Tigecycline for the treatment of patients with Clostridium difficile infection: an update of the clinical evidence.

PURPOSE: Clostridium difficile infection (CDI) is the most common cause of nosocomial diarrhea in adult patients and is associated with considerable morbidity and mortality. Apart from the standard treatment regimens, tigecycline has shown significant in vitro activity against C. difficile but data regarding its clinical impact remains controversial. The aim of this article is to update the evidence related to the clinical role of tigecycline against C. difficile. METHODS: PubMed and Scopus databases were searched for relevant literature published from January 2015 to July 2018. RESULTS: Six retrospective cohort studies, 1 prospective study, 1 case series, and 2 case reports provided data regarding the effectiveness of tigecycline against C. difficile and were included in our evaluation. Also, we performed a meta-analysis based on 186 patients (from 4 studies) that showed clinical cure 79% (95% CI 73.0-84.5%). CONCLUSION: Despite the heterogeneity of the included studies and the small number of patients, the available evidence suggests that tigecycline might be considered as a potential therapeutic option for patients with CDIs, especially in severe cases.

Patient house calls in Attica and Thessaloniki, Greece (2005-2015): a model for out-of-hospital multispecialty emergency medicine.

BACKGROUND: The SOS-doctors are a network of physicians who perform house-call visits in the areas of Attica and Thessaloniki, Greece. METHODS: Patients requesting medical services by the SOS doctors during the period 1/1/2005 - 31/12/2015 were eligible for inclusion in this retrospective analysis. RESULTS: During this period 335, 212 home visits were performed. Females used this service more frequently compared to males (60.5% versus 39.5%). Among the age-groups, patients aged over 75 years made 56.6% of all house calls. Fewer phone requests were recorded during autumn than in winter (21.1% versus 29.1%). Infections were the most common cause of house-visits (29%), followed by cardiovascular diseases (10.3%), musculoskeletal (9.1%), gastrointestinal (6.3%) and neurological disorders (3.7%). An increasing demand for radiology at home was observed, starting at 352 calls in 2009 and reaching 2230 in 2015. Finally, 9.2% of patients were advised to be admitted into a hospital. CONCLUSION: A shift towards older age, but not the oldest old (> 90 years), and acute conditions was observed during the study period. The study confirms that home visits retain a significant role in the modern health care systems.

Fosfomycin.

The treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, the in vitro activity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.

Activity of cefiderocol (S-649266) against carbapenem-resistant Gram-negative bacteria collected from inpatients in Greek hospitals.

Background: Cefiderocol (S-649266), a siderophore cephalosporin, utilizes a novel mechanism of entry into the periplasmic space of Gram-negative bacteria and is broadly stable to ESBLs and carbapenemases. Methods: A collection of carbapenem-resistant Gram-negative bacteria isolated from clinical specimens in 18 Greek hospitals was tested for susceptibility to cefiderocol, meropenem, ceftazidime, cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam, amikacin, ciprofloxacin, colistin and tigecycline. Broth microdilution plates were used to determine MICs. Results: In total 189 non-fermentative Gram-negative bacteria (107 Acinetobacter baumannii and 82 Pseudomonas aeruginosa ) and 282 Enterobacteriaceae (including 244 Klebsiella pneumoniae , 14 Enterobacter cloacae and 11 Providencia stuartii ) were studied. For both A. baumannii and P. aeruginosa the MIC 90 of cefiderocol was 0.5 mg/L. For K. pneumoniae , E. cloacae and P. stuartii the MIC 90 of cefiderocol was 1, 1 and 0.5 mg/L, respectively. Tigecycline was the second most active antibiotic, followed by colistin. Conclusions: Cefiderocol exhibited greater antimicrobial activity in vitro against carbapenem-resistant Gram-negative bacteria than comparator antibiotics.

The dilemma of monotherapy or combination therapy in community-acquired pneumonia.

SCOPE: To study the factors associated with mortality in hospitalized patients with community-acquired pneumonia treated with monotherapy or combination therapy. METHODS: PubMed and Scopus were searched. Patients receiving macrolides, ß-lactams and fluoroquinolones, as monotherapy or in combination, were included. Meta-analyses and meta-regressions were performed. RESULTS: Fifty studies were included. Overall, monotherapy was not associated with higher mortality than combination (RR 1.14, 95% CI 0.99-1.32, I2 84%). Monotherapy was associated with higher mortality than combination in North American and retrospective studies. ß-lactam monotherapy was associated with higher mortality than ß-lactam/macrolide combination in the primary (1.32, 1.12-1.56, I2 85%) and most sensitivity analyses. There was no difference in mortality between fluoroquinolone monotherapy and ß-lactam/macrolide combination (0.98, 0.78-1.23, I2 73%). In meta-regressions, the moderators that could partially explain the observed statistical heterogeneity were the frequency of cancer patients (P = .03) and Pneumonia Severity Index score IV (P = .008). CONCLUSION: Due to the considerable heterogeneity and inclusion of unadjusted data, it is difficult to recommend a specific antibiotic regimen over another. Specific antibiotic regimens, study design and the characteristics of the population under study seem to influence the reported outcomes.

Women Physicians in Byzantium.

Women were allowed to practice the medical profession during the Byzantine Empire. The presence of female physicians was not an innovation of the Byzantine era but actually originated from ancient Greece and Rome. The studies and the training of women doctors were apparently equivalent to those of their male colleagues. The principal medical specialties of the female doctors were gynecology and midwifery. Byzantine legislation treated relatively equally both female and male doctors. For this reason, it can be assumed that the presence of female doctors was correlated with the position of women in Byzantine society. However, there is not sufficient information in the literature to clarify whether female and male doctors used to earn equal payment for the same service.

Substandard/counterfeit antimicrobial drugs.

Substandard/counterfeit antimicrobial drugs are a growing global problem. The most common substandard/counterfeit antimicrobials include beta-lactams (among antibiotics) and chloroquine and artemisin derivatives (among antimalarials). The most common type of substandard/counterfeit antimicrobial drugs have a reduced amount of the active drug, and the majority of them are manufactured in Southeast Asia and Africa. Counterfeit antimicrobial drugs may cause increased mortality and morbidity and pose a danger to patients. Here we review the literature with regard to the issue of substandard/counterfeit antimicrobials and describe the prevalence of this problem, the different types of substandard/counterfeit antimicrobial drugs, and the consequences for the individuals and global public health. Local, national, and international initiatives are required to combat this very important public health issue.

Impact of oseltamivir use on the reduction of complications in patients with influenza: a prospective study.

To evaluate the factors associated with oseltamivir prescription and to study the effectiveness of oseltamivir in reducing influenza-related complications. A prospective cohort study using the SOS Doctors (a network of physicians who perform house-call visits in Attica, Greece). Patients with confirmed or clinically suspected influenza were followed up to 14 days during the 2011-2012 influenza period. 410 patients with confirmed or suspected influenza were included. Healthy adults were mainly enrolled, with a median age of 44 years. Influenza diagnosis was mainly based on clinical criteria (65.8 % of patients). Oseltamivir was prescribed for 45.4 % of them. In a multivariate analysis, prescription of oseltamivir was associated with the attending physician (p < 0.001), positive influenza test (p < 0.001) and diabetes (p = 0.027). Data on complications were available for 351 patients, and 50 (15.8 %) of them reported at least one. Seven patients required hospitalization. Types of complications (pneumonia, bronchitis, etc.) were not significantly different between patients receiving and those not receiving oseltamivir. In the multivariate analysis, higher oseltamivir prescription rate was associated with fewer complications (p < 0.001). Bearing in mind the limitations of a non-randomized study, in a real-life setting, oseltamivir prescription and the rate of complications in patients with influenza were associated with the attending physician, underlying diseases and diagnostic tests. Overall, when the frequency of oseltamivir prescription increased, the influenza-related complications decreased.

Hepatitis B vaccine alone or with hepatitis B immunoglobulin in neonates of HBsAg+/HBeAg- mothers: a systematic review and meta-analysis.

OBJECTIVES: The cost-effectiveness of augmenting immunization against hepatitis B infection with hepatitis B immunoglobulin (HBIG) remains controversial, particularly for the subpopulation of babies of HBsAg+/HBeAg- mothers that are considered as low-infective. We aimed to evaluate the effectiveness of vaccine alone compared with vaccine plus HBIG for the immunization of babies of HBsAg+/HBeAg- mothers. METHODS: We searched PubMed, Scopus and Cochrane Central Register of Controlled Trials databases to identify studies comparing the effectiveness of combined immunization (vaccine plus HBIG) with vaccine alone in neonates of HBsAg+/HBeAg- mothers. A systematic review and meta-analysis of eligible studies was performed. RESULTS: A total of nine eligible studies were identified (four randomized controlled trials). No difference was found regarding the primary outcome of our meta-analysis, namely occurrence of hepatitis B infection, between neonates who received vaccine only, compared with those who received both vaccine and HBIG (four studies, 3426 patients, OR=0.82, 95% CI=0.41-1.64). This finding was consistent with regards to seroprotection rate (four studies, 1323 patients, OR=1.24, 95% CI=0.97-1.58). Safety data were not reported in the included studies. CONCLUSIONS: The available limited published evidence suggests that vaccine alone seems to be equally effective to the combination of HBIG and hepatitis B vaccine for neonates of HBsAg+/HBeAg- mothers in preventing infection. Further studies are needed in order to clarify the potential benefit of combined immunization to this specific subgroup of patients.

Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis.

Infectious complications after cardiac implantable electronic device (CIED) implantation are increasing over time and are associated with substantial mortality and healthcare costs. The aim of this study was to systematically summarize the literature on risk factors for infection after pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantation. Electronic searches (up to January 2014) were performed in PubMed, Scopus, and Web of Science databases. Sixty studies (21 prospective, 9 case-control, and 30 retrospective cohort studies) met the inclusion criteria. The average device infection rate was 1-1.3%. In the meta-analysis, significant host-related risk factors for infection included diabetes mellitus (odds ratio (OR) [95% confidence interval] = 2.08 [1.62-2.67]), end-stage renal disease (OR = 8.73 [3.42-22.31]), chronic obstructive pulmonary disease (OR = 2.95 [1.78-4.90]), corticosteroid use (OR = 3.44 [1.62-7.32]), history of the previous device infection (OR = 7.84 [1.94-31.60]), renal insufficiency (OR = 3.02 [1.38-6.64]), malignancy (OR = 2.23 [1.26-3.95]), heart failure (OR = 1.65 [1.14-2.39]), pre-procedural fever (OR = 4.27 [1.13-16.12]), anticoagulant drug use (OR = 1.59 [1.01-2.48]), and skin disorders (OR = 2.46 [1.04-5.80]). Regarding procedure-related factors, post-operative haematoma (OR = 8.46 [4.01-17.86]), reintervention for lead dislodgement (OR = 6.37 [2.93-13.82]), device replacement/revision (OR = 1.98 [1.46-2.70]), lack of antibiotic prophylaxis (OR = 0.32 [0.18-0.55]), temporary pacing (OR = 2.31 [1.36-3.92]), inexperienced operator (OR = 2.85 [1.23-6.58]), and procedure duration (weighted mean difference = 9.89 [0.52-19.25]) were all predictors of CIED infection. Among device-related characteristics, abdominal pocket (OR = 4.01 [2.48-6.49]), epicardial leads (OR = 8.09 [3.46-18.92]), positioning of two or more leads (OR = 2.02 [1.11-3.69]), and dual-chamber systems (OR = 1.45 [1.02-2.05]) predisposed to device infection. This systematic review on risk factors for CIED infection may contribute to developing better infection control strategies for high-risk patients and can also help risk assessment in the management of device revisions.

Deaths attributable to carbapenem-resistant Enterobacteriaceae infections.

We evaluated the number of deaths attributable to carbapenem-resistant Enterobacteriaceae by using studies from around the world published before April 9, 2012. Attributable death was defined as the difference in all-cause deaths between patients with carbapenem-resistant infections and those with carbapenem-susceptible infections. Online databases were searched, and data were qualitatively synthesized and pooled in a metaanalysis. Nine studies met inclusion criteria: 6 retrospective case-control studies, 2 retrospective cohort studies, and 1 prospective cohort study. Klebsiella pneumoniae was the causative pathogen in 8 studies; bacteremia was the only infection in 5 studies. We calculated that 26%-44% of deaths in 7 studies were attributable to carbapenem resistance, and in 2 studies, which included bacteremia and other infections, -3% and -4% of deaths were attributable to carbapenem resistance. Pooled outcomes showed that the number of deaths was significantly higher in patients with carbapenem-resistant infections and that the number of deaths attributable to carbapenem resistance is considerable.

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.

Proportion of extended-spectrum ß-lactamase (ESBL)-producing isolates among Enterobacteriaceae in Africa: evaluation of the evidence--systematic review.

OBJECTIVES: Extended-spectrum ß-lactamases (ESBLs) have become widespread around the world. We sought to evaluate the proportion of ESBL-producing isolates among Enterobacteriaceae in Africa. METHODS: A systematic search in the PubMed and Scopus databases was performed in order to identify studies providing the proportion of ESBL-producing isolates among patients either infected or colonized with Enterobacteriaceae. In an effort to incorporate contemporary data, only studies published from 2005 onwards and, among them, only those including isolates that were recovered from 2000 onwards were eligible. RESULTS: Twenty-six studies (409 ,215 isolates) from 13 African countries met the inclusion criteria. The proportion of ESBL-producing isolates among 13 studies reporting on isolates from a urinary source varied from 1.5% to 22.8%. Four other studies evaluated various clinical samples from different hospitals, showing that the proportion varied from 12.8% to 21.1%. Last, the proportions were 0.7%, 14%, 15.2% and 75.8%, respectively, in four studies evaluating patients with bloodstream infection. In particular, the proportion was 0.7% in a study from Malawi where ceftriaxone was the only available cephalosporin and was 75.8% in a study from Egypt that included only patients from intensive care units. In total, the proportion of ESBL-producing isolates was <15% in 16 out of 26 studies. CONCLUSIONS: Data originating from a small number of African countries suggest that the proportion of ESBL-producing isolates among Enterobacteriaceae may not be high in Africa, but is certainly not negligible. Further studies are needed from countries where no or limited relevant data are available.

Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis.

We sought to study whether the better pharmacokinetic and pharmacodynamic (PK/PD) properties of carbapenems and piperacillin/tazobactam, when the duration of infusion is longer, were associated with lower mortality. PubMed and Scopus were searched for studies reporting on patients treated with extended (≥3 hours) or continuous (24 hours) versus short-term duration (20-60 minutes) infusions of carbapenems or piperacillin/tazobactam. Fourteen studies were included (1229 patients). Mortality was lower among patients receiving extended or continuous infusion of carbapenems or piperacillin/tazobactam compared to those receiving short-term (risk ratio [RR], 0.59; 95% confidence interval [CI], .41-.83). Patients with pneumonia who received extended or continuous infusion had lower mortality than those receiving short-term infusion (RR, 0.50; 95% CI, 0.26-0.96). Data for other specific infections were not available. The available evidence from mainly nonrandomized studies suggests that extended or continuous infusion of carbapenems or piperacillin/tazobactam was associated with lower mortality. Well-designed randomized controlled trials are warranted to confirm these findings before such approaches become widely used.

Evaluation of antimicrobial susceptibility of Enterobacteriaceae causing urinary tract infections in Africa.

Our objective was to evaluate the antimicrobial susceptibility of Enterobacteriaceae causing urinary tract infections (UTIs) in adults in Africa. The PubMed database was systematically searched to identify relevant studies published after 2000. Google, World Health Organization, and African Field Epidemiology networks were also searched. Twenty-eight studies, accounting for 381,899 urine isolates from 14 African countries, met the inclusion criteria. Escherichia coli, Klebsiella spp., and Proteus spp. were the most commonly encountered uropathogens. Cefotaxime, imipenem, fosfomycin, and ciprofloxacin were the antibiotics with the highest activity against E. coli isolates from outpatients, with susceptibility being 92 to 99, 100, 100, and 68 to 91%, respectively. The susceptibility among Klebsiella spp. isolates from outpatients varied from 80 to 100% for amikacin and from 53 to 100% for ciprofloxacin, while susceptibility was 74 to 78, 97, and 77% for ciprofloxacin, amikacin, and fosfomycin, respectively, among Klebsiella species isolates from inpatients or patients with hospital-acquired UTIs. With regard to Proteus spp., the highest activity was observed among fluoroquinolones; 71 to 100% of the P. mirabilis isolates were susceptible to ciprofloxacin in four studies, and 74 to 100% of the P. vulgaris isolates were susceptible to ofloxacin in two studies. The currently available evidence suggests that the antimicrobial susceptibility patterns of Enterobacteriaceae uropathogens in African countries were similar to those in countries of southeast Europe. Further original studies are warranted from African countries for which there is limited published data.

A prospective study of characteristics and outcomes of bacteremia in patients with solid organ or hematologic malignancies.

OBJECTIVE: To study the epidemiology and outcomes of bacteremia in patients with hematologic or solid organ malignancies cared for at the University Hospital of Heraklion, Greece. METHODS: This prospective study was conducted during a 4-year period (2007-2011). Patients with bacterial and fungal blood stream infections were followed until discharge. Mortality was the primary outcome, while duration of hospitalization, relapses, time to relapse, and defervescence were the secondary outcomes. RESULTS: Ninety-nine patients with neoplasia (104 episodes) were included. Bacteremia developed mainly in patients with hematologic malignancies (56%). Secondary bacteremias due to respiratory and urinary tract infections were most commonly identified. Gram-negative bacteria were the predominantly isolated pathogens (65%); Pseudomonas spp. was the most common cause (19%), followed closely by E. coli (18%) and Klebsiella pneumoniae (17%). In-hospital mortality was 26.2%. No differences in mortality were seen among patients in different subgroups according to isolated bacteria (according to Gram's stain, species, or number of isolated bacteria in positive cultures), hematologic or solid organ malignancy, neutropenia, and primary or secondary bacteremia. However, patients with bacteremia due to extensively drug resistant bacteria had higher mortality than patients with bacteremia due to multidrug resistant or susceptible pathogens. Patients required a prolonged period of hospitalization (21.8 ± 14.9 days), which was complicated with relapses or reinfections in another body site in 27 % of them. CONCLUSION: Gram-negative bacteria were the predominantly isolated pathogens from patients with cancer in our population. The overall mortality remains high.

Incidence, clinical, microbiological features and outcome of bloodstream infections in patients undergoing hemodialysis.

OBJECTIVES: Infection is a common cause of death among hemodialysis patients. The study investigated incidence, risk factors, clinical features and outcome of bloodstream infections (BSIs) in haemodialysis patients. METHODS: The records of haemodialysis patients from 1999 to 2005 were reviewed. Risk factors were investigated by multivariate analysis. RESULTS: There were identified 148 bacteremic episodes, in 102 patients. The BSI rate was 0.52 per 1000 patient-days. Of the 148 episodes, 34 occurred in patients with permanent fistulae (0.18/1000 patient-days); 19 in patients with grafts (0.39/1000 patient-days); 28 in patients with permanent tunneled central catheters (1.03/1000 patient-days); and 67 in those with temporary-catheter (3.18/1000 patient-days). With fistula as reference, the BSI ratio was 1.84 with arteriovenous graft (P=.029), 4.85 with permanent central venous catheter (P<.001), and 14.88 with temporary catheter (P <.001). Catheter related were 41 episodes (28%). Gram positive organism were responsible for 96 episodes (65%), with S. aureus ( 55%) the most frequent, followed by S. epidermidis (26%) and Gram-negative for 36 (23%), with E. coli (39%) the most frequent. Infection was polymicrobial in 14 (9.5%). Diabetes (p<0.001), low serum albumin (p=0.040) and low hemoglobin (p<0.001) were significant risk factors. During hospitalization 18 patients (18%) died. Septic shock (p<0.001) and polymicrobial infection (p=0.041) were associated with in-hospital mortality. CONCLUSION: The risk of BSI in patients undergoing hemodialysis is related to the catheter type and vascular access. Septic shock and polymicrobial infection predispose to unfavourable outcome.