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.

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.

Current diagnosis and management of infectious mononucleosis.

PURPOSE OF REVIEW: Infectious mononucleosis is a common, usually self-limited disease. However, infectious mononucleosis may present with severe manifestations. Complications may also occur. Consequently, diagnostic and treatment issues regarding infectious mononucleosis are of major importance. RECENT FINDINGS: In this review, we focus on the evaluation of articles providing diagnosis and treatment data for infectious mononucleosis, published during the past 2 years. Twelve studies, deriving from extended search in PubMed, were included. Nine studies provided diagnosis data. The evaluated diagnostic methods were real-time PCR (RT-PCR), IgM/IgG antibodies measured with different assays [measurement of Epstein-Barr virus viral load (EBV-VL) in peripheral blood, neutrophil/lymphocyte/monocyte counts, C-reactive protein values, and monospot test]. The sensitivities reported for RT-PCR were high. The available treatment data were scarce (three studies). Two of them suggested that antivirals (mainly acyclovir and valacyclovir) may have a role in the treatment of infectious mononucleosis with complications, whereas the remaining study presented novel potential therapeutic patents including 5-substituted uracyle, azacytosine derivatives, and peptides inhibiting EBV-mediated membrane fusion. SUMMARY: RT-PCR and measurement of EBV-VL may provide useful tools for the early diagnosis of infectious mononucleosis in cases with inconclusive serological results. Antiviral agents may provide a useful treatment option in patients with severe infectious mononucleosis.

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.

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.

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]).

ß-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis.

We aimed to assess the accuracy of measuring serum or plasma (1→3)-ß-D-glucan (BDG) for the diagnosis of invasive fungal infections (IFIs) by means of a meta-analysis of relevant studies. We searched in bibliographic databases for relevant cohort or case-control studies. We primarily compared BDG between patients with proven or probable IFIs (excluding Pneumocystis jirovecii infections), according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group or similar criteria, and patients without IFIs (excluding healthy individuals as controls). A total of 2979 patients (594 with proven or probable IFIs), included in 16 studies, were analyzed. The pooled sensitivity of BDG was 76.8% (95% confidence interval [CI], 67.1%-84.3%), and the specificity was 85.3% (95% CI, 79.6%-89.7%). The area under the summary receiver operating characteristic curve was 0.89. Marked statistical heterogeneity was noted. BDG has good diagnostic accuracy for distinguishing proven or probable IFIs from no IFIs. It can be useful in clinical practice, if implemented in the proper setting and interpreted after consideration of its limitations.

Once versus multiple daily dosing of aminoglycosides for patients with febrile neutropenia: a systematic review and meta-analysis.

BACKGROUND: Once daily dosing (ODD) of aminoglycosides has become a standard of care for most patient populations. However, the use of ODD of aminoglycosides has not been clarified in febrile neutropenia. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared the effectiveness and safety of ODD versus multiple daily dosing (MDD) of aminoglycosides in patients with febrile neutropenia. We searched the PubMed, Scopus, Cochrane Central Register of Trials and clinicaltrials.gov databases up to July 2010. RESULTS: A total of five and eight RCTs were included in the effectiveness and safety analyses, respectively. We observed a trend towards better effectiveness of the ODD regimen in the clinically evaluable population {five RCTs, 403 patient-episodes, risk ratio (RR)  = 1.18 [95% confidence interval (95% CI): 0.98, 1.42]}, but not in the microbiologically evaluable population [three RCTs, 119 patient-episodes, RR = 1.11 (95% CI: 0.84, 1.48)]. The occurrence of nephrotoxicity was similar between the two groups [seven RCTs, 1643 patient-episodes, RR = 0.74 (95% CI: 0.36, 1.50)], as was ototoxicity [six RCTs, 862 patient-episodes, RR = 1.05 (95% CI: 0.51, 2.19)]. There was no difference in mortality [four RCTs, 403 patient-episodes, RR = 0.77 (95% CI: 0.21, 2.78)]. CONCLUSIONS: Although the generalization of our findings may be restricted by the relatively small sample size and other methodological limitations of the included RCTs, ODD appears to be at least as effective and as safe as MDD in patients with febrile neutropenia. RCTs comparing ODD versus MDD in patients with bacteraemia and profound or prolonged neutropenia would be of additional value.

Resistance to polymyxins: Mechanisms, frequency and treatment options.

Polymyxins act by binding to lipid A moiety of the bacterial lipopolysaccharide and subsequently disintegrating the bacterial membranes. The most important mechanism of resistance includes modifications of the bacterial outer membrane structure, including lipopolysaccharide. Lipopolysaccharide modification is mostly mediated by PmrA/PmrB and PhoP/PhoQ two-component regulatory systems. These mechanisms exist with some differences in many gram-negative bacterial species. Resistance to polymyxins is generally less than 10%. In specific regions, such as the Mediterranean basin, Korea and Singapore, they tend to be higher. Heteroresistance to polymyxins is associated with exposure to polymyxins and especially suboptimal therapeutic dosage. Polymyxin combination regimens, tigecycline and fosfomycin may be useful options for the treatment of polymyxin-resistant gram-negative infections.

Fosfomycin versus other antibiotics for the treatment of cystitis: a meta-analysis of randomized controlled trials.

BACKGROUND: Cystitis is a common infection. The alarmingly high resistance rates exhibited by contemporary uropathogens necessitate the re-evaluation of old antibiotics. OBJECTIVES: To evaluate the effectiveness and safety of fosfomycin compared with other antibiotics for the treatment of patients with cystitis. METHODS: We performed a meta-analysis of randomized controlled trials (RCTs), generated from searches performed in PubMed, Scopus and Cochrane CENTRAL, which involved patients with cystitis treated with fosfomycin versus other antibiotics. RESULTS: Twenty-seven trials (eight double-blind) were included. Sixteen of these 27 trials involved exclusively non-pregnant female patients, 3 involved adult mixed populations of older age, 5 involved pregnant patients and 3 involved paediatric patients. Regarding clinical success, no difference was found in the comprehensive analysis regarding all comparators combined [10 RCTs, 1657 patients, risk ratio (RR) = 1.00, 95% confidence interval (CI) = 0.98-1.03] in trials involving non-pregnant females and in trials involving mixed populations. Insufficient relevant data were provided from trials involving paediatric and pregnant patients. No difference between fosfomycin and comparators was also found in all comparisons regarding the remaining effectiveness outcomes (namely microbiological success/relapse/re-infection). Fosfomycin had a comparable safety profile with the evaluated comparators in non-pregnant women, mixed and paediatric populations, whereas it was associated with significantly fewer adverse events in pregnant women (4 RCTs, 507 patients, RR = 0.35, 95% CI = 0.12-0.97). CONCLUSIONS: In the era of high drug resistance rates, reported even among community-acquired uropathogens, fosfomycin may provide a valuable alternative option for the treatment of cystitis in non-pregnant and pregnant women and in elderly and paediatric patients.

Effectiveness and safety of neuraminidase inhibitors in reducing influenza complications: a meta-analysis of randomized controlled trials.

BACKGROUND: Several studies suggest that neuraminidase inhibitors (NIs) can reduce the duration of influenza symptoms. However, data regarding their effectiveness in reducing influenza complications are scarce. METHODS: We evaluated the effectiveness of NIs in reducing influenza complications and mortality of patients with seasonal influenza, by performing a meta-analysis of randomized controlled trials (RCTs), retrieved from PubMed, Cochrane Central Register of Controlled Trials and Scopus databases, comparing NIs with placebo. RESULTS: Eleven RCTs (10 double-blind) were included; 8 involved adults/adolescents. In total, 5315 patients were included; 3491 (65.7%) with confirmed infection. Total influenza-related complications were significantly less likely in otherwise healthy patients with confirmed influenza infection that were treated with NIs versus placebo [7 RCTs, 2621 patients, risk ratio (RR) = 0.74, 95% confidence interval (CI) = 0.58-0.95] This finding was more pronounced in high-risk patients [4 RCTs, 475 patients, RR = 0.37, 95% CI = 0.24-0.59]; P < 0.01 for the chi(2) test for subgroup differences. In the comparisons regarding individual complications, a trend in favour of NIs was observed. Acute otitis media was significantly less likely in patients with confirmed influenza infection treated with NIs versus placebo (3 RCTs, 1124 patients, RR = 0.50, 95% CI = 0.30-0.85). No differences were found in the comparisons regarding the safety outcomes. No deaths were observed in trials that reported on mortality. CONCLUSIONS: NIs seem to be effective in reducing total influenza-related complications in otherwise healthy and high-risk patients, and have an acceptable safety profile. However, RCTs providing separate data for mild to serious complications and detailed reporting of adverse events and mortality are needed.

Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria.

BACKGROUND: The alarming increase in drug resistance and decreased production of new antibiotics necessitate the evaluation of combinations of existing antibiotics. Fosfomycin shows no cross-resistance to other antibiotic classes. Thus, its combination with other antibiotics may potentially show synergy against resistant bacteria. OBJECTIVE: To evaluate the available published evidence regarding the in vitro synergistic activity of fosfomycin with other antibiotic agents against Gram-positive and Gram-negative bacteria. METHODS: PubMed and the Cochrane Library were searched. RESULTS: Forty-one studies, including 34 (82.9%) conducted/published before 2000, were eligible for inclusion. The relatively limited number of isolates examined and the considerable heterogeneity of the retrieved studies regarding the definitions of synergy and the methodologies used hamper conclusive remarks for specific combinations of fosfomycin with other antibiotics. Yet, in the 27 studies providing data for Gram-positive strains (16 for Staphylococcus aureus, 3 for coagulase-negative staphylococci, 5 for Streptococcus pneumoniae, and 3 for Enterococcus spp.), fosfomycin showed synergy against methicillin-resistant Staphylococcus aureus when combined with cefamandole, cephazolin, ceftriaxone, ciprofloxacin, imipenem, and rifampicin. Data regarding Gram-negative strains reported from 15 studies (12 exclusively for P. aeruginosa, 2 exclusively for Enterobacteriaceae, 1 for both, and 1 for Acinetobacter baumannii) suggested that fosfomycin showed an estimable synergistic effect with gentamicin, amikacin, ceftazidime, cefepime, ciprofloxacin, levofloxacin, and aztreonam against P. aeruginosa. CONCLUSIONS: The synergistic combination of fosfomycin with other antibiotics may be a useful alternative treatment option for Gram-negative and Gram-positive infections. Additional studies using more stringent definitions of synergy, and studies reporting on the clinical efficacy of fosfomycin combinations in the current era of high antimicrobial resistance are needed.

Tuberculosis of the oral cavity: a systematic review.

The recent increase in the incidence of tuberculosis, combined with an emerging global resistance to antituberculous drugs, warrants an increased awareness of the involvement of Mycobacterium tuberculosis in persistent or atypical lesions in the oral cavity. We sought to review the published reports of mycobacterial infection of the oral cavity found in the literature in otherwise uncompromised patients, from 1950 to the present day, and analyzed the documented manifestations. M. tuberculosis infects all parts of the mouth (soft and hard palate, uvula, buccal mucosa, gingivae, lips, tongue, maxilla, and mandible) more often in men than in women, appearing predominantly in the form of ulcerative lesions. It was found as a secondary infection in 58% (54% pulmonary, 4% extrapulmonary) of patients and as a primary infection in 42% of patients. Carcinomas are found to co-exist in the same lesion site in 3% of patients. In approximately 50% of patients, an oral manifestation of TB has led to the diagnosis of a previously unknown systemic infection, which resulted in a timely and effective treatment. The investigation for tuberculosis should therefore be actively pursued in the dental surgery. Diagnostic work-up for systemic involvement and control of healthcare-associated spread is important, while therapeutic options are still considered adequate.

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.

Susceptibility of urinary tract bacteria to fosfomycin.

We evaluated the in vitro activity of fosfomycin against urinary isolates in a region in Greece that exhibits considerable antimicrobial resistance by evaluating retrospectively relevant susceptibility data retrieved from the microbiological library of the University Hospital of Heraklion, Crete, Greece. We examined 578 urinary isolates. In total, 516 (89.2%) were susceptible to fosfomycin; 415 isolates were gram negative, and 101 isolates were gram positive. Fosfomycin appears to exhibit good levels of in vitro activity against the examined urinary isolates.

Seasonality of mortality: the September phenomenon in Mediterranean countries.

BACKGROUND: Seasonal increases in the mortality rate have been associated with excessively cold or hot weather. We evaluated monthly patterns of mortality in selected countries. METHODS: We analyzed all-cause mortality statistics from 5 European Mediterranean countries (Cyprus, France, Greece, Italy, Spain), Sweden, North America (United States and Canada), Australia, New Zealand and Japan. We extracted and tabulated data on monthly all-cause mortality in the general population from the earliest to the latest year that records were available. RESULTS: We identified relevant data for a period of 2-57 years in each country. In the Mediterranean countries, the lowest average daily mortality was observed in September (all countries, 125/168 [74%] years). The fewest deaths were in August in Sweden (14/20 [70%] years) and North America (32/50 [64%] years). The fewest deaths in Japan occurred in July (2/2 [100%] years). In the southern hemisphere, the lowest mortality in Australia occurred in March (7/10 [70%] years) and in February for New Zealand (cumulative over 24 years). INTERPRETATION: Mortality in the general population declines in the late summer to early fall months in the countries evaluated. Environmental parameters may partly account for these associations, and further research is needed on the contribution of additional factors such as summer vacations.

Increasing contribution of China in modern biomedical research. Statistical data from ISI Web of Knowledge.

BACKGROUND: China is one of the most rapidly developing countries with a huge population spreading on a chaotic area. For centuries Chinese medicine was based on tradition, religion and experience. However, the last two decades under the pressure of globalization Chinese medicine is turning gradually to evidence-based medicine, contributing in international biomedical research. MATERIAL/METHODS: A bibliometric analysis through the ISI Web of Knowledge was performed. We collected data regarding the amount of Chinese publications in different biomedical fields, the presence of Chinese authors in high impact international journals, the contribution of China's universities in research and finally the number and the quality of local Chinese journals, which have entered the ISI database. RESULTS: According to ISI database a significant increase occurred in both the quantity and quality of the Chinese biomedical publishing activity. This was indicated by the major rise in the amount of published papers, the average augmentation of citations per paper and the constantly increasing presence of Chinese researchers in top medical journals. Chinese institutions appeared also more productive and local journals gained more representation in the ISI database. CONCLUSIONS: China's contribution in biomedical research really blossomed after 1990 and especially after 2000. The extent of this contribution may not be proportional to the total research activity performed in China, but it is this part of knowledge that becomes exported and interacts with the rest of the international research activity, promoting research potential in biomedicine.

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.