Development of sulfonamides, discovery of gramicidin, and Fleming’s observation of the antibiotic activity by penicillin followed by Florey and Chain’s successful purifying of penicillin marked the evolution of the antibiotics. Purification of beta-lactam antibiotics and innovations in fermentation technology has taken pharmaceutical science to brilliant heights. At the same time, antibiotic resistance has been posing a serious challenge to the medical domain. Antibiotic resistance can be defined as a form of drug resistance whereby some (or, less commonly, all) sub-populations of a microorganism, usually a bacterial species, are able to survive exposure to one or more antibiotics (Costelloe et.al, 2010). Antibiotic resistance has been attributed to horizontal transfer of genes and unlinked point mutations in the pathogen genome. There are four main mechanisms by which bacteria exhibit resistance to antimicrobials; drug inactivation or modification, alteration of target site, alteration of metabolic pathway and reduced drug accumulation. Some of the common pathogens that have been shown to exhibit antibiotic resistance are Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis , Pseudomonas aeruginosa, Clostridium difficile, Escherichia coli and Acinetobacter baumannii. Growing antibiotic resistance has also triggered a search for more effective and more powerful antibiotics.
Drug resistant pathogenic bacterial species pose serious challenges in the treatment of infections in the clinical and ICU settings. A sharp decline in the number of newly approved antibiotics (McCormack et.al, 2012) has further complicated the treatment process. Multidrug resistant pathogens (MDR pathogens) are very common today. The list of such resistant pathogens has multiplied from the popular MRSA to VISA (vancomycin-intermediate S.aureus), VRSA (vancomycin-resistant S.aureus), ESBL (Extended spectrum beta-lactamase), VRE (Vancomycin-resistant Enterococcus) and MRAB (Multidrug-resistant A. baumannii). Antibiotic resistance is a serious public health threat as it pertains to pathogenic organisms. There is no doubt that antibiotic resistant bacteria existed before the widespread of use of antibiotics (Peter et.al, 2010), but their extensive use has put an unnoticed evolutionary pressure on the pathogens leading to the development of drug resistant populations and the spread of resistance between bacterial species (Stefano et.al, 2010).
The Challenge of Esbls (Extended-Spectrum Class A Beta-Lactamases)
A comprehensive review on the challenge of Esbls (Extended-Spectrum Class A Beta-Lactamases) in antibiotic therapy has been published (Iraj et.al, 2010). Beta-lactamases are among the most heterogeneous group of resistance enzymes. More than seven hundred distinct beta-lactamases have been described so far. These globular proteins are composed of alpha–helices and beta–pleated sheets. Despite a significant amount of amino acid sequence variability, beta-lactamases share a common overall topology. In general, ESBL are capable of hydrolyzing penicillins, cephalosporins of the first, second, third and fourth generations, and the monobactam aztreonam (but not the cephamycins or carbapenems). In contrast, ESBLs (particularly TEM and SHV family derivatives) are readily inhibited by the commercially available betalactamase inhibitors (i.e., clavulanic acid, tazobactam, or sulbactam). This unique property serves as an important phenotypic test that is conveniently exploited to identify ESBLs in bacteria. Escherichia coli and Klebsiella pneumoniae possessing extended-spectrum class A beta-lactamases (ESBLs) continue to pose serious treatment challenges. In the last decade the most common beta-lactamases were of the TEM and SHV varieties. Now, CTX-M enzymes have been discovered. The Klebsiella pneumoniae carbapenemases (KPC) (ESBL type enzymes that confer resistance to extended spectrum cephalosporins and carbapenems) present the most significant challenge today. It is evident from published literature that 10–40% of strains of Escherichia coli and Klebsiella pneumoniae express ESBLs. The epidemiology of ESBLs reveals the widespread emergence of the CTX-Mtype. PER and OXA type enzymes are more common in P. aeruginosa and Acinetobacter spp. E. coli expressing CTX-M have been isolated from urinary tract infections (UTIs). These E. coli are also resistant to quinolones, aminoglycosides, and sulfonamides (Duredoh et.al, 2012).
Factors Contributing to Drug Resistance
The misuse and overuse of antibiotics have led to multidrug resistant species. Over the counter sales of antibiotics without prescription, indiscriminate addition of antibiotics to livestock feed (John, 2012) and lack of a standard treatment protocol based on a drug resistance profile for clinical isolates (Gardiner, 2012) have contributed towards the menace of drug resistance. This has also led to colonization by multidrug resistant superbugs. This is true especially with the extensive use of glycopeptides, cephalosporins and quinolones (McCormack et.al, 2012). The volume of antibiotics prescribed is a major factor for an increase in bacterial resistance rather than compliance with antibiotics (Peter et.al, 2009). Even a single dose of an antibiotic can lead to a greater risk of resistant organisms to that antibiotic in an individual over a period of time. Recent research has shown that antibiotic resistance is proportional to the duration of treatment (Peter et.al, 2009). At the same time, an insufficient course of antibiotics may lead to relapse with an infection that is now more antibiotic resistant (McCormack et.al, 2012). Most of the antibiotic prescriptions are empirical and not based on an antibiotic sensitivity profile of a particular infectious isolate. This is largely due to the severity of an infection and the time available to arrest the progress of infections. This is more relevant in life threatening situations like lobar pneumonia, meningitis or cholera. Recent research suggest that the doctors prescribe simple short course of antibiotics, followed by a clinical and laboratory evaluation, decide on the next course and stop the dose in the absence of clinical/ laboratory evidence of infection (Costelloe et.al, 2010).
Recent trends in antibiotic research include Archaeocins, a new class of potentially useful antibiotics that are derived from the Archaea group of organisms (Stefano et.al, 2010). Myxopyronin (Myx), an alpha-pyrone antibiotic, the first in a new class of inhibitors of bacterial RNA polymerase (RNAP) that target switch 1 and switch 2 of the RNAP switch region has caught the attention of researchers worldwide (Nanjwade et.al, 2010). The myxopyronin binds to and inhibits the crucial bacterial enzyme, RNA polymerase. The myxopyronin changes the structure of the switch-2 segment of the enzyme, inhibiting its function of reading and transmitting DNA code. This prevents RNA polymerase from delivering genetic information to the ribosomes.
The studies and discussions reflect the importance of documentation of an antibiotic sensitivity profile of pathogenic isolates before treatment. The documentation of the sensitivity profile should be recognized as an essential clinical procedure and integrated into the treatment protocol to combat the seriously growing problem of multiple drug resistance.
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