M. (1999) Patterns of Macrolide Resistance Determinants among Community-Acquired Streptococcus pneumoniae Isolates over a 5-Year Period of Decreased Macrolide Susceptibility Rates. Antimicrobial Agents and Chemotherapy, 43, 2510-2512.

[95]   Descheemaeker, P., Chapelle, S., Lammens, C., Hauchecorne, M., Wijdooghe, M., Vandamme, P., Ieven, M. and Goossens, H. (2000) Macrolide Resistance and Erythromycin Resistance Determinants among Belgian Streptococcus pyogenes and Streptococcus pneumoniae Isolates. Journal of Antimicrobial Chemotherapy, 45, 167-173.

[96]   Reinert, R.R., Simic, S., Al-Lahham, A., Reinert, S., Lemperle, M. and Lutticken, R. (2001) Antimicrobial Resistance of Streptococcus pneumoniae Recovered from Outpatients with Respiratory Tract Infections in Germany from 1998 to 1999: Results of a National Surveillance Study. Journal of Clinical Microbiology, 39, 1187-1189.

[97]   Cochetti, I., Tili, E., Vecchi, M., Manzin, A., Mingoia, M., Varaldo, P.E. and Montanari, M.P. (2007) New Tn916-Related Elements Causing erm(B)-Mediated Erythromycin Resistance in Tetracycline-Susceptible Pneumococci. Journal of Antimicrobial Chemotherapy, 60, 127-131.

[98]   Cochetti, I., Tili, E., Mingoia, M., Varaldo, P.E. and Montanari, M.P. (2008) erm(B)-Carrying Elements in Tetracycline-Resistant Pneumococci and Correspondence between Tn1545 and Tn6003. Antimicrobial Agents and Chemotherapy, 52, 1285-1290.

[99]   Henderson-Begg, S.K., Roberts, A.P. and Hall, L.M.C. (2009) Diversity of Putative Tn5253-Like Elements in Streptococcus pneumoniae. International Journal of Antimicrobial Agents, 33, 364-367.

[100]   Jacobs, M.R., Koornhof, H.J., Robins-Browne, R.M., Stevenson, C.M., Vermaak, Z.A., Freiman, I., Miller, G.B., Witcomb, M.A., Isaacson, M., Ward, J.I. and Austrian, R. (1978) Emergence of Multiply Resistant Pneumococci. New Engl J Med, 299, 735-740.

[101]   Maiden, M.C. (1998) Horizontal Genetic Exchange, Evolution, and Spread of Antibiotic Resistance in Bacteria. Clinical Infectious Diseases, 27, S12-S20.

[102]   Weinberger, D.M., Malley, R. and Lipsitch, M. (2011) Serotype Replacement in Disease after Pneumococcal Vaccination. The Lancet, 378, 1962-1973.

[103]   Brueggemann, A.B., Pai, R., Crook, D.W. and Beall, B. (2007) Vaccine Escape Recombinants Emerge after Pneumococcal Vaccination in the United States. PLoS Pathogens, 3, e168.

[104]   Hanage, W.P., Fraser, C., Tang, J., Connor, T.R. and Corander, J. (2009) Hyper-Recombination, Diversity, and Antibiotic Resistance in Pneumococcus. Science, 324, 1454-1457.

[105]   Feil, E.J., Smith, J.M., Enright, M.C. and Spratt, B.G. (2000) Estimating Recombinational Parameters in Streptococcus pneumoniae from Multilocus Sequence Typing Data. Genetics, 154, 1439-1450.

[106]   Croucher, N.J., Harris, S.R., Fraser, C., Quail, M.A., Burton, J., van der Linden, M., Mcgee, L., von Gottberg, A., Song, J.H., Ko, K.S., Pichon, B., Baker, S., Parry, C.M., Lambertsen, L.M., Shahinas, D., Pillai, D.R., Mitchell, T.J., Dougan, G., Tomasz, A., Klugman, K.P., Parkhill, J., Hanage, W.P. and Bentley, S.D. (2011) Rapid Pneumococcal Evolution in Response to Clinical Interventions. Science, 331, 430-434.

[107]   Wyres, K.L., Lambertsen, L.M., Croucher, N.J., McGee, L., von Gottberg, A., Linares, J., Jacobs, M.R., Kristinsson, K. G., Beall, B.W., Klugman, K.P., Parkhill, J., Hakenbeck, R., Bentley, S.D. and Brueggemann, A.B. (2013) Pneumococcal Capsular Switching: A Historical Perspective. The Journal of Infectious Diseases, 207, 439-449.

[108]   Woodhead, M., Blasi, F., Ewig, S., Garau, J., Huchon, G., Leven, M., Ortqvist, A., Schaberg, T., Torres, A., van der Heijden, G., Read, R. and Verheij, T.J. (2011) Guidelines for the Management of Adult Lower Respiratory Tract Infections—Full Version. Clinical Microbiology and Infection, 17, 1-59.

[109]   Hung, I.F., Tantawichien, T., Tsai, Y.H., Patil, S. and Zotomayor, R. (2013) Regional Epidemiology of Invasive Pneumococcal Disease in Asian Adults: Epidemiology, Disease Burden, Serotype Distribution, and Antimicrobial Resistance Patterns and Prevention. International Journal of Infectious Diseases, 17, e364-373.

[110]   Tunkel, A.R, Hartman, B.J., Kaplan, S.L., Kaufman, B.A., Roos, K.L., Scheld, W.M. and Whitley, R.J. (2004) Practice Guidelines for the Management of Bacterial Meningitis. Clinical Infectious Diseases, 39, 1267-1284.

[111]   Donkor, E.S., Newman, M.J., Oliver-Commey, J., Bannerman, E., Dayie, N.T.K.D. and Badoe, E.V. (2010) Invasive Disease and Paediatric Carriage of Streptococcus pneumoniae in Ghana. Scandinavian Journal of Infectious Diseases, 42, 254-259.

[112]   Falade, A.G., Lagunju, I.A., Bakare, R.A., Odekanmi, A.A. and Adegbola, R.A. (2009) Invasive Pneumococcal Disease in Children Aged<5 Years Admitted to 3 Urban Hospitals in Ibadan, Nigeria. Clinical Infectious Diseases, 48, 190-196.

[113]   Antonio, M., Dada-Adegbola, H., Biney, E., Awine, T., O’Callaghan, J., Pfluger, V., Enwere, G., Okoko, B., Oluwalana, C., Vaughan, A., Zaman, S.M., Pluschke, G., Greenwood, B.M., Cutts, F. and Adegbola, R.A. (2008) Molecular Epidemiology of Pneumococci Obtained from Gambian Children Aged 2-29 Months with Invasive Pneumococcal Disease during a Trial of a 9-Valent Pneumococcal Conjugate Vaccine. BMC Infectious Diseases, 8, 81.

[114]   Traore, Y., Tameklo, T.A., Njanpop-Lafourcade, B.M., Lourd, M., Yaro, S., Niamba, D., Drabo, A., Mueller, J.E., Koeck, J.L. and Gessner, B.D. (2009) Incidence, Seasonality, Age Distribution, and Mortality of Pneumococcal Meningitis in Burkina Faso and Togo. Clinical Infectious Diseases, 48, 181-189.

[115]   Kacou-N’douba, A., Guessennd-Kouadio, N., Kouassi-M’Bengue, A. and Dosso, M. (2004) Evolution of Streptococcus pneumoniae Antibiotic Resistance in Abidjan: Update on Nasopharyngeal Carriage, from 1997 to 2001. Médecine et Maladies Infectieuses, 34, 83-85.

[116]   Kisakye, A., Makumbi, I., Nansera, D., Lewis, R., Braka, F., Wobudeya, E., Chaplain, D., Nalumansi, E., Mbabazi, W. and Gessner, B.D. (2009) Surveillance for Streptococcus pneumoniae Meningitis in Children under 5 Years of Age: Implications for Immunization in Uganda. Clinical Infectious Diseases, 48, S153-S161.

[117]   Rivera-Olivero, I.A., Bogaert, D., Bello, T., del Nogal, B., Sluijter, M., Hermans, P.W. and de Waard, J.H. (2007) Pneumococcal Carriage among Indigenous Warao Children in Venezuela: Serotypes, Susceptibility Patterns, and Molecular Epidemiology. Clinical Infectious Diseases, 45, 1427-1434.

[118]   Liu, C., Xiong, X., Xu, W., Sun, J., Wang, L. and Li, J. (2013) Serotypes and Patterns of Antibiotic Resistance in Strains Causing Invasive Pneumococcal Disease in Children Less than 5 Years of Age. PLoS ONE, 8, e54254.

[119]   Baggett, H.C., Peruski, L.F., Olsen, S.J., Thamthitiwat, S., Rhodes, J., Dejsirilert, S., Wongjindanon, W., Dowell, S.F., Fischer, J.E., Areerat, P., Sornkij, D., Jorakate, P., Kaewpan, A., Prapasiri, P., Naorat, S., Sangsuk, L., Eampokalap, B., Moore, M.R., Carvalho, G., Beall, B., Ungchusak, K. and Maloney, S.A. (2009) Incidence of Pneumococcal Bacteremia Requiring Hospitalization in Rural Thailand. Clinical Infectious Diseases, 48, S65-S74.

[120]   Saha, S.K, Naheed, A., Arifeen. S.E., Islam, M., Al-Emran, H., Amin, R., Fatima, K., Brooks, W.A., Breiman, R.F., Sack, D.A. and Luby, S.P. (2009) Surveillance for Invasive Streptococcus pneumoniae Disease among Hospitalized Children in Bangladesh: Antimicrobial Susceptibility and Serotype Distribution. Clinical Infectious Diseases, 48, S75-S81.

[121]   Shah, A.S., Knoll, M.D., Sharma, P.R., Moisi, J.C., Kulkarni, P., Lalitha, M.K., Steinhoff, M. and Thomas, K. (2009) Invasive Pneumococcal Disease in Kanti Children’s Hospital, Nepal, as Observed by the South Asian Pneumococcal Alliance Network. Clinical Infectious Diseases, 48, S123-S128.

[122]   Zaidi, A.K.M., Khan, H., Lasi, R. and Mahesar, W. (2009) Surveillance of Pneumococcal Meningitis among Children in Sindh, Southern Pakistan. Clinical Infectious Diseases, 48, S129-S135.

[123]   Batuwanthudawe, R., Karunarathne, K., Dassanayake, M., de Silva, S., Lalitha, M.K., Thomas, K., Steinhoff, M. and Abeysinghe, N. (2009) Surveillance of Invasive Pneumococcal Disease in Colombo, Sri Lanka. Clinical Infectious Diseases, 48, S136-S140.

[124]   Reinert, R.R., Reinert, S., van der Linden, M., Cil, M.Y., Al-Lahham, A. and Appelbaum, P. (2005) Antimicrobial Susceptibility of Streptococcus pneumoniae in Eight European Countries from 2001 to 2003. Antimicrobial Agents and Chemotherapy, 49, 2903-2913.

[125]   Jenkins, S.G., Brown, S.D. and Farrell, D.J. (2008) Trends in Antibacterial Resistance among Streptococcus pneumonie Isolated in the USA: Update from PROTEKT US Years 1-4. Annals of Clinical Microbiology and Antimicrobials, 7, 1.

[126]   Roca, A., Bassat, Q., Morais, L., Machevo, S., Sigauque, B., O’Callaghan, C.T., Letang, E., Mandomando, I., Nhalungo, D., Quintó, L. and Alonso, P. (2009) Surveillance of Acute Bacterial Meningitis among Children Admitted to a District Hospital in Rural Mozambique. Clinical Infectious Diseases, 48, S172-S180.

[127]   Fraser, D., Givon-Lavi, N., Bilenko, N. and Dagan, R. (2001) A Decade (1989-1998) of Paediatric Invasive Pneumococcal Disease in 2 Populations Residing in 1 Geographic Location: Implications for Vaccine Choice. Clinical Infectious Diseases, 33, 421-427.

[128]   Weisblum, B. (1995) Insights into Erythromycin Action from Studies of Its Activity as Inducer of Resistance. Antimicrobial Agents and Chemotherapy, 39, 797-805.

[129]   Leclercq, R. and Courvalin, P. (2002) Resistance to Macrolides and Related Antibiotics in Streptococcus pneumoniae. Antimicrob Agents Chemother, 46, 2727-2734.

[130]   Fukuda, H. and Hiramatsu, K. (1999) Primary Targets of Fluoroquinolones in Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy, 43, 410-412.

[131]   Gill, M.J., Brenwald, N.P. and Wise, R. (1999) Identification of an Efflux Pump Gene, pmrA, Associated with Fluoroquinolone Resistance in S. pneumoniae. Antimicrobial Agents and Chemotherapy, 43, 187-189.

[132]   Connell, S.R., Tracz, D.M., Nierhaus, K.H. and Taylor, D.E. (2003) Ribosomal Protection Proteins and Their Mechanism of Tetracycline Resistance. Antimicrobial Agents and Chemotherapy, 47, 3675-3681.

[133]   Nikaido, H. (2009) Multidrug Resistance in Bacteria. Annual Review of Biochemistry, 78, 119-146.

[134]   Padayachee, T. and Klugman, K.P. (1999) Molecular Basis of Rifampin Resistance in Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy, 43, 2362-2365.