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.     

Inducible beta-lactamases: clinical and epidemiologic implications for use of newer cephalosporins

The emergence of resistance to multiple beta-lactam antibiotics is a major problem in patients infected with organisms that characteristically produce inducible beta-lactamases--e.g., species of Pseudomonas, Enterobacter, Serratia, Citrobacter, indole-positive Proteus, and Providencia. Resistance has emerged in 14%-56% of patients infected with these organisms and treated with one of the newer cephalosporins. The emergence of resistance has been associated with clinical failure or relapse in 25%-75% of these patients. Combination therapy appears to have little impact on rates of resistance or its clinical consequences. Multiply resistant organisms have spread widely in some hospitals, and this trend has been correlated closely with the extent of use of the newer cephalosporins. The magnitude of the problem is frequently underestimated because many properly performed susceptibility tests fail to detect resistance when it is actually present and because some methods used to calculate rates minimize the impact of the emergence of resistance among organisms with inducible beta-lactamases.     

Third-line rescue therapy for Helicobacter pylori infection

H pylori gastric infection is one of the most prevalent infectious diseases worldwide. The discovery that most upper gastrointestinal diseases are related to H pylori infection and therefore can be treated with antibiotics is an important medical advance. Currently, a first-line triple therapy based on proton pump inhibitor (PPI) or ranitidine bismuth citrate (RBC) plus two antibiotics (clarithromycin and amo-xicillin or nitroimidazole) is recommended by all consensus conferences and guidelines. Even with the correct use of this drug combination, infection can not be eradicated in up to 23% of patients. Therefore, several second line therapies have been recommended. A 7 d quadruple therapy based on PPI, bismuth, tetracycline and metronidazole is the more frequently accepted. However, with second-line therapy, bacterial eradication may fail in up to 40% of cases. When H pylori eradication is strictly indicated the choice of further treatment is controversial. Currently, a standard third-line therapy is lacking and various protocols have been proposed. Even after two consecutive failures, the most recent literature data have demonstrated that H pylori eradication can be achieved in almost all patients, even when antibiotic susceptibility is not tested. Different possibilities of empirical treatment exist and the available third-line strategies are herein reviewed.     

High-risk febrile neutropenia in Auckland 2003-2004: the influence of the microbiology laboratory on patient treatment and the use of pathogen-specific therapy

Background: International guidelines recommend routine microbiological assessment of patients with febrile neutropenia, but do not recommend a change from broad-spectrum antibiotic therapy to pathogen-specific therapy when a clinically relevant organism has been isolated. The aim of the study was to determine the aetiology of febrile neutropenia in adult haematology patients at Auckland City Hospital, to document the changes in treatment made following isolation of a clinically relevant organism and to assess adverse outcomes in any patient who received pathogen-specific therapy after a positive culture result. Methods: The results of all microbiological tests together with antibiotic therapy were recorded from consecutive patients with fever and a neutrophil count <0.5 × 10⁹/L over 1 year beginning in May 2003. Results: One thousand one hundred and ninety-six specimens were collected from 81 patients during 116 episodes of febrile neutropenia. A pathogen was isolated from blood cultures in 40 episodes: Gram-positive cocci accounted for 46% of isolates and Gram-negative bacilli for 35%. Isolation of a pathogen from blood cultures resulted in a change of treatment in 25 of 40 (62.5%, 95%CI 46–77%) episodes. In 12 of these episodes, antibiotic therapy was optimized to a single pathogen-specific agent. No adverse events or subsequent changes in antibiotic therapy occurred in any of these 12 patients. Isolation of a pathogen from specimens other than blood seldom led to a change in therapy. Conclusion: Isolation of a pathogen from blood cultures often allows antibiotic therapy to be simplified to a pathogen-specific regimen. Further study of this approach is warranted.     

The clinical and laboratory characteristics of patients with chronic hepatitis B using current or past antiviral therapy in Korea: a multi-center, nation-wide, cross-sectional epidemiologic study

Background/Aims

The proper assessment of the current disease status of patients with chronic hepatitis B would be valuable for establishing optimal management strategies.

Methods

The clinical and laboratory characteristics of 2,954 patients with current or previous antiviral treatment (46.2±10.8 years, 69.7% male) enrolled from 46 referral hospitals and 129 local hospitals or clinics throughout Korea were analyzed.

Results

The disease status included chronic hepatitis, cirrhosis, and hepatocellular carcinoma in 79.9%, 16.4%, and 3.7% of the patients, respectively. The major mode of hepatitis B virus (HBV) infection was vertical transmission. The hepatitis C virus (HCV) co-infection rate was 1.5%; however, only 50.8% of patients were evaluated for HCV. The use of herbal or complementary medicines was reported in 33.5% of the patients. The majority of patients (97.6%) were treated with oral nucleoside/nucleotide analogues. Several characteristics were different between the patients treated at referral hospitals and local hospitals/clinics, including the disease state, choice of antiviral drug, and methods of HBV DNA measurement.

Conclusions

This study provides a comprehensive picture of the clinical and laboratory characteristics of patients treated in Korea. Efforts to optimize management strategies are warranted.     

Nosocomial infection control: scope and implications for health care--a historical view.

Knowing where we have come from helps to decide where we should be going. Many principles and practices of modern infection control were developed in the nineteenth and early twentieth century. The story is one of halting, yet relentless, progress. The history of these discoveries and their application to infection control, then and now, is described, such as principles of hygiene, antiseptic surgery, antimicrobial therapy, and improved hospital design. Many of the issues today are not new, nor are some of the fundamental solutions. An acceptance of this historical continuum may temper expectations and make us more accepting of change.     

The present and future of the microbiology laboratory in the control of human immunodeficiency virus (HIV) infection

Until recently, the role of the Microbiology Laboratory with regard to HIV infection was limited to the serological diagnosis, if the contribution to the management of opportunistic infections that complicate the evolution of the disease is excluded. The follow-up of the outcome and monitoring of the response to antiretroviral therapy has been done through CD4 1 lymphocite counts at the Immunology laboratory. In recent years, other important technics for the clinical care of HIV-infected patients have been incorporated to the laboratory of Microbiology: measurement of plasma HIV RNA levels, which has become the main parameter to monitor the response to therapy and for the taking of decisions regarding the beginning and changes of treatment; resistance testing to antiretroviral drugs, not yet fully implemented in our laboratories; and therapeutic drug monitoring, with a role still to be defined. For the near future, new tools will come that, firstly, will improve the existing ones (greater sensitivity to detect HIV RNA in plasma, greater ease of interpretation of the results of genotypic resistance testing, wide access to phenotypic studies) and, secondly, new tools that will allow a more individualized care of the patients (monitoring of some toxic side effects, pharmacogenomics, immunogenomics).     

Human Mycobacterium bovis infection in Buenos Aires: epidemiology, microbiology and clinical presentation

We performed a retrospective study of clinical, epidemiological and microbiological characteristics of patients with confirmed Mycobacterium bovis infection treated at Francisco Mu?iz Hospital, Buenos Aires, Argentina, between 1996 and 2008. A total of 39 patients were included, accounting for 0.4% of tuberculosis cases in our hospital. Of these, 93% had at least one risk factor for M. bovis; the most frequent was occupational exposure (65%), followed by history of living in a rural area (31%) and consumption of unpasteurised milk (4%). Pulmonary disease was the most frequent clinical presentation. Rifampicin resistance and multidrug resistance were seen in two patients, both of whom had human immunodeficiency virus infection.     

Gene therapy for hemophilia: Current status and laboratory consequences

Since the cloning and characterization of the factor VIII (FVIII) and factor IX genes in the mid-1980s, gene therapy has been perceived as having significant potential for the treatment of severe hemophilia. Now, some 35 years later, these proposals are close to being realized through the licensing of the first clinical gene therapy product. Adeno-associated viral vector-mediated gene therapy for hemophilia A and B has been extensively investigated in preclinical models over the past 20 years, and since 2011, there has been increasing evidence in early phase clinical trials that this therapeutic strategy can provide safe and effective rescue of the hemostatic phenotype in severe hemophilia. As the uptake of hemophilia gene therapy progresses, it is clear that many aspects of the gene therapy process require crucial laboratory support to ensure safe and effective outcomes from his new therapeutic paradigm. These laboratory contributions extend from evaluations of the gene therapy vehicle, assessments of the patient immune status for the vector, and ultimately the performance of assays to determine the hemostatic benefit of the gene therapy and potentially of its long-term safety on the host genome. As with many aspects of past hemophilia care, the safe and effective delivery of gene therapy will require an informed and coordinated contribution from laboratory science.     

Anti-angiogenic therapy: rationale,challenges and clinical studies

Physiological angiogenesis occurs during embryogenesis, wound healing and reproductive functions in adults. Abnormal angiogenesis takes place in certain chronic diseases (diabetes, psoriasis, rheumatoid arthritis, etc.) and tumours. Genetic changes and local stresses including hypoxia, glucose deprivation and oxidative stress play a pivotal role in angiogenesis switch, which is necessary for tumour development and is rate-limiting for tumour progression. Angiogenesis is tightly regulated by pro- and anti-angiogenic growth factors with a series of complex and interrelated steps. Activated endothelial cells (ECs) migrate as a solid cord and, subsequently, form lumina; the sprout tips then anastomose to form vessel loops or networks. One of the final events is the laying down of a basement membrane and the structural support of pericytes. The molecular alterations that sustain angiogenesis represent novel targets for rationally designed anti-cancer treatment strategies. Inhibition of angiogenesis presents certain advantages on conventional therapies, such as the direct accessibility from the circulation, and the potential low rate of drug resistance related to the genetic stability of ECs. Certain anti-angiogenic compounds were found to have potent anticancer property in in vivo experimental studies. Nevertheless, in contrast to preclinical studies, the first generation of anti-angiogenic drugs tested in clinical trials have shown a moderate activity in advanced disease partly due to suboptimal schedules of therapy or biases in study design.     

Hybrid therapy for Helicobacter pylori infection: A systemic review and meta-analysis

AIM: To compare the effectiveness of hybrid therapy with other recommended regimens using meta-analysis.METHODS: Bibliographical searches for randomized trials comparing hybrid and other therapies were performed in PubMed, the Cochrane Library and relevant congresses up to February 2015 using the following keywords (all fields and/or MeSH): (“Helicobacter pylori” or “H. pylori”) and (“hybrid therapy” or “sequential-concomitant therapy”). Meta-analyses were performed with Cochrane Review Manager 5.1. The random effect model proposed by DerSimonian and Laird and the Mantel-Haenszel method were used to estimate the pooled relative risk and 95%CI of the efficacy outcomes between hybrid therapy and other eradication therapies.RESULTS: Eight studies (2516 subjects) met entry criteria. The antimicrobial resistance in the study groups ranged from 6.9% to 23.5%. The mean cure rates of hybrid therapy by intention-to-treat (ITT) and per-protocol analyses were 88.5% (n = 1207; range: 80.0% to 97.4%) and 93.3% (n = 1109; range: 85.7% to 99.1%), respectively. Meta-analysis showed there was no significant difference in ITT eradication rate between hybrid and sequential therapy (relative risk: 1.01; 95%CI: 0.92-1.11). Subgroup analysis revealed hybrid therapy was more effective than sequential therapy in the non-Italian populations (95%CI: 1.01-1.18) and was only less effective in one, Italian population (95%CI: 0.83-0.98). There was no significant difference in eradication rate between hybrid therapy and concomitant therapy (95%CI: 0.93-1.02). No head-to-head comparisons of hybrid therapy and standard triple therapy or bismuth quadruple therapy were found. However, a multicenter, randomized trial showed that reverse hybrid therapy was superior to standard triple therapy (95.5% vs 88.6% ITT; P = 0.011).CONCLUSION: Hybrid therapy appears to be an effective, safe, and well-tolerated treatment for H. pylori infection in the era of increasing antibiotic resistance.