Extended-spectrum beta-lactamases

Resistance to broad-spectrum cephalosporins among Klebsiella pneumoniae has increased significantly, particularly in the intensive care unit setting, in the past decade.The problem has been noted not only in the United States, but around the world. A major mechanism responsible for this is the emergence of extended-spectrum beta-lactamases (ESBLs).These plasmid-mediated beta-lactamases confer resistance to broad-spectrum beta-lactam antibiotics, including third- and fourth-generation cephalosporins, aztreonam, and extended-spectrum penicillins. Other resistances, such as aminoglycoside and trimethoprim-sulfamethoxazole resistance, are often cotransferred on the same plasmid. Fluoroquinolone resistance is also frequently associated, resulting in an organism resistant to most broad-spectrum options. The carbapenems are currently considered the drug of choice for these pathogens. Prevention and control measures are important because of the multiresistant nature of these pathogens. Such traditional infection control measures as contact precautions are recommended. In addition, because this type of antimicrobial resistance appears to be particularly influenced by antibiotic use, antibiotic control measures may also be a very important intervention in controlling the spread of ESBLs.     

New beta-lactamases in gram-negative bacteria: diversity and impact on the selection of antimicrobial therapy.

Of the 340 discrete beta-lactamases that have been identified, the most important groups of enzymes that are continuing to proliferate include the plasmid-encoded cephalosporinases, the metallo-beta-lactamases, and the extended-spectrum beta-lactamases. Resistance to specific beta-lactam-containing antimicrobial agents frequently can be traced to a single beta-lactamase, but this task is becoming more difficult for the clinical microbiology laboratory. Other factors, such as multiple beta-lactamase production, transferable multidrug-resistance genes, alterations in outer-membrane porins, and possible antibiotic efflux, all may contribute to a resistance phenotype. Appreciation of these factors may help the physician make a more informed decision when choosing therapy to try to avoid selection of even more pathogenic strains.     

Optimizing therapy for infections caused by enterobacteriaceae producing extended-spectrum beta-lactamases

The spread of multidrug-resistant Enterobacteriaceae is complicating the treatment of nosocomial infections. In many parts of the world, resistance to third-generation cephalosporins exceeds 10% of total nosocomial isolates and 30% of isolates detected in the intensive care unit. This resistance is frequently due to the acquisition of plasmids containing genes encoding for extended-spectrum beta-lactamases (ESBLs). Furthermore, these mobile elements often carry genes encoding resistance to other drugs such as aminoglycosides. A high risk of poor clinical outcome has been observed in patients infected with ESBL producers receiving third-generation cephalosporins, even if the organism appears susceptible to the antibiotic. For this reason, clinical microbiology laboratories are advised to incorporate specific ESBL detection methodology into routine clinical practice. This should prevent erroneous use of cephalosporins for these infections. Most ESBL producers remain susceptible to carbapenems, and these agents are considered the drugs of choice against ESBL-producing organisms. Unfortunately, there is now an increasing occurrence of carbapenem resistance in the Enterobacteriaceae. In this context, clinical response to new antibiotics (e.g., tigecycline) and old antibiotics (e.g., colistin) with good in vitro activity against ESBL producers needs to be evaluated.     

Antibiotic resistance in the intensive care unit

Antimicrobial resistance has emerged as an important determinant of outcome for patients in the intensive care unit (ICU). This is largely due to the administration of inadequate antimicrobial treatment, which is most often related to bacterial antibiotic resistance. In addition, the escalating problem of antimicrobial resistance has substantially increased overall health care costs. This increase is a result of prolonged hospitalizations and convalescence associated with antibiotic treatment failures, the need to develop new antimicrobial agents, and the implementation of broader infection control and public health interventions aimed at curbing the spread of antibiotic-resistant pathogens. Intensive care units are unique because they house seriously ill patients in confined environments where antibiotic use is extremely common. They have been focal points for the emergence and spread of antibiotic-resistant pathogens. Effective strategies for the prevention of antimicrobial resistance in ICUs have focused on limiting the unnecessary use of antibiotics and increasing compliance with infection control practices. Clinicians caring for critically ill patients should consider antimicrobial resistance as part of their routine treatment plans. Careful, focused attention to this problem at the local ICU level, using a multidisciplinary approach, will have the greatest likelihood of limiting the development and dissemination of antibiotic-resistant infections.     

Multiresistente pulmonale Erreger auf der Intensivstation

Multiresistant bacteria are most prominent on intensive care units. The incidence of nosocomial pneumonia is highest in patients with invasive ventilation. The typical resistant bacteria in the lung are Pseudomonas aeruginosa, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus (MRSA) and enterobacteria producing extended-spectrum beta-lactamases (ESBL). Broad-spectrum antibiotics are used in intensive care medicine in many cases, but the number of antibiotic treatments used in the ICU is associated with the development of multiresistant organisms. Strategies for high-quality antibiotic treatment with emphasis on diminishing overuse are essential. Infection control and antibiotic stewardship strategies should be developed.     

Therapeutic considerations in the treatment of respiratory infections caused by ceftazidime-resistant Klebsiella pneumoniae

Klebsiella pneumoniae are important human pathogens, particularly as causes of nosocomial respiratory tract infections. Intrinsically resistant to ampicillin, in recent years K. pneumoniae strains have acquired resistance to a broad variety of extended-spectrum cephalosporins. This resistance is most commonly mediated by the extended-spectrum beta-lactamases (ESBLs), plasmid-mediated enzymes that have evolved through point mutations in the genes encoding the more susceptible penicillinases TEM-1 and SHV-1. In a small minority of cases, K. pneumoniae have also been found to express extended-spectrum cephalosporin resistance by the elaboration of plasmid-mediated AmpC-type enzymes. These mutant enzymes confer resistance to extended-spectrum cephalosporins, penicillins, and in some cases cefamycins or beta-lactam-beta-lactamase inhibitor combinations. The most reliable and effective antimicrobial treatment of infections caused by these strains are the carbapenems imipenem and meropenem.     

Update on Pseudomonas aeruginosa and Acinetobacter baumannii infections in the healthcare setting

PURPOSE OF REVIEW: Infections with Pseudomonas aeruginosa and Acinetobacter baumannii are of great concern for hospitalized patients, especially with multidrug-resistant strains. This review focuses on recent data that may help us to understand the emergence, spread, and persistence of antibiotic resistance, and summarizes the optional treatment feasible for these resistant bacteria. RECENT FINDINGS: Multidrug-resistant P. aeruginosa and A. baumannii are increasingly causing nosocomial infections; multidrug-resistant clones are spreading into new geographic areas, and susceptible strains are acquiring resistance genes. New extended-spectrum beta-lactamases and carbapenemases are emerging, leading to pan-resistant strains. Current studies focus on the effect of antibiotics on gene expression in P. aeruginosa biofilms and their contribution to resistance to therapy. Treatment options for multidrug-resistant P. aeruginosa and A. baumannii infections are limited in most cases to carbapenems. Sulbactam is a treatment option for pan-resistant A. baumannii, and or renewed use of an old drug, colistin, is being entertained for pan-resistant A. baumannii and P. aeruginosa. Immunotherapy is a promising new modality being explored. Prevention of emergence of resistance through combination therapy and pharmacokinetic strategies are studied. SUMMARY: The emergence and spread of multidrug-resistant P. aeruginosa and A. baumannii and their genetic potential to carry and transfer diverse antibiotic resistance determinants pose a major threat in hospitals. The complex interplay of clonal spread, persistence, transfer of resistance elements, and cell-cell interaction contribute to the difficulty in treating infections caused by these multidrug-resistant strains. In the absence of new antibiotic agents, new modalities of treatment should be developed.     

Infecciones causadas por bacterias gramnegativas multirresistentes: enterobacterias, Pseudomonas aeruginosa, Acinetobacter baumannii y otros bacilos gramnegativos no fermentadores

Multiresistant Gram-negative bacteria represent a major health problem worldwide. This is related to the severity of the infections they cause, the difficulties for empiric (even directed) treatment, the ease of multiresistance spread, and the absence of new antimicrobial agents active against this group of pathogens. Accordingly, antimicrobial therapy should be based on the results of susceptibility testing, and may require using antimicrobial combinations. The production of extended-spectrum beta-lactamases represents the most important current problem of resistance among enterobacteria; these organisms cause nosocomial infections, but can also be cultured from non-hospitalised patients. In our country, enterobacteria producing plasmid-mediated AmpC enzymes or most carbapenemases are still uncommon, at the moment. Enterobacteria expressing these types of beta-lactamases present high rates of resistance to aminoglycosides and quinolones, because plasmids coding for beta-lactamases also contain other genes involved in additional resistances and/or the selection of additional chromosomal mutations. Among multiresistant Gram-negative non-fermenting bacteria, the most clinically relevant organism is Pseudomonas aeruginosa, an organism with intrinsic resistance to multiple agents and with ability to capture acquired resistance mechanisms. Other organisms in the latter group include Acinetobacter baumannii, with increasing rates of resistance to antimicrobial agents, and to a lesser extent Stenotrophomonas maltophilia.     

Extended-spectrum beta-lactamases: a challenge for clinical microbiologists and infection control specialists

Since first reported in Europe in the early 1980s, extended-spectrum beta-lactamases (ESBLs) have spread worldwide. When producing these broad-spectrum plasmid-encoded enzymes, organisms become highly effective at inactivating penicillins, most cephalosporins, and aztreonam. Mainly produced by Klebsiella spp, ESBLs have been isolated worldwide in different species, most of them belonging to the Enterobacteriaceae. ESBL-producing bacteria can appear as in vitro susceptible to beta-lactams by conventional laboratory methods, making the laboratory diagnosis problematic. Once detected, all beta-lactams except carbapenem and beta-lactamase inhibitor compounds should be reported as resistant. In addition, organisms harboring ESBLs are frequently resistant to other antibiotic classes, such as fluoroquinolones and aminoglycosides. Because of the very limited remaining alternatives for treatment and ESBLs significant prevalence worldwide, infection control remains the best way to deal with this bacterial resistance mechanism.     

Hospital-acquired infections: diseases with increasingly limited therapies.

About 5% of patients admitted to acute-care hospitals acquire nosocomial infections. A variety of factors contribute: increasing age of patients; availability, for treatment of formerly untreatable diseases, of extensive surgical and intensive medical therapies; and frequent use of antimicrobial drugs capable of selecting a resistant microbial flora. Nosocomial infections due to resistant organisms have been a problem ever since infections due to penicillinase-producing Staphylococcus aureus were noted within a few years of the introduction of penicillin. By the 1960s aerobic Gram-negative bacilli had assumed increasing importance as nosocomial pathogens, and many strains were resistant to available antimicrobials. During the 1980s the principal organisms causing nosocomial bloodstream infections were coagulase-negative staphylococci, aerobic Gram-negative bacilli, S. aureus, Candida spp., and Enterococcus spp. Coagulase-negative staphylococci and S. aureus are often methicillin-resistant, requiring parenteral use of vancomycin. Prevalence of vancomycin resistance among enterococcal isolates from patients in intensive care units has increased, likely due to increased use of this drug. Plasmid-mediated gentamicin resistance in up to 50% of enterococcal isolates, along with enhanced penicillin resistance in some strains, leaves few therapeutic options. The emergence of Enterobacteriaceae with chromosomal or plasmid-encoded extended spectrum beta-lactamases presents a world-wide problem of resistance to third generation cephalosporins. Control of these infections rests on (i) monitoring infections with such resistant organisms in an ongoing fashion, (ii) prompt institution of barrier precautions when infected or colonized patients are identified, and (iii) appropriate use of antimicrobials through implementation of antibiotic control programs.     

Interhospital transfer of pan-resistant Acinetobacter strains in Johannesburg, South Africa

BACKGROUND: Acinetobacter species infections are increasingly found to cause nosocomial infections, particularly in intensive care units. These pathogens are difficult to eliminate from the hospital environment, and the emergence of multiple-drug-resistant strains complicates patient treatment. In this retrospective study, several strains were analyzed to study the possible spread of pan-resistant strains. METHODS: Macrorestriction analysis was performed on isolates collected in July 2001 from Johannesburg Hospital and strains collected from a number of hospitals in Johannesburg a year later. RESULTS: A strain endemic to Johannesburg Hospital that was cefepime and ceftazidime sensitive in 2001 developed resistance to these antibiotics within 1 year. This and other resistant strains were found to have spread among academic and private hospitals in the area by July 2002. CONCLUSIONS: The development of resistance is believed to be a response to antibiotic pressure and the spread of resistant strains a result of health care worker and/or patient transfer among hospitals. This snapshot epidemiologic study highlights the need to institute stricter infection control measures to limit the spread of organisms such as Acinetobacter among hospitals.     

Acinetobacter baumannii:An emerging pathogenic threat to public health

Over the last three decades, Acinetobacter has gained importance as a leading nosocomial pathogen, partly due to its impressive genetic capabilities to acquire resistance and partly due to high selective pressure, especially in critical care units. This low-virulence organism has turned into a multidrug resistant pathogen and now alarming healthcare providers worldwide. Acinetobacter baumanni(A. baumannii) is a major species, contributing about 80% of all Acinetobacter hospital-acquired infections. It disseminates antibiotic resistance by virtue of its extraordinary ability to accept or donate resistance plasmids. The procedures for breaking the route of transmission are still proper hand washing and personal hygiene(both the patient and the healthcare professional), reducing patient's biofilm burden from skin, and judicious use of antimicrobial agents. The increasing incidence of extended-spectrum beta-lactamases and carbapenemases in A. baumannii leaves almost no cure for these "bad bugs".To control hospital outbreaks of multidrug resistantAcinetobacter infection, we need to contain their dissemination or require new drugs or a rational combination therapy. The optimal treatment for multidrug-resistant A. baumannii infection has not been clearly established, and empirical therapy continues to require knowledge of susceptibility patterns of isolates from one's own institution. This review mainly focused on general features and introduction to A. baumannii and its epidemiological status, potential sources of infection, risk factors, and strategies to control infection to minimize spread.     

The enterococcus: "putting the bug in our ears"

High-level resistance to gentamicin among clinical isolates of enterococci has been found with increasing frequency in recent years. In this issue, Zervos and colleagues report findings from a prospective study in which they assessed the frequency of colonization and infection with such organisms at a university medical center, demonstrating probable person-to-person spread. Their findings suggest that hospitals should conduct systematic screening for enterococci with high-level resistance to gentamicin, that antimicrobial treatment habits be modified to limit the emergence of such organisms, and that rigorous infection control be practiced to minimize their spread. These observations are particularly timely because it has become clear that enterococci are extremely versatile pathogens which are both well suited for survival and capable of causing serious illness, especially in hospitalized patients treated with some of the newer broad-spectrum antibiotic agents. Enterococci with high-level resistance to gentamicin are also of growing concern because their resistance to many antibiotic agents severely limits the clinician's options for treatment.     

Escalation of antimicrobial resistance among Streptococcus pneumoniae: implications for therapy

Over the past 2 decades, antimicrobial resistance among Streptococcus pneumoniae, the most common cause of community-acquired pneumonia (CAP), has escalated dramatically worldwide. In the late 1970s, strains of pneumococci displaying resistance to penicillin were described in South Africa and Spain. By the early 1990s, penicillin-resistant clones of S. pneumoniae spread rapidly across Europe and globally. Additionally, resistance to macrolides and other antibiotic classes escalated in tandem with penicillin resistance. Six international clones (serotypes 6A, 6B, 9V, 14, 19F, 23F) were responsible for most of these resistant isolates. Currently, 20 to 30% of S. pneumoniae worldwide are multidrug resistant (MDR) (i.e., resistant to > or = 3 different classes of antibiotics). Despite the dramatic escalation in the rate of antimicrobial resistance among pneumococci worldwide, the clinical impact of antimicrobial resistance is difficult to define. Treatment failures due to antibiotic-resistant pneumococci have been reported with meningitis, otitis media, and lower respiratory tract infections, but the relation between drug resistance and treatment failures has not been convincingly established. Clinical failures often reflect factors independent of antimicrobial susceptibility of the infecting organisms. Host factors (e.g., extremes of age; underlying immunosuppressive or debilitating disease; comorbidities), or factors that affect intrinsic virulence of the organisms (e.g., capsular subtype) strongly influence prognosis. Mortality rates are higher in the presence of multilobar involvement, renal insufficiency, need for intensive care unit (ICU) care, hypoxemia, severe derangement in physiological parameters, and comorbidities. Given these confounding factors, determining the impact of antimicrobial resistance on clinical outcomes is difficult, if not impossible. Prospective, randomized trials designed to assess the clinical significance of antimicrobial resistance among pneumococci are lacking, and for logistical reasons, will never be done. Does in vitro resistance translate into clinical failures? Should changing resistance patterns modify our choice of therapy for CAP or for suspected pneumococcal pneumonia? This review discusses several facets, including mechanisms of antimicrobial resistance among specific antibiotic classes, epidemiology and spread of antimicrobial resistance determinants regionally and worldwide, risk factors for acquisition and dissemination of resistance, the impact of key international clones displaying MDR, the clinical impact of antimicrobial resistance, and strategies to limit or curtail antimicrobial resistance among this key respiratory tract pathogen.     

Infection in the intensive care unit: prevention strategies

PURPOSE OF THE REVIEW: Nosocomial infections remain among the most common treatment complications, particularly in intensive care unit patients. In many countries antibiotic resistance is increasingly hampering treatment of these infections. Preventive strategies have therefore become more important and have been directed both against the development of specific infections and against the spread of antibiotic-resistant pathogens. The present review addresses recent data on the latter issue. In particular, we discuss the first approaches to use mathematical modelling as a tool to analyse and guide strategies to prevent infection, and the effects of antibiotic cycling. RECENT FINDINGS: Several mathematical models to address the dynamics of pathogen transmission in hospital settings have been developed. One of the models may allow quantification of the effects of different strategies to prevent infection in intensive care units, and another may be used to determine the relative importance of different colonization routes, without the need for expensive genotyping methods. The results of the first prospective studies on antibiotic cycling are inconclusive, and again mathematical modelling may help to provide testable hypotheses for such interventions. Finally, recent studies have shown that alcohol-based hand rubs are better than hand washing with soap and water for most hand disinfection purposes. SUMMARY: The first results of use of mathematical modelling to guide infection control strategies should be subjected to prospective, empirical testing in order to determine their clinical usefulness. More rigorously designed studies are needed to determine the benefits of antibiotic cycling strategies. Hands should be disinfected with alcohol-based hand rubs, which should be available at each bedside.     

Staphylococcal infections in the intensive care unit

Staphylococcus aureus and coagulase-negative staphylococci are among the most common causes of nosocomial infections in the intensive care unit (ICU). The clinical presentation of staphylococcal device-related infections, pneumonias, or surgical wound infections is not unique. However, treatment of these infections is increasingly problematic because of the resistance of clinical isolates to a widening number of antimicrobial agents.The confluence of critically ill patients and the need for multiple invasive procedures, as well as the use of broad-spectrum antimicrobial agents in the ICU, set the stage for the emergence of these multidrug-resistant staphylococci. In the past 10 years, there has been a progressive increase in the overall resistance of staphylococci to antimicrobial agents. Conventional infection control measures, such as handwashing and isolation precautions, to prevent the spread of staphylococcal infections in the ICU setting remain of critical importance. New approaches, including the prophylactic use of topical antistaphylococcal agents to eliminate nasal colonization in high-risk ICU patients and the development of antistaphylococcal vaccines, are currently being investigated.     

Descriptive and molecular epidemiology of Gram-negative bacilli infections in the neonatal intensive care unit

PURPOSE OF REVIEW: The critically ill neonate is particularly prone to life threatening bacterial infections compared with other patient populations. Current patterns of neonatal sepsis caused by Gram-negative bacilli are reviewed to enable the clinician to better anticipate and effectively respond to neonatal infection by these serious pathogens. RECENT FINDINGS: With increasing use of intrapartum antibiotics for prophylaxis against early-onset group B streptococcal infection, there is growing concern that the incidence of neonatal sepsis by Gram-negative pathogens may rise. Although several surveys indicate no such increase to date, studies in selected neonatal intensive care unit populations have suggested a recent elevation in newborn infection caused by Escherichia coli and other bacillary pathogens. Most recent investigations reveal growing antibiotic resistance in those Gram-negative bacilli causing neonatal infection. Modern molecular genotyping methods have been applied to Gram-negative bacilli in the neonatal intensive care unit in order to understand their epidemiology in greater detail. In most instances these techniques have been used to identify the sources and prevalence of an outbreak strain, and to devise rational interventions to control the epidemic. Studies utilizing molecular genotyping during non-outbreak periods indicate that Gram-negative bacilli, even those expressing antibiotic resistance, may be acquired very early in the intensive care unit course, and that different clones are introduced and lost in the infants' indigenous flora throughout their stay. These studies further indicate that cross-transmission of bacillary pathogens occurs regularly even in the absence of a recognized epidemic. SUMMARY: Gram-negative bacilli are prominent causes of infection in the neonatal intensive care unit. Their incidence, antibiotic susceptibility pattern, and modes of acquisition continue to evolve in the modern intensive care unit setting.