Penicillin-resistant Streptococcus pneumoniae

Moxifloxacin is an 8-methoxyquinolone with enhanced potency against important Gram-positive pathogens, notably Streptococcus pneumoniae (penicillin-resistant and penicillin-susceptible strains), and class activity against Gram-negative bacteria. Its activity is not affected by beta-lactamases. Moxifloxacin may therefore represent a promising alternative for treatment of respiratory tract infections (1). 

Streptococcus pneumoniae Penicillin susceptible Penicillin intermediate Penicillin resistant Group B Streptococcus Staphylococcus aureus Methicillin susceptible Methicillin resistant Staphylococcus epidermidis Listeria monocytogenes... 

Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), or Streptococcus pneumoniae (penicillin-susceptible strains only). 

Miguet, L., Tervosen, A., Gerards, T., Pasha, F.A., Luxen, A., Disteche-Nguyen, M., and Thomas, A. (2009) Discovery of new inhibitors of resistant streptococcus pneumoniae penicillin binding protein (PBP) 2x by structure-based virtual screening. Journal of Medicinal Chemistry, 52, 5926-5936. 

In contrast to macrolides, the targets of (3-lactams, the penicillin binding proteins (PBPs) require several mutations in order to become resistant while simultaneously maintaining their viable function as cell wall transpeptidases/transglycosidases. Thus, in order to achieve clinically relevant resistance Streptococcus pneumoniae uses a unique strategy to rapidly accumulate several point mutations. Due to its natural competence for transformation during respiratory tract... 

Higher dose amoxicillin, amoxicillin-davulanate (eg., 90 mg/kg/day) is used for penicillin-resistant Streptococcus pneumoniae fluoroquinolones are avoided in pediatric patients because of the potential for cartilage damage however, their use in pediatrics is emerging. Doses shown are extrapolated from adults and will require further study. 

Treatment failure or prior antibiotic therapy in past 4-6 weeks High suspicion of penicillin-resistant Streptococcus pneumoniae... 

The emergence of multidrug-resistant Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci... 

Levofloxacin (1), the levo-isomer or the (5)-enantiomer of ofloxacin, received FDA approval in 1996 (Fish, 2003 Hurst et al., 2002 Mascaretti, 2003 Norrby, 1999 North et al., 1998). The initial approval covered community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, uncomplicated skin and skin structure infections, acute pyelonephritis, and complicated urinary tract infections (North et al., 1998). Four years later, the levofloxacin indication list grew to include community-acquired pneumonia caused by penicillin-resistant Streptococcus pneumoniae. In addition, in 2002, nosocomial (hospital-acquired) pneumonia caused by methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Haemophilus influenzae, Kliebsella pneumoniae, and Escherichia coli was added (Hurst et al., 2002). Finally in 2004, LVX was approved as a post-exposure treatment for individuals exposed to Bacillus anthracis, the microbe that causes anthrax, via inhalation (FDA, 2004). 

Worldwide Streptococcus pneumoniae % susceptibility to penicillin is decreasing. In some countries up to two-thirds of the clinical isolates have reduced susceptibility to penicillin or are highly resistant to this drug. Moreover, the rate of resistance to other drugs commonly used for RTI including erythromycin, tetracycline and trimethoprim-sulfamethoxazole is higher in penicillin-resistant than penicillin-susceptible strains. Monitoring local or hospital resistance patterns of pneumococci is, therefore, needed. 

Staphylococcus aures (penicillin-sensitive) Staphyloccocus aureus (penicillin-resistant) Streptococcus pyogenes Streptococcus pneumoniae Enterococcus faecalis ... 

Streptococcus pneumoniae Arthritis otitis pneumonia sinusitis If penicillin sensitive ampicillin or penicillin G or V If penicillin resistant vancomycin rifampin A cephalosporin erythromycin azithromycin clarithromycin imipenem meropenem a fluoroquinolone trimethoprim-sulfamethoxazole... 

M Jamin, R Hakenbeck, JM Frere. Penicillin-binding protein 2x as a major contributor to intrinsic 3-lactam resistance of Streptococcus pneumoniae. FEBS Lett 331 101-104, 1993. 

G Zhao, WK Yeh, RH Carnahan, J Flowkowitsch, TI Meier, WE Alborn, GW Becker, SR Jaskunas. Biochemical characterization of penicillin-resistant and -sensitive penicillin-binding protein 2x transpeptidase activities of Streptococcus pneumoniae and mechanistic implications in bacterial resistance to [3-lactam antibiotics. J Bacteriol 179 4901-4908, 1997. 

CG Dowson, A Hutchison, JA Brannigan, RC George, D Hansman, J Linares, A Tomasz, J Maynard-Smith, BG Spratt. Horizontal transfer of penicillin-binding protein genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Proc Natl Acad Sci (USA) 86 8842-8846, 1989. 

CG Dowson, A Hutchison, BG Spratt. Extensive remodeling of the transpeptidase domain of penicillin-binding protein 2B of a penicillin-resistant South African isolate of Streptococcus pneumoniae. Mol Microbiol 3 95-102, 1989. 

G Laible, R Hakenbeck, MA Sicard, B Joris, JM Ghuysen. Nucleotide sequences of the pbpX genes encoding the penicillin-binding proteins 2x from Streptococcus pneumoniae R6 and a cefotaxime-resistant mutant, C506. Mol Microbiol 3 1337-1348, 1989. 

A Severin, AM Figueiredo, A Tomasz. Separation of abnormal cell wall composition from penicillin-resistance through genetic transformation of Streptococcus pneumoniae. J Bacteriol 178 1788-1792, 1996. 

A Severin, MV Vaz Pato, AM Figureiredo, A Tomasz. Drastic changes in the peptidoglycan composition of penicillin-resistant laboratory mutants of Streptococcus pneumoniae. FEMS Microbiol Lett 130 31-35, 1995. 

Due to its powerful specific activity against commonly isolated community-acquired respiratory tract pathogens [33,149-158], including penicillin-sensitive and -resistant Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus, Haemophilus spp., Moraxella catarrhalis and atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila and Klebsiella pneumoniae and anaerobic bacteria [159-162], moxifloxacin was developed as a respiratory tract anti-infective [163-168]. 

DalhoffA, etal. Penicillin-resistant Streptococcus pneumoniae review of moxifloxacin activity. Clin. Infect. Dis., 2001, 32 (Suppl. 1), S22-S29. 

Church D, et al. Efficacy of moxifloxacin in the treatment of acute bacterial sinusitis caused by penicillin-resistant Streptococcus pneumoniae. In 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract 833. Toronto, 2000. 

A further mode of /S-lactam resistance is due to an alteration in the PBP s structure, resulting in ineffective binding of the antibiotic. Notable examples of this mode of resistance include methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. 

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