Table 1: Common multidrug resistant bacteria and their possible mechanisms.

Transcription

1 1. INTRODUCTION Septicemia is a term classically associated with clinical signs and symptoms characteristic of systemic toxicity secondary to bloodstream invasion by microorganisms or associated toxins (Kang-Birken and Dipiro, 2002). The number and rate per 10,000 population of hospitalizations for septicemia more than doubled from 2004 to 2008 in United States of America (Hall, Williams, DeFrances and Golosinskiy, 2011). With a mortality rate of almost 30%, sepsis is considered a leading cause of death worldwide (Slade, Tamber and Vincent, 2003). It is the 10th leading cause of death in United States of America with 32,238 deaths, 1.4% of all deaths, in the year 2002 (Kochanek and Smith, 2004). According to National Neonatal Perinatal Database, the incidence of neonatal septicemia is 24/1000 live births in India (Aggarwal, Sarkar, Deorari and Paul, 2001). Recently, an annual report on births and deaths in Delhi by Delhi government s Finance, Planning and Urban Development Scheme has reported 8.15% mortality due to septicemia (IndiaNewsPost- Over 900 births and 300 deaths in Delhi every day.htm). Septicemia is one of the most serious and life threatening infections in dialysis patients. It accounts for over three fourths of deaths (US Renal Data System, 1997). It is a leading cause of neonatal mortality and a significant proportion of newborns are infected with Klebsiella species in neonatal intensive care units (NICUs) (Jain, et al., 2003; Boo, Ng and Lim, 2005). Neonatal septicemia (NNS) continues to be a major problem for neonates in NICUs around the world (Gaynes, et al., 1991; Brodie, et al., 2000; Lin, et al., 2000), with the incidence in the USA varying from 5 to 32% (US Renal Data System, 1997). The most common infection sites leading to bacterial entry into the circulatory system are lungs, urinary tract, abdominal cavity and primary infections of the bloodstream (Nicolls, Morgan and Morris, 2000; Cohen, 2002). Many microorganisms can cause septicemia, but majority of them are Gram-negative aerobes that includes Escherichia coli, Pseudomonas species, Klebsiella species, Acinetobacter species, Salmonella typhi, Enterobacter aerogenes and Proteus species. The numbers of infections with 1

2 Gram-positive organisms, particularly infection with coagulase-negative staphylococci associated with intravascular catheters are increasing (Eykyn, Gransden and Phillips, 1990). Among other major Gram-positive organisms causing septicemia are Staphylococcus aureus, enterococcus species and Streptococci group of bacteria. Pediatric and geriatric patients have been reported to be at special risk of septicemia and its fatal outcomes (French, Chend, Duthie and Cockram, 1990; Eykyn, Gransden and Phillips, 1990). Immunosuppression, old age, drug resistant urinary tract infections (UTIs), severe diabetes mellitus, advanced cancer and severe burn injuries are major risk factors for septicemia. Other risk factors may include seasonal variation. Hlady and Klontz (1996) reported that in Florida Vibrio infections caused gastroenteritis (51%), wound infections (24%) and primary septicemia (17%). They reported also that raw oyster consumption was responsible for 83% of septicemia. Septicemia is a medical emergency, where accurate microbiological diagnosis is of vital importance and blood cultures should be taken before considering antimicrobial therapy. It is important to remove the source of infection along with initiating antibiotic therapy to prevent re-infection of the bloodstream. Antimicrobial agents are the mainstay of therapy for the treatment of septicemia. These patients should, therefore receive aggressive course of parenteral antimicrobial therapy at the earliest, because of seriousness of the illness and paucity of time. Broad spectrum antibiotics are usually given empirically before accurate identification of the microorganism is known (Dellinger, et al., 2008). Combination therapy with more than one antibiotic is often indicated in critical patients. As the infecting organism(s) is not known at the beginning and empirical treatment is instituted, reassessment of antimicrobial regimen to optimize efficacy, prevent development of resistance, avoid toxicity and minimise cost is required (Dellinger, et al., 2008). Many studies have reported inappropriate treatment of bloodstream infections (BSIs) due to antimicrobial resistance that increases the risk of fatal outcome, in terms of greater patient morbidity, higher mortality rates, and increased healthcare cost (Blomberg, et al., 2005; Garnacho- Monlevo, et al., 2008). On the contrary, there are a number of clinical studies that suggest timely and appropriate antimicrobial chemotherapy has a beneficial effect on patients outcome in BSIs (Diekema, et at., 1999; Ibrahim, et al., 2000; Fraser, et al., 2

3 2006; Kumar, et al., 2006). The lethality of septicemia in terms of mortality rate has declined in recent two decades. However, the increasing cases of septicemia particularly in developing countries is still a major health problem that creates biggest challenge for the clinicians in selection of suitable antimicrobial agents, as it is further complicated by the development of resistance in organisms to antimicrobial agents, which is the mainstay of treatment for septicemia. Increasing antimicrobial resistance among BSIs have been reported in many studies conducted in India (Mehta, Dutta and Gupta, 2005; Kaistha, et al., 2009), and other countries worldwide (Sader, et al., 2002; Kato-Maeda, et al., 2003; Biedenbach, Moet and Jones, 2004). Antibacterial use has resulted in a major healthcare problem due to the development and spread of resistant bacteria. Acquired antimicrobial resistance constitutes a major challenge for the clinicians in selection of antimicrobial therapy for septicemia. Antimicrobial resistance increases patient morbidity, mortality rates, and adds to increase healthcare costs (del Rio, et al., 2009; Tumbarello, et al., 2010; de Kraker, et al., 2011). Increasing antimicrobial resistance is reported for pathogens such as coagulase-negative staphylococci and Staphylococcus aureus, which are the most common bacteria isolated from blood cultures of intensive care unit (ICU) patients (Weinstein, et al., 1997; Kollef, 2001; Niederman, 2001; Blomberg, et al., 2005). Recently, linear trend of increasing resistance to chloramphenicol among isolates of non-typhoidal Salmonella, Escherichia coli, Staphylococcus aureus and Haemophilus influenzae were reported (Mandomando, et al., 2010). Studies from Chandigarh, North India have reported resistance of Staphylococcus aureus and enterococcus species to ampicillin and amoxicillin (Agnihotri, Kaistha and Gupta, 2004; Kaistha, et al., 2009). Resistance of Staphylococcus aureus to gentamicin also has been documented (Decousser, et al., 2003; Kaistha, et al., 2009). In the past two decades the prevalence of multidrug resistant (MDR) bacterial strains is spreading to commonly used antimicrobial agents. MDR can be defined as resistance to 3 or more classes of antimicrobial agents (CLSI- M2-A9, 2006). The infection caused by MDR bacteria prolong the hospital stay, make therapy very difficult and ultimately lead to the use of expensive and broad spectrum antimicrobials. It further deepens the problem, especially when the resistance is associated to different classes of drugs involving differing resistance mechanisms 3

4 (Pagani, et al., 2004). Some of the most common MDR bacteria with their mechanisms of resistance are examples of this emerging crisis [Table 1]. MDR has lead to limited use of some members of third generation cephalosporin in case of Klebsiella pneumoniae infection (Brun-Buisson, et al., 1987; Hobson, Mackenzie and Gould, 1996; Subha, Devi and Ananthan, 2003). Nosocomial outbreaks of MDR Pseudomonas aeruginosa have been described in various European hospitals (Spencer, 1996; Sidorenko, Gelfand and Mamontova, 1999). Multidrug resistance occurs by a variety of resistance mechanisms, therefore, there are fewer treatment alternatives available for some patients of bacterial infections (Tsakris, et al., 2000; Luzzaro, et al., 2001). Table 1: Common multidrug resistant bacteria and their possible mechanisms. Microorganisms Common resistance mechanisms Coagulasenegative Drug inactivation meca gene staphylococci Enzymatic inactivation Staphylococcus Multidrug efflux pump aureus Antibiotic-target modification Enzymatic inactivation Gene cassette, SCCmec (Staphylococcal Chromosomal Cassette) Enterococci Intrinsic resistance Alteration of PBPs Beta-lactamase production Bypass of antibiotic target Permeability barriers or efflux pumps Enzymatic inactivation Transfer of resistance gene Antimicrobial for References multidrug resistant pathogens Arbekacin, (Rehm, 2002; Cefoxitin, Klingenberg, Oxacillin et al., 2004) Linezolid, (Rehm, 2002) Quinupristin, Dalfopristin Ampicillin-vancomyci (Gold and combination, Moellerin Jr, Linezolid, 1996; Quinupristin, Cetinkaya, Falk Dalfopristin and Mayhall, 2000) 4

5 Acinetobacter Multidrug efflux pump Colistin, (Pachon-Ibanez, species Antibiotic-modifying enzymes et al., 2004; Antibiotic-target modification Tigecycline Jamal, et al., 2009) Salmonella typhi Beta-lactamase production (Yan, et al., Plasmid mediated gene 2005; Zaidi, et production al., 2007) AmpC-producing strains Escherichia coli β-lactamases (extended- Carbapenems, (Subha, Devi spectrum β-lactamases) and Ananthan, Carbapenemases Tigecycline, 2003; Antibiotic-target modificationn Colistin Cunha, 2006; Michalopoulos and Falagas, 2008) Pseudomonas Instrinsic antibiotic resistance Polymyxin B, (Cunha, 2006; aeruginosa Metallo-beta-lactamases Colistin, Michalopoulos Carbapenemases and Falagas, Over expression of multidrug Tigecycline 2008; Tam, et efflux pump al., 2010) Antibiotic-modifying enzymes Reduced outer membrane permeability Klebsiella β-lactamases (extended- Carbepenems, (Subha, Devi pneumoniae spectrum β-lactamases) and Ananthan, Carbapenemases Tigecycline, 2003; Antibiotic-target modification Colistin, Bratu, et al., Polymyxin B 2005; Cunha, 2006) Knowledge of hospital epidemiology and antimicrobial susceptibility pattern of blood isolates in patients of septicemia help physicians to effectively manage BSIs. However, it is also clear that not all agents to which bacteria are deemed susceptible in the laboratory have the same clinical outcome if used for the treatment. Limited information is available about evidence based or even empiric antimicrobial use for 5

6 septicemia therapy in India. So the present study was conducted to explore and describe the clinical characteristics, causative pathogens, current antimicrobial prescribing practices, clinical outcome, acquisition cost of the therapy and adverse drug reactions (ADRs) due to antimicrobial therapy for septicemia in a teaching hospital in South Delhi. The knowledge of bacterial resistance pattern is essential in different geographical regions in different categories of patients. Hence the present study was also set to investigate the antimicrobial resistance pattern and to determine the frequency rates of MDR phenotypes in patients of septicemia admitted in a teaching hospital. The data presented here would be useful in the timely selection of appropriate antimicrobial therapy for septicemia in our setup. 6