Multi Drug Resistance: A Global Concern

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The Multidrug Resistance Associated Proteins ((MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8 and MRP9) belong to the ATP-binding cassette superfamily (ABCC family) of transporters expressed differentially in the liver, kidney, intestine and blood-brain barrier. MRPs transport a structurally diverse array of endo- and xenobiotics and their metabolites (in particular conjugates) and are subject to induction and inhibition by a variety of compounds. An increased efflux of natural product anticancer drugs and other anticancer agents by MRPs in cancer cells is associated with tumor resistance. These transporting proteins play a role in the absorption, distribution and elimination of various compounds in the body. There are increased reports on the clinical impact of genetic mutations of genes encoding MRP1-9. Therefore, MRPs have an important role in drug development, since a better understanding of their function and regulating mechanism can help minimize and avoid drug toxicity, unfavorable drug-drug interactions, and to overcome drug resistance.

Klebsiella pneumoniae is one of the most common nosocomial pathogens. K. pneumoniae strains producing Extended-Spectrum β-Lactamase enzymes (ESBLs) with transferable resistance to all β-lactam (except cephamycins and carbapenems) were first detected in the mid-1980s in Western Europe. Nowadays, there is a worldwide and non-uniform spread of K. pneumoniae expressing ESBL phenotype with prevalence as high as 45.4 percent. For infections caused by these strains, treatment with carbapenem drugs has been associated with the best outcomes in terms of survival and bacteriologic clearance. To date, carbapenem-resistance has been unusual in isolates of K. pneumoniae. Nevertheless, several recent studies have well documented the emergence of carbapenem resistance in Enterobacteriacae, including Klebsiella spp., which should be considered of major public concern. Resistance to carbapenems in Enterobacteriaceae is generally caused by hydrolyzing enzymes. The most important among these are carbapenemases, primarily the serine β-lactamase KPC and metallo- β- lactamase VIM. The genes coding for these enzymes are carried by plasmids that often carry other resistance factors as well, resulting in extensively drug-resistant bacteria.Outbreaks of bla (VIM-1) positive carbapenem-resistant K. pneumoniae (CRKP) have been reported from some European countries. In the United States, carbapenem-resistance has been observed in strains of K. pneumoniaeproducing class A carbapenemases, namely, KPC-1, KPC-2 and KPC-3. During 2006, strains of CRKP (KPC-2 and KPC-3) spread through Israeli hospitals and became a major national outbreak. Prior exposure to carbapenem and quinolones was found to be of resistance of K. pneumoniae to carbapenems.Infections due to CRKP have several important implications. First, these infections are spreading worldwide rapidly and are associated with a high estimated attributable mortality. Second, to control the spread of KPC enzymes appears to be difficult. Plasmids are easily transferred and resistant genes can spread within species and even from species to species of Enterobacteriaceae. Finally, and even more worrisome is that most KPC-possessing K. pneumoniae isolates are resistant not only to carbapenems, but also to almost all antibiotics currently in use. The clinical usefulness of a very few drugs showing in vitro activity against these strains remains to be proved.

During the last decade, both Gram-positive and Gram-negative bacteria that are resistant to most or all available antibacterial classes are increasingly prevalent in the nosocomial environment, particularly among immunocompromised patients and those hospitalized in intensive care units. Among Gram-positive bacteria, increasing concerns are posed for health care- and community-associated methicillin-resistant Staphylococcus aureus, S. aureus with reduced susceptibility or resistance to vancomycin and vancomycin-resistant enterococci. Gram-negative bacteria have also developed multidrug resistance, which in the family of Enterobacteriacae is commonly due to the production of extended-spectrum β-lactamases and carbapenemases of metallo- or serine-β-lactamase type (mainly VIM-, IMP-, or KPC-types). Further, multidrug resistant non-fermenting Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii are common, necessitating the application of concerned efforts for their control. The control of multidrug resistant organisms requires approaches that include knowledge of their local and international epidemiological spread, accurate detection and surveillance, rational use of antibiotic treatment options and enhanced infection control measures. In the following sections of this chapter, such approaches will be presented for each category of the aforementioned major multidrug resistant bacteria.

Trends of resistance among gram-negative bacteria are progressively on the rise and it appears that control measures may not yet be successfully achieved. Multi-drug resistant bacteria often complicate treatment options and result in unfavorable morbidity. Thailand experiences the emergence of various resistant phenotypes in the last decade. For example, extended-spectrum β-lactamase (ESBL)-producing bacteria have reached ca. 40% among Escherichia coli and Klebsiella pneumoniae isolates. The rapidly spread of ESBL family, CTX-M, is highly endemic in this area. It is noteworthy that ESBL producers are now recognized as a cause of community-onset infection, and thus indicating a more difficult situation to control. In addition, probably due to a heavy use of carbapenem agents against ESBL producers, carbapenem-resistant Enterobacteriaceae have recently emerged. Pseudomonas aeruginosa and Acinetobacter baumannii are predominantly nosocomial pathogens. They are notorious for their extreme resistance to available antimicrobial agents, in which ca. 30% and 70%, respectively, of our clinical isolates are classified as “extensive drug resistance”. This leads to an unwilling use of colistin, a high toxicity drug with a little experience for use in human. Although it is effective against these organisms, it is unfortunate that colistin-resistant isolates have lately been identified, likely reflecting an increased use of colistin. An inefficiency of antimicrobial stewardship program and a lack of policy for controlling antibiotic purchase over the counter are believe to, at least in part, contribute to this abrupt expansion of resistant bacteria. In this chapter, various resistant phenotypes among gram-negative bacteria posing a health care problem in Thailand, as well as their resistant genotypic characteristics and molecular epidemiology, will be discussed.

Prevention and control of tuberculosis in middle and low income countries is a great challenge for health care workers as well as funding agencies. Issues which pose challenges in these countries are different from the developed world and hence need to be addressed in a different manner. Key challenges remain; high prevalence of tuberculosis especially drug resistant tuberculosis, Multidrug Resistant Tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB), Human Immunodefiency Virus (HIV) and TB co morbidity, local, social and structural factors (which are different from region to region), economic constrains, poor diagnostic facilities etc. To meet these challenges, building a strategy on case management, maintaining high quality of care and preventing drug resistance, building human resource capacity, improving diagnosis and fostering operation research in area of tuberculosis should be the health care priority in these countries. Here, we have focused on each one of the important issues which adversely impact the control and prevention of tuberculosis in economically weaker countries.

Drug resistance in tuberculosis (TB) is known since the start of anti-tubercular therapy to treat tuberculosis. It arises as a result of inadequate treatment procedures or poor compliance to drugs by the patients, which result in selection and spread of resistant tubercle bacilli in the population. Multidrug resistance (MDR), and recently extensive drug resistance (XDR), have become a great challenge to our fight against TB. The resistant forms of tuberculosis are difficult to treat and the treatment is lengthy, more toxic and costlier than for drug sensitive form. The accumulation of mutations in the genes targeted by anti-TB drug is the primary mechanism behind the development of resistance. However, other mechanisms such as impermeability of bacterial cell to drugs and activation of efflux mechanisms also contribute significantly to drug resistance. Current tests to diagnose resistant TB are either lengthy, less sensitive or less specific or are expensive enough to be used in low financial clinical settings. The drugs being used to treat drug resistant TB are again costly, have side effects and still are less effective. To develop suitable and effective diagnostic tools and cheaper and less toxic effective drugs against resistant tuberculosis, a comprehensive understanding of its molecular mechanisms is needed.

Antibiotic resistance in bacteria is an increasing problem worldwide. Bacteria are challenging the scientists with a hard-hitting weapon called as ‘Extended Spectrum Beta Lactamases’ (ESBLs). Now, CTX-M enzymes have become the most prevalent beta-lactamases found in clinical isolates, leaving behind the TEM and SHV types. Organisms that produce both an ESBL and a carbapenemase may become resistant to virtually all β-lactams, leading to therapeutic dead-ends. Structural studies of ESBLs indicate that active site expansion and remodeling are responsible for this extended hydrolytic activity. Continuing questions still exist regarding the optimal detection method for ESBLs. Presently, the therapy relies on β-lactam/ β-lactamases inhibitor combinations, carbapenems and piperacillin - tazobactam plus aminoglycoside combination. In light of the emergence of carbapenemases, the presumed status of carbapenems as the therapy of choice against ESBL-producing pathogens is in question. Moreover, this review explores CTX-M, the most prevalent ESBL at molecular level so that the reader may appreciate “structure-function relationships” in these enzymes.

Staphylococcus aureus has been recognized as an extremely successful hospital pathogen that has established itself firmly in the community as well. In addition to its compendium of virulence factors, it has the immense propensity to develop resistance to antimicrobials belonging to different classes. The emergence of methicillin resistant S. aureus (MRSA) that carries transferable multiple antibiotic resistance to the class of β-lactams alone or to other antimicrobials as well, is a serious public health concern. The development of community-associated MRSA (CA-MRSA) from a genetic lineage different from that of hospital-associated MRSA (HA-MRSA) was unexpected, as was the observation that different strains of CA-MRSA from different parts of the world co-evolved simultaneously. Considering these observations with the virulence of the organism, and the transferable nature of the methicillin resistance genetic element, it is not surprising that MRSA is regarded as a pathogen that warrants utmost attention of the medical and scientific community. The need for urgent measures for its control cannot be overemphasized.

Acinetobacter baumannii is an opportunistic gram-negative pathogen with increasing relevance in a variety of hospital-acquired infections especially among intensive-care-unit patients. Resistance to antimicrobial agents is the main advantage of A. baumannii in the hospital setting. A. baumannii epidemics described worldwide are caused by a limited number of genotypic clusters of multidrug-resistant strains that successfully spread among hospitals of different cities and countries. In this chapter, we will focus on the mechanisms responsible for antimicrobial drug resistance in A. baumannii and the epidemiology of multidrug-resistant A. baumannii in health-care facilities.

Since the early 1990s, there has been a substantial increase in the emergence and dissemination of antimicrobial resistance in foodborne and zoonotic pathogens, such as Campylobacter, Salmonella and Escherichia coli causing human infections in several developed countries. This increase has been attributed to the potential use of antimicrobials for prophylactic treatment of food animals and humans. While these drugs were successful in the treatment of most diseases in animals and humans, they have contributed to the emergence of drug-resistant bacteria. Several studies have addressed the public health significance of antimicrobial resistance in foodborne pathogens. Attention has been particularly focused on the pros and cons of short term and long term use of antimicrobial agents in food of animals for growth promotion and disease prevention. The public health risk of emergence, spread and transmission of drug-resistant foodborne pathogens in the farm-to-the-fork continuum warrants appropriate actions by both the scientific community and the regulatory agencies in advocating restrictions on the approval and use of new and existing drugs. In this chapter, we have described the prevalence, specific mechanisms (based on the class of drugs) and dissemination of antimicrobial resistance in Campylobacter, Salmonella and E. coli. These three pathogens were selected because they constitute the bulk of bacterial illnesses worldwide. The review will highlight the importance of addressing the issue of conventional and emerging drug-resistant foodborne bacteria in foods, animals and humans so that steps can be taken to minimize their spread in the environment.

Data available on bacterial resistance to antibiotics in the Middle East and some African countries mainly comprised sporadic nosocomial outbreaks. However, some surveillance studies, such as the PEARLS and ARMed have examined resistance determinants and patterns of common nosocomial pathogens in some Middle Eastern and North African countries. But no national surveillance figures have been published in any of these individual countries. In this chapter we will present reported rates of bacterial resistance to antibiotics in clinically important pathogens such as MRSA, Escherichia coli and other selected Enterobacteriaceae in this geographical region. In addition, we will discuss studies on nosocomial pathogens notorious for multidrug resistance such as Acinetobacter baumannii, Pseudomonas aeruginosa, as well as ESBL producers of the Enterobacteriaceae that are prevalent in some Middle Eastern and African countries. These clinically important pathogens were reported to possess various ESBL genes of the TEM-, SHV-, CTX-M-families; as well as the carbapenem hydrolyzing metallo- and OXA-type β-lactamases. Other resistance determinants were also reported and include the integron associated qnr gene, and the aac (6')-Ib-cr gene which codes for aminoglycoside resistance and reduced susceptibility to ciprofloxacin. In addition, community acquired infections caused by MRSA and ESBL producers of the Enterobacteriaceae that have been reported in this geographical region will be covered. Because of the disturbing high rates of bacterial resistance to antibiotics in this geographical region, some countries found it compelling to initiate Infection Control programs to hamper the spread of resistant pathogens.

Much of the focus of today's media is directed on multidrug-resistant gram-positive bacteria. However, resistance within gram-negative bacilli continues to rise, occasionally creating situations in which few or no antibiotics that retain activity are available. Gram-negative bacteria are important causes of urinary tract infections, bloodstream infections, hospital- and healthcare-associated pneumonias, and various intra-abdominal infections. In Saudi Arabia, among Escherichia coli isolates from outpatients, 50% are resistant to ampicillin, 33% are resistant to trimethoprim-sulfamethoxazole (TMP-SMZ), and 14% are resistant to ciprofloxacin. Among isolates from inpatients, 63% of E. coli are resistant to ampicillin, 44% are resistant to TMP-SMZ, and 33% are resistant to ciprofloxacin. Multidrug resistance is detected in 2-28% of outpatient isolates and 7.4-39.6% of inpatient isolates. For Pseudomonas aeruginosa, the resistance rates of outpatient and inpatient isolates to piperacillin, ceftazidime, imipenem, and ciprofloxacin are 4.6% and 11.5%, 2.4% and 10%, 2.6% and 5.8%, and 3% and 6%, respectively. Multi-drug resistance is observed in 1-2% of inpatient isolates. Acinetobacter calcoaceticus-baumannii has high rates of resistance to ampicillin (86%), cefoxitin (89%), and nitrofurantoin (89%). The rate of resistance to imipenem is 3%; to ticarcillin-clavulanic acid, 16.5%; to gentamicin, 26%; and to ceftazidime, 38%. Multidrug resistance is observed in 14%-35.8%. Acinetobacter calcoaceticus-baumannii complex were recovered. The organism showed high rates of resistance to ampicillin (86%), cefoxitin (89%), and nitrofurantoin (89%). The rate of resistance to imipenem was 3%; to ticarcillin-clavulanic acid, 16.5%; to gentamicin, 26%; and to ceftazidime, 38%. Multidrug resistance is observed in 14%-35.8%.

β-lactamases are the major mechanism of resistance against β-lactam antibiotics among Gram-negative bacteria. On the basis of their amino acid sequence, β-lactamases are divided into four classes: A, B, C and D. This classification was first proposed by Ambler. The classes A, C and D include enzymes that hydrolyse their substrates by forming an acyl enzyme through an active site, whereas class B β-lactamases are metallo-enzymes which utilise one or two ions in their active sites. The massive use of expanded-spectrum cephalosporins, since the 1980s, has been conducive for the emergence of extended-spectrum β-lactamases (ESBLs) in the clinical setting, a group of enzymes capable of hydrolysing a wide range of expanded-spectrum β-lactams, including the oxyiminocephalosporins, but they are inactive against cephamicins and carbapenems. The emergence and widespread of ESBLs compromised the usefulness of carbapenems in clinical therapy leading to the emergence and diffusion of carbapenemases and in particular metallo-β-lactamases

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