Bacterial infections and multidrug resistance

According to WHO Antimicrobial resistance (AMR) is resistance of a microorganism to an antimicrobial medicine to which it was originally sensitive. Clinical infections with such organisms pose serious therapeutic challenges, with increasing reports of poor patient outcomes and death.It threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi. It is an increasingly serious threat to global public health that requires action across all government sectors and society (WHO 2014).

Emergence of CRE is due to the the ability of these organisms to produce carbapenem hydrolysing β- lactamases (Elizabeth et al 2013). Among β-lactamases, MBLs are most feared because it is transferable and hydrolyse almost all drugs including carbapenems. Lack of drug penetration due to mutation in porin, loss of certain outer membrane protein and efflux mechanism are the mechanism for carbapenem resistance (Harish et al 2008).

Antibiotic resistance is the acquired ability of the pathogen to withstand an antibiotic that kills off its sensitive counterparts, such resistance usually arising from random mutations in existing genes or from intact genes that already serve a similar purpose. Exposure to antibiotics and other antimicrobial products, whether in the human body, in animals, or the environment, applies selective pressure that encourages resistance to emerge favouring both ‘naturally resistant strains’ and which have ‘acquired resistance’ (ASM 2009). It is the temporary or permanent ability of an organism and its progeny to remain viable or multiply under environmental conditions, that would otherwise destroy or inhibit other cells (Hugo and Russell 1993).

The diversity of the microbial world and the relatively specific activities of antimicrobial agents virtually ensure widespread resistance among bacteria    (Forbes et al 2007). Hence several factors like inoculum effect, intrinsic susceptibility, tolerance should be taken into account before classifying organism as resistance or susceptible (Murray et al 2003).  Strong correlation has been observed between use of the antibiotics for treatment and antibiotic resistance development over the past half century (Davies et al 2010).

There are several mechanisms of resistance like decreased permeability of bacterial membranes; antibiotic efflux; altered target sites; inactivating enzymes (Opal et al 2009). The factors playing significant role in the increases and decreases of prevalence of resistant strains include host and clone specificity, plasmid and clone specificity, virulence, interactions with other commensal flora, duration of the selection pressure, and variable gene expression (WHO 2004 and ASM 2009). Strong correlation has been observed between use of the antibiotics for treatment and antibiotic resistance development over the past half century (Davies et al 2010).

The evolution of resistant strains is a natural phenomenon that happens when microorganisms are exposed to antimicrobial drugs, and resistant traits can be exchanged between certain types of bacteria. Soon the new phenotype with resistance appears its spread is favored by the degree of resistance expressed, the ability of the organism to tolerate the resistance mechanism, linkage to other genes, site of primary colonization etc. The rapidity and completeness of the resistance gene spread are often unpredictable. Overuse of antibiotics in a hospital can cause a selective pressure on microorganisms, which in turn, can enhance the antimicrobial resistance in bacteria. Inappropriate use of antibiotics has been reported to be involved in increasing the antibiotic resistance (Namdar et al 2010). The misuse of antimicrobial medicines accelerates this natural phenomenon. Poor infection control practices encourage the spread of AMR.

The recent appearance of β- lactamases capable of hydrolyzing carbapenems, in addition to other carbapenem resistance, creates an increasing therapeutic dilemma (Livermore et al 1995). Carbapenem resistant gram-negative bacterial species such as S. marcescens and P. aeruginosa have emerged in Japan, and these isolates usually produce IMP- 1metallo-beta lactamase (Yoshichika et al 1999). These Gram negative bacilli are rapidly acquiring resistance to one or more antimicrobial agents traditionally used for treatment is a matter of concern (Gupta et al 2005).         

Infections caused by resistant microorganisms often fail to respond to the standard treatment, resulting in prolonged illness and greater risk of death. The death rate for patients with serious infections treated in hospitals is about twice that in patients with infections caused by non-resistant bacteria. AMR reduces the effectiveness of treatment, thus patients remain infectious for a longer time, increasing the risk of spreading resistant microorganisms to others (Jones et al 2009).

According to CDC, multidrug resistance is defined as resistance to two or more classes of antimicrobial agents. Multidrug resistance is defined as resistance to at least two antibiotics of different classes including aminoglycosides, chloramphenicol, tetracyclines and/or erythromycin (Huys et al 2005). It is one of the major threat to the health problem throughout the world as it is in increasing trend.

The emergence of resistance in responsible pathogens have worsened the scenario making it difficult for prompt treatment with use of optimum use of antibiotics.  Most importantly, microorganisms like K. pneumoniae, A. baumanii, P. aeruginosa, E. coli and Enterobacter spp. Furthermore, pan antibiotic-resistant (PDR) and newly reported cases of extremely drug resistance (XDR) infections due to highly resistant Gram-negative pathogens—namely Acinetobacter spp, multidrug-resistant (MDR) P. aeruginosa producing metallo β-lactamases (MBL) has been increasingly reported from around the world (Bollero et al 2001; Boucher et al  2008;  Falagas et al 2006 ;  Paterson et al 2007).

Emergence of multidrug resistance in Nepal is in increasing trend which is challenging the therapeutic effects. Inappropriate use of different antibiotics is the major cause of prevailing resistance. Its pattern has been studied by many researchers in Nepal. In a study conducted at Tribhuvan University Teaching Hospital (TUTH), 47.5% of the isolates from the sputum and 60.4% of urinary isolates were MDR strains among which 24.27% and 16% of the isolates from sputum and urine respectively were ESBL producers ( Pokhrel et al 2004). In a similar study conducted at TUTH, 68.33% of the urinary and 71.43% of the sputum isolates were MDR with 12 urinary isolates and 3 isolates from sputum demonstrating ESBL activity (Bomjan 2005). In a study of Salmonella serovars isolated from urban drinking water supply of Nepal, 35 Salmonella isolates were MDR and all the isolates of S. enteritidis.and four isolates of S. typhimurium indicated presence of one of the ESBL (Bhatta et al 2007). In another study of nosocomial isolates in Kathmandu Medical College (KMC), Citrobacter spp. was accounted as the most frequently isolated nosocomial pathogen with high prevalence of MDR strain followed by K. pneumoniae and E. coli (Thapa et al 2009). Another study on the resistance pattern of fluoroquinolone to Salmonella isolates in NPHL, 2(4.88%) isolates of Salmonella Typhi were multidrug resistant ( Acharya 2008).63.38% isolates of the total 314 isolates studied in NPHL were found to be multidrug resistant of which 62% isolates of the total tested MDR were ESBL positive and 42.37% isolates demonstrated MBL activity (Poudyal 2010).   In pregnant women 20% E.coli of and 36.4% of K. pneumoniae were found to be the ESBL producers at Paropakar Maternity and Women’s Hospital (Thapa 2011).In sputum sample at Nepal Public Health Laboratory, 14.28% of K.  pneumonia and  25% of E. coli were found to be ESBL ( Bhaila 2011).

of 59 MDR isolates tested for ESBL production in National Kidney Centre, 35 (59.32%) bacterial isolates tested positive for ESBL production, consisting of E. coli i.e. 29/35(82.85%) followed by K. pneumoniae 4/35 (11.42%) and P. aeruginosa 2/35(5.71%). Only one isolate showed MBL production (Panta 2013).

 In a study conducted at Alka Hospital, out of the 267 isolates of Enterobacteriaceae, 38.6% isolates were Multi-drug resistant, among which 27% were ESBL producer  (Paudel 2012).