Proposed amendments regarding the definitions of multidrug-resistant and extensively drug-resistant bacteria.

INTRODUCTION: It is fortunate that an international panel of experts proposed definitions for multidrug-resistant (MDR) and extensively drug-resistant (XDR) in the past. AREAS COVERED: In our opinion, these definitions need amendments in order to be semantically more accurate. EXPERT OPINION: We suggest for the MDR definition to add to 'MDR is defined as non-susceptibility to at least one agent in three or more antimicrobial categories' that this non-susceptibility is at most to the total number of all antimicrobial categories minus two, so that the definition reads: MDR is defined as non-susceptibility to at least one agent in three or more antimicrobial categories and up to (and including) the total number of all antimicrobial categories minus two. We suggest that the experts' definition of XDR as 'non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories)' has to be modified regarding the content of the parenthesis to: (i.e. bacterial isolates remain susceptible to only one or two or even none antimicrobial category [in this latter setting bacterial isolates are resistant to at least one antimicrobial agent in all antimicrobial categories and concurrently there is at least one antimicrobial agent to which the isolate is susceptible to]).

Benefits of prolonged infusion of beta-lactam antibiotics in patients with sepsis: personal perspectives.

INTRODUCTION: In the current era of relatively scarce antibiotic production and significant levels of antimicrobial resistance, optimization of pharmacokinetics and pharmacodynamics of antibiotic therapy is mandatory. Prolonged infusion of beta-lactam antibiotics in comparison to the intermittent infusion has the theoretical advantage of better patient outcomes. Apparently, conflicting data in the literature possibly underestimate the benefits of prolonged infusion of antibiotic treatment. AREAS COVERED: We provide our perspective on the subject based on our experience and by critically evaluating literature data. EXPERT OPINION COMMENTARY: In our opinion, the available data are suggestive of the beneficial role of prolonged infusion of beta-lactams in regard to piperacillin/tazobactam and carbapenems after administering a loading dose. While more data from randomized controlled trials are necessary to solidify or negate the evident benefits of prolonged infusion of the aforementioned antibiotics, clinicians should strongly consider this mode of administration of relevant antibiotics, especially in patients with severe infections.

Addressing clinical safety of antimicrobial resistance: personal perspectives.

Introduction: Antimicrobial resistance is an important challenge for patients, societies, practicing physicians and health care organizations worldwide. Predictions in regard to the morbidity and mortality of antimicrobial resistance are grave especially in the setting of an era where the pipeline of production of antimicrobial agents is relatively dry.Areas covered: Herein, a viewpoint will be provided regarding antimicrobial bacterial resistance as a clinical safety need based on personal experience and data from the literature.Expert opinion: A variety of antibiotics has been produced during the last decade but novelty regarding truly new antimicrobial agents is rather little, as these new antibiotics are mainly based on modifications of known pharmaceutical molecules. Therefore, as there is still a desperate need to address optimal clinical safety in regard to antimicrobial resistance, we believe that strong financial incentives and rewards to producers of antimicrobial agents (especially new in concept) are necessary. Furthermore, global surveillance of antimicrobial resistance as suggested by the World Health Organization, coordination of measures of justified and appropriate use of antibiotics and application of strict infection control principles are needed to lessen the negative clinical impact of antimicrobial resistance.

Options for treating carbapenem-resistant Enterobacteriaceae.

PURPOSE OF REVIEW: To address the therapeutic management of carbapenem-resistant Enterobacteriaceae on the basis of literature of the last 12 months. RECENT FINDINGS: Retrospective and prospective (nonrandomized noncontrolled) studies provide data regarding the management of infections due to carbapenem-resistant Enterobacteriaceae. The combination of a carbapenem with colistin or high-dose tigecycline or aminoglycoside or even triple carbapenem-containing combinations if the minimum inhibitory concentration (MIC) range of carbapenem (meropenem and imipenem) resistance is 8 mg/l or less seems to have an advantage over monotherapy with either colistin or tigecycline or fosfomycin. For Enterobacteriaceae with MIC for carbapenems over 8 mg/l, combination regimens involve colistin, tigecycline usually administered in a double dose than that suggested by its manufacturer, fosfomycin and aminoglycosides in various combinations. SUMMARY: Suggestions based on the limited literature cannot be made safely. Combination regimens involving carbapenems for Enterobacteriaceae with MICs 8 mg/l or less for carbapenems (in dual combination with colistin or high-dose tigecycline or aminoglycoside or even triple combinations) seem to confer some therapeutic advantage over monotherapy. For Enterobacteriaceae with higher than the above-mentioned MICs, a combination of two or even three antibiotics among colistin, high-dose tigecycline, aminoglycoside and fosfomycin seems to confer decreased mortality.

Frequency of the off-label use of monoclonal antibodies in clinical practice: a systematic review of the literature.

BACKGROUND: The monoclonal antibodies represent novel therapeutic options for many clinical entities. This study aimed to study the frequency of the off-label use to total use of different monoclonal antibodies in clinical practice. METHODS: This study systematically searched the PubMed and Scopus databases for relevant studies. RESULTS: Fifteen studies were considered eligible for inclusion in this review. Eight of the included studies referred to the off-label use of anti-neoplastic monoclonal antibodies, three referred to immunosuppressive ones, and four to other types of monoclonal antibodies. The most studied anti-neoplastic monoclonal antibody was rituximab; which was prescribed off-label at a frequency varying between 16-75%, mostly for an unapproved diagnosis. Bevacizumab was prescribed off-label for age-related macular degeneration more often than ranibizumab, the approved monoclonal antibody for this condition. Of the immunosuppressive monoclonal antibodies, infliximab was used off-label in an average of 15.4% (range=2.8-25%) and adalimumab in 10.5% (range=0-15.4% in different years). CONCLUSION: The frequency of off-label use of different types of monoclonal antibodies varies, but appears to be considerably high for specific monoclonal antibodies or indications. In certain examples, this might reflect implementation into clinical practice of relevant scientific data, albeit not of the strength or quality that suffices for receipt of regulatory approval. In others, it might relate to the sub-optimal effectiveness and considerable toxicity of the conventional therapies. Still, the clinician should bear in mind the potential costs and toxicity that can be associated with off-label use of monoclonal antibodies.

Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence.

We sought to evaluate the effectiveness of the antibiotic treatment administered for infections caused by carbapenemase-producing Enterobacteriaceae. The PubMed and Scopus databases were systematically searched. Articles reporting the clinical outcomes of patients infected with carbapenemase-producing Enterobacteriaceae according to the antibiotic treatment administered were eligible. Twenty nonrandomized studies comprising 692 patients who received definitive treatment were included. Almost all studies reported on Klebsiella spp. In 8 studies, the majority of infections were bacteremia, while pneumonia and urinary tract infections were the most common infections in 12 studies. In 10 studies, the majority of patients were critically ill. There are methodological issues, including clinical heterogeneity, that preclude the synthesis of the available evidence using statistical analyses, including meta-analysis. From the descriptive point of view, among patients who received combination treatment, mortality was up to 50% for the tigecycline-gentamicin combination, up to 64% for tigecycline-colistin, and up to 67% for carbapenem-colistin. Among the monotherapy-treated patients, mortality was up to 57% for colistin and up to 80% for tigecycline. Certain regimens were administered to a small number of patients in certain studies. Three studies reporting on 194 critically ill patients with bacteremia showed individually significantly lower mortality in the combination arm than in the monotherapy arm. In the other studies, no significant difference in mortality was recorded between the compared groups. Combination antibiotic treatment may be considered the optimal option for severely ill patients with severe infections. However, well-designed randomized studies of specific patient populations are needed to further clarify this issue.

Antimicrobial activity and clinical effectiveness of sisomicin: an evaluation of the literature (1995-2011).

The authors sought to evaluate whether sisomicin has a place in the current therapeutic armamentarium. PubMed and Scopus databases were systematically searched. Ten cohort studies and 11 case reports and case series were included evaluating, in total, 383 Gram-positive and 83 Gram-negative isolates. Sisomicin was active in vitro against 41% of Enterococcus spp., 97% of Staphylococcus spp. and was the most active in vitro (74%) aminoglycoside against Stenotrophomonas maltophilia isolates in one study. Regarding clinical effectiveness, sisomicin topical cream was effective in all 290 patients with pyoderma in one study, while the intravenous formulation of sisomicin was effective as prophylaxis for the development of postoperative pneumonia in 91% of lung surgery patients in another. In conclusion, sisomicin may be useful against certain pathogens; however, clinical data are scarce. Further studies are needed and may shed additional light in this area.

Predictors of mortality in patients with infections due to multi-drug resistant Gram negative bacteria: the study, the patient, the bug or the drug?

OBJECTIVE: To study the predictors of mortality among patients with multi-drug resistant Gram negative (MDRGN) infections and the role of MDRGN bacteria in the outcome of such patients. METHODS: PubMed and Scopus databases were searched (until June 30, 2012). Data were extracted and analyzed using the technique of meta-analysis. RESULTS: 30 studies (25 retrospective) were included in the analysis; 9 provided data on predictors of mortality for MDRGN infections only, while 21 provided data for MDRGN vs non-MDRGN infections. Acinetobacter spp were the most commonly studied bacteria followed by Pseudomonas aeruginosa and Enterobacteriaceae. Significant diversity was observed among studies regarding the evaluated predictors of mortality. Infection severity and underlying diseases were the most commonly reported independent predictors of mortality followed by multidrug resistance, inappropriate treatment and increasing age. In studies that included only patients with MDRGN infections, cancer (RR 1.65, 95% CI 1.13-2.39) and prior or current ICU stay (1.27, 1.02-1.56) were associated with mortality. In studies that included patients with MDRGN and non-MDRGN infections, septic shock (3.36, 2.47-4.57), ICU stay (2.15, 1.45-3.20), pneumonia (1.65, 1.09-2.52), isolation of MDRGN bacteria (1.49, 1.21-1.83), inappropriate definitive (2.05, 1.12-3.76) and empirical treatment (1.37, 1.25-1.51), and male gender (1.13, 1.05-1.21) were most commonly observed in patients who died than patients who survived. CONCLUSION: Significant diversity and statistical heterogeneity was observed. Beyond comorbidity and severity scores, MDR and inappropriate treatment were also identified as predictors of mortality.

Frequency of the off-label use of antibiotics in clinical practice: a systematic review.

Antibiotics constitute a major class among drugs commonly prescribed either empirically or for microbiologically documented infections in clinical practice. In addition, due to medical necessity physicians are forced, at times, to prescribe medications for off-label indications. The authors sought to record the frequency of the off-label use of antibiotics among both adult and pediatric patients. PubMed and Scopus databases were searched to identify relevant studies. A total of 25 studies met the inclusion criteria (725,124,505 prescriptions); 16 were prospective and nine retrospective. Fifteen studies reported on the pediatric population, seven on adults who had received a specific antibiotic, two on adult critical-care patients, and one on the general outpatient population. In the pediatric population, the percentage of off-label prescriptions varied from 1 to 94%. Off-label prescriptions varied from 19 to 43% in adult critical-care patients. Last, one study reporting on general outpatient care showed that 23% of prescriptions were off-label. Antibiotics are frequently prescribed as off-label among patient populations. The wide variation observed in the off-label use of antibiotics among pediatric patients might be attributed to the heterogeneity among the study populations regarding the age of children. Although this unapproved manner of prescribing cannot always be avoided, clinicians should only use unapproved drugs in cases when there are no effective alternatives are available and based on scientific evidence regarding safety and effectiveness.

Impact of vancomycin minimum inhibitory concentration on clinical outcomes of patients with vancomycin-susceptible Staphylococcus aureus infections: a meta-analysis and meta-regression.

Although the vancomycin minimum inhibitory concentration (VMIC) susceptibility breakpoint for Staphylococcus aureus was recently lowered to ≤2 mg/L, it is argued that isolates in the higher levels of the susceptible range may bear adverse clinical outcomes. Clinical outcomes (all-cause mortality and treatment failure) of patients with S. aureus infections by 'high-VMIC' (conventionally defined as VMIC >1 mg/L but ≤2 mg/L) and 'low-VMIC' (VMIC≤1 mg/L) isolates were compared by performing a systematic review and meta-analysis. The effect of potential confounders was assessed by univariate meta-regression analyses. In total, 33 studies (6210 patients) were included. Most studies were retrospective (28/33), used the Etest (22/33) and referred to meticillin-resistant S. aureus (MRSA) infections (26/33) and bacteraemia (23/33). Irrespective of VMIC testing method, meticillin resistance and site of infection, the high-VMIC group had higher mortality [relative risk (RR)=1.21 (95% confidence interval 1.03-1.43); 4612 patients] and more treatment failures [RR=1.67 (1.26-2.21); 2049 patients] than the low-VMIC group. The results were not affected by the potential confounders and were reproduced in the subset of patients with MRSA infections [mortality, RR=1.19 (1.02-1.40), 2956 patients; treatment failure, RR=1.69 (1.26-2.25), 1793 patients]. In conclusion, infection by vancomycin-susceptible S. aureus with VMIC>1mg/L appears to be associated with higher mortality than VMIC≤1mg/L. Further research is warranted to verify these results and to assess the impact of VMIC on meticillin-susceptible S. aureus infections. Evaluation of alternative antimicrobial agents also appears justified.

Risk factors for development of Clostridium difficile infection due to BI/NAP1/027 strain: a meta-analysis.

OBJECTIVE: To identify risk factors for the development of Clostridium difficile infection (CDI) due to C. difficile BI/NAP1/027 strain. METHODS: PubMed and Scopus databases were searched for studies that sought to identify risk factors for CDI due to the BI/NAP1/027 strain. The technique of meta-analysis was applied. RESULTS: Five studies compared CDI BI/NAP1/027 patients to CDI patients infected with non-BI/NAP1/027 strains, one compared CDI BI/NAP1/027 patients to non-CDI patients, and one provided data for both comparisons. The meta-analysis showed that fluoroquinolones were associated with a higher risk of CDI due to BI/NAP1/027 when compared to non-BI/NAP1/027 CDI (odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.37-2.80). A trend towards a lower risk for CDI due to BI/NAP1/027 was observed with cephalosporins when compared to non-BI/NAP1/027 CDI (OR 0.70, 95% CI 0.46-1.07). Prior macrolides were not associated with a higher risk for CDI BI/NAP1/027 when compared with non-BI/NAP1/027 CDI controls (OR 0.88, 95% CI 0.44-1.78). Clindamycin administration was associated with a lower risk for CDI due to BI/NAP1/027 when compared to non-BI/NAP1/027 CDI (OR 0.24, 95% CI 0.12-0.48). Age over 65 years was associated with an increased risk of CDI BI/NAP1/027 compared to non-BI/NAP1/027 CDI (OR 1.77, 95% CI 1.31-2.38). CONCLUSIONS: Fluoroquinolones and age over 65 years were associated with a higher risk of CDI due to the BI/NAP1/027 strain. Clindamycin was associated with a lower risk of CDI due to BI/NAP1/027.

Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum ß-lactamases: a systematic review and meta-analysis.

OBJECTIVES: To study the comparative mortality associated with carbapenems and alternative antibiotics for the treatment of patients with extended-spectrum ß-lactamase (ESBL)-positive Enterobacteriaceae bacteraemia. METHODS: We searched systematically PubMed and Scopus databases for studies providing data for mortality among patients treated with carbapenems, ß-lactam/ß-lactamase inhibitor combinations (BL/BLIs) or non-BL/BLIs (mainly cephalosporins and fluoroquinolones), preferably as monotherapy. Studies focusing on patients of all ages with community- and healthcare-associated bacteraemia were eligible. Data were pooled using the technique of meta-analysis. RESULTS: Twenty-one articles, studying 1584 patients, were included. Escherichia coli and Klebsiella pneumoniae were the most commonly studied bacteria. Delay in appropriate treatment up to 6 days was reported. Carbapenems were used mainly as definitive therapy. Carbapenems were associated with lower mortality than non- BL/BLIs for definitive [risk ratio (RR) 0.65, 95% CI 0.47-0.91] and empirical (RR 0.50, 95% CI 0.33-0.77) treatment. No statistically significant differences in mortality were found between carbapenems and BL/BLIs administered as definitive (RR 0.52, 95% 0.23-1.13) or empirical (RR 0.91, 95% CI 0.66-1.25) treatment. BL/BLIs were not associated with lower mortality than non-BL/BLIs administered either definitively (RR 1.59, 95% 0.83-3.06) or empirically (RR 0.82, 95% 0.48-1.41). Data regarding subgroups according to the setting, comorbidity and bacterial species could not be extracted. CONCLUSIONS: Based on data from non-randomized studies, carbapenems may be considered the treatment of choice for empirical treatment of patients with ESBL-producing Enterobacteriaceae bacteraemia. The role of BL/BLIs should be further evaluated for definitive treatment. Further research should focus on faster identification of ESBL-positive pathogens and potential differences in the treatment of each bacterial species.

Efficacy and safety of telavancin in clinical trials: a systematic review and meta-analysis.

INTRODUCTION: The epidemiology and antibiotic resistance of Staphylococcus aureus have evolved, underscoring the need for novel antibiotics, particularly against methicillin-resistant S. aureus (MRSA). Telavancin is a bactericidal lipoglycopeptide with potent activity against Gram-positive pathogens. OBJECTIVE: To systematically review and synthesize the available evidence from randomized controlled trials (RCTs) evaluating telavancin in the treatment of patients with infections due to Gram-positive organisms with the methodology of meta-analysis. RESULTS: Six RCTs comparing telavancin with vancomycin were included; 4 (2229 patients) referred to complicated skin and soft tissue infections (cSSTIs) and 2 (1503 patients) to hospital-acquired pneumonia (HAP). Regarding cSSTIs, telavancin and vancomycin showed comparable efficacy in clinically evaluable patients (odds ratio [OR] =1.10 [95% confidence intervals: 0.82-1.48]). Among patients with MRSA infection, telavancin showed higher eradication rates (OR=1.71 [1.08-2.70]) and a trend towards better clinical response (OR=1.55 [0.93-2.58]). Regarding HAP, telavancin was non-inferior to vancomycin in terms of clinical response in two Phase III RCTs; mortality rates for the pooled trials were comparable with telavancin (20%) and vancomycin (18.6%). Pooled data from cSSTIs and HAP studies on telavancin 10 mg/kg indicated higher rates of serum creatinine increases (OR=2.22 [1.38-3.57]), serious adverse events (OR=1.53 [1.05-2.24]), and adverse event-related withdrawals (OR=1.49 [1.14-1.95]) among telavancin recipients. CONCLUSION: Telavancin might be an alternative to vancomycin in cases of difficult-to-treat MRSA infections. The potent antistaphylococcal activity of telavancin should be weighted against the potential for nephrotoxicity.

Impact of antibiotic MIC on infection outcome in patients with susceptible Gram-negative bacteria: a systematic review and meta-analysis.

The objective of this study was to analyze the impact of MIC values within the susceptible range of antibiotics on the outcomes of patients with Gram-negative infections. The PubMed and Scopus electronic databases were searched. We identified 13 articles (1,469 patients) that studied the impact of antibiotic MICs on the outcomes of infections; ß-lactams were studied in 10 of them. Infections due to Salmonella enterica strains with high fluoroquinolone MICs were associated with more treatment failures than those due to strains with low MICs (relative risk [RR], 5.75; 95% confidence interval [CI], 1.77 to 18.71). Among non-Salmonella enterobacteriaceae, there was no difference in treatment failures depending on the MIC value (RR, 1.18; 95% CI, 0.71 to 1.97); however, a higher all-cause mortality was observed for patients infected with strains with high MICs (RR, 2.03; 95% CI, 1.05 to 3.92). More treatment failures were observed for patients infected with nonfermentative Gram-negative bacilli when strains had high MICs (RR, 5.54; 95% CI, 2.72 to 11.27). The mortality rate for patients with infections with Gram-negative nonfermentative bacilli with high MICs was also higher than for those with low MICs (RR, 2.39; 95% CI, 1.19 to 4.81). The limited available data suggest that there is an association between high MICs, within the susceptible range, and adverse outcomes for patients with Gram-negative infections.

Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence.

The objective of this review was to evaluate the frequency of treatment failure and recurrence of Clostridium difficile infection (CDI) following treatment with vancomycin or metronidazole in recently performed studies (last 10 years). Searches in PubMed and Scopus were performed by two reviewers independently. Data regarding treatment failure and recurrence following metronidazole and vancomycin treatment were extracted and analysed. In total, 39 articles (7005 patients) were selected for inclusion in the systematic review. The reported treatment failure was 22.4% with metronidazole (16 studies) and 14.2% with vancomycin (8 studies). Recurrence of CDI occurred in 27.1% of patients following metronidazole treatment (18 studies) and 24.0% of patients following vancomycin treatment (8 studies). Mean treatment failure and recurrence in the selected studies was 22.3% (24 studies) and 22.1% (37 studies). The reported outcomes depended on the study design (higher in prospective and retrospective cohort studies than in randomised controlled trials), geographic location of the study (higher in North America than in Europe and Asia), funding (higher in studies funded by non-profit organisations than pharmaceutical companies), mean age of the studied population (higher in older patients) and duration of follow-up (higher in studies with follow-up >1 month). In conclusion, infection with C. difficile is associated with 22.4% and 14.2% treatment failure and 27.1% and 24.0% recurrence after treatment with metronidazole and vancomycin, respectively. The variation in the reported outcomes amongst studies depends on the study design, location, funding, age and follow-up period.

Susceptibility of Gram-negative bacteria to isepamicin: a systematic review.

We sought to review the potential role of isepamicin against infections with contemporary Gram-negative bacteria. We searched PubMed and Scopus databases to identify relevant microbiological and clinical studies published between 2000 and 2010, and we retrieved 11 and three studies, respectively. A total of 4901 isolates were examined in the in vitro studies. Isepamicin had higher in vitro activity compared with amikacin in four studies, was as active as amikacin in six studies and in the remaining study both were inactive. Regarding specifically the studies that included multidrug-resistant bacteria, isepamicin appeared superior to amikacin in two studies, as active as amikacin in one study and both did not exhibit activity in one study. In the clinical studies, isepamicin was as active as amikacin for the treatment of 55 children with urinary tract infections. In conclusion, isepamicin might be active in vitro against Gram-negative bacteria with resistance to amikacin and other aminoglycosides.