Methicillin-resistant Staphylococcus aureus (MRSA) carrying the important virulence determinant, Panton-Valentine leukocidin (PVL), is an emerging infectious pathogen associated with skin and soft tissue infections as well as life-threatening invasive diseases. In carrying out the first PVL prevalence study in Nepal, we screened 73 nosocomial isolates of S. aureus from 2 tertiary care Nepali hospitals and obtained an overall PVL-positivity rate of 35.6% among the hospital isolates: 26.1% of MRSA and 51.9% of methicillin sensitive S. aureus (MSSA) isolates were found to be positive for the PVL genes. PVL prevalence was not associated with a specific (i) infection site, (ii) age group, or (iii) hospital of origin. It was found to be positively associated with heterogeneous MRSA (73.3%) compared to homogeneous MRSA (3.2%) and MSSA (51.9%); negatively associated with multiresistant MRSA (22%) compared to nonmultiresistant MRSA (60%) and MSSA (51.9%); and positively associated with macrolide-streptogramin B resistance (93.8%) compared to macrolide-lincosamide-streptogramin B resistance (0%) and no-resistance (45.8%) types. Macrolide-streptogramin B resistance was confirmed by the presence of msr(A) gene. Restriction pattern analyses provided evidence to support the circulation of a limited number of clones of PVL-positive MRSA, arguing for the adaptability of these isolates to a hospital setting.

Staphylococcus aureus is a Gram-Positive bacteria that are responsible to cause skin infections and also shows toxic shock syndrome. Several antibiotics were given against the S. aureus infections but eventually, the prevalence of multidrug resistance of Staphylococcus aureus started emerging. Since then Methicillin-resistant Staphylococcus aureus strains (MRSA)were very common which causes nosocomial infections. Microorganisms for the need of the survival undergoes mutational changes either in their chromosomal DNA/RNA which confers the resistance. One of the famous examples is the resistance against methicillin in Staphylococcus aureus. The evolution of S. aureus is successful in developing multiple resistant strains. Plasmids are capable of carrying the resistant genes and also several toxic genes. In a recent study, it has been observed that drug resistance genes are located in the R plasmids and they are also responsible in conferring multi drug resistance and induce less utilization of multiple antimicrobial therapy. MRSA was not only resistant to methicillin, studies proved MRSA strains were resistant to macrolides, tetracyclines, chloramphenicol. Resistance to vancomycin was very evidently observed, and its transfer among the population and rising of resistant strains was becoming a major threat globally. The resistance of all these antimicrobial agents against the pathogenic microorganisms are taking a rise in some patients due to prolong use of the antimicrobial agents by these patients. The multi drug resistance has enhanced the mortality and morbidity rate which referred to the infecting agents as the “Super Bugs”. Survival of the microorganisms has increased due to the gradual development of extensive resistance against varied antimicrobial drugs. Possible treatments with combinations are found to be the only hope for infections against S. aureus. Few drugs are in development such as Dalbavancin, Oritavancin, Tigecycline. These are the possible treatments upon which the work is going on to reduce the resistance against the invasive MRSA. This chapter highlights the profiles of Staphylococcus aureus and the resistance patterns along with transmission and the role of the plasmid in transmitting the resistance.

Kumar et al.: Gut Microbial Changes in Response to AntibioticsWidespread usage of antibiotics disrupted the host bacterial mutualism in the human intestine. The antibiotic alterations can drive the functionality of the gut microbiota towards a state similar to those observed under various disease states in humans. The emergence of antibiotic-resistant bacteria further spurred the development of the antimicrobial crisis all over the world. Antibiotics have an essential role in treating various diseases. To understand the intricate relationship between antibiotics and human gut microbiota, the basic understanding of the microbial signature of gut dysbiosis in human patients and murine models in response to antibiotics treatment is very crucial. Therefore, we examined the effects of most commonly used antibiotics on human and murine gut microbiota, when administered alone or in a combination, under this article.

Purpose: The preclinical pharmacokinetic and pharmacodynamic properties of a potent fluoroketolide RBx14255 against Streptococcus pneumoniae and Haemophilus influenzae was compared with telithromycin and human clinical dose was predicted for preclinical development. Methods: The in vitro pharmacokinetic characterization was performed for solubility, Caco-2 permeability, microsomal stability, CYP inhibition and plasma protein binding. In vivo pharmacokinetic studies were performed in Swiss albino mice, Sprague Dawley rats and Beagle dogs. The pharmacodynamic studies were carried out in mouse against S. pneumoniae in systemic infection and against S. pneumoniae and H. influenzae in rat lung infection models. Results: RBx14255 showed superior potency and efficacy in mouse and rat infection models. RBx14255 showed pH dependent solubility (0.41 mg/mL at pH 6.8 and >1 mg/mL at pH 1.2), moderate Caco-2 permeability (A to B: 12 nm/s) with high efflux ratio. It showed high plasma protein binding (>97%) in mouse and low binding (45-70%) in rat, dog and human. The compound is mainly metabolized through CYP3A4. Pharmacokinetic parameters and absolute bioavailability of both, RBx14255 and telithromycin are similar in mouse. Both the ketolides showed low plasma clearance (18% of the normal hepatic blood flow rate) in mouse, moderate to high clearance in rat and dog. Mean oral bioavailability was high in mouse (≥85%), moderate in rat (RBx14255: 15% and telithromycin: 51%) and high to moderate in dog (RBx14255: 98% and telithromycin: 56%). The predicted efficacious dose for a 70 kg man ranges from 124 mg BID to 226 mg BID. Conclusion: RBx14255 displayed significantly better pharmacodynamics which correlates with the pharmacokinetic properties against S. pneumoniae and H. influenzae as compared to telithromycin. The predicted human efficacious doses are in the range of 124-226 mg, making it amenable to oral dosage form drug in human. This could be a promising clinical candidate for future studies.