Multiple drug resistance: A daunting challange

Bhuwaneswor Prasad Kandel

Lecturer (Medical Microbiology),

Prithvi Narayan Campus, Pokhara, Nepal

Bacterial resistance to various antibiotics has been observed since their discovery and the pace of development of new antibiotics in recent years has been paralleled by the appearance of resistance to these antibiotics creating a growing health problem of global magnitude. The relentless threat posed by microbial drug resistance has achieved the dimension of a global pandemic, with a relevant impact in terms of morbidity, mortality and health-care associated costs. The growing threat posed by increasing prevalence of extended spectrum β-lactamases (ESBLs) and carbapenemases among gram-negative bacteria has resulted in infections that can be extremely difficult to treat. Extensive and indiscriminant use of various antimicrobials in clinical and agricultural practices has been creating the major selective force for emergence and global dissemination of resistant strains and resistance genes. Misuse and overuse of antibiotics by clinicians and retailers, their use by patients in suboptimal dose and duration, and use of leftover antibiotics by patients, all have contributed to emergence and spread of multidrug resistant (MDR) bacteria. Residents of long-term care facilities (LTCF) and ambulatory patients are among the main reservoirs of most of antibiotic-resistant bacteria with severe and chronic illness, increased antimicrobial exposure, altered physiological states, use of indwelling devices, surgery, etc. being reported risk factors for infection with MDR organisms leading to treatment failure and prolonged period of hospital stay.

Based on different clinical settings, distribution pattern of pathogens, the drugs used to treat them, and their drug resistance patterns, multidrug resistance can most commonly be defined as resistance to at least two or more different classes of antibiotics.  After their first detection  in the late 1950s and early 1960s, MDR bacteria have been emerging continuously challenging the antibiotic chemotherapy. Among the MDR organisms, MRSA (Methicillin resistant Staphylococcus aureus), VRSA (Vancomycin resistant S. aureus), VRE (vancomycin resistant Enterococci), ESBL producing gram-negative bacteria, Pseudomonas, Acinetobacter, Klebsiella, Enterobacter species, and Escherichia coli warrant special attention because of their limited therapeutic options. Extensively drug resistant (XDR) and pandrug resistant (PDR) Acinetobacter baumannii,  Pseudomonas aeruginosa and Klebsiella pneumoniae are also emerging increasingly and frequently in hospitalized patients for which no adequate therapeutic options exist. These limitations may influence antibiotic usage patterns in ways that suppress normal flora and favor colonization by potential MDR pathogens, i.e. selective advantage.

Multidrug resistance in bacteria is mainly due to the expulsion of more than one class of drug by multidrug efflux pumps that recognize a broad range of structural and chemically different substrates. Transfer of the genes coding for these pumps across organisms is uncommon because of the inherent genetic complexity of these pumps. Efflux pumps responsible for multiple drug resistance include highly drug specific ABC transporters and major secondary transporters, viz. MFS, RND, SMR, DMT and MATE transporters that are involved in multiple drug resistance. The over expression of chromosomally encoded RND pumps in gram-negative bacteria and sometimes combinations of different types of efflux pumps can have synergy for outer membrane impermeability and multidrug efflux resulting in higher level of intrinsic multidrug resistance. ¹² The antibiotic susceptibility of bacterial cells is also affected due to occurrence of “persister” cells and by biofilm formation.

Many studies have shown the MDR phenotypes among European and Asian S. aureus clinical isolates ranging from 37.5% to 68.1%. National Nosocomial Infections Surveillance System (NNIS) has also reported many fold increase in resistance among some enteric bacteria and P. aeruginosa, and 20% increase in carbapenem resistant Acinetobacter spp. from 1986 to 2003. The Study for Monitoring Antimicrobial Resistance Trends (SMART) demonstrated increased detection of ESBL-production among E. coli, Klebsiella spp, and Enterobacter. Increase in ESBL production and carbapenem resistance in K. pneumoniae has been reported from Pakistan. ESBL production and multidrug resistance even to wider range of newer and older antibiotics is also higher among common clinical isolates in Nepal too. These studies show the higher prevalence and emergence of multidrug resistance globally among common clinical pathogens.

Multiple drug resistant organisms render therapy more precarious and costly, and sometimes unsuccessful. Individuals may succumb to MDR infections because all available drugs have failed, especially in the developing world. The progressive increase of MDR pathogens has called for a reevaluation of current antibiotic therapy. Monitoring MDR organisms in different healthcare settings is important to detect newly emerging antimicrobial resistance profiles and searching for newer therapeutic alternatives.