Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms.

Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

Lefamulin. Comment on: "Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms. Microorganisms, 2019, 7, 270".

On 18 August 2019, an article was published in Microorganisms presenting novel, approved anti-Gram-positive antibiotics. On 19 August 2019, the U.S. Food and Drug Administration announced the approval of lefamulin, a representative of a new class of antibiotics, the pleuromutilins, for the treatment of adult community-acquired bacterial pneumonia. We present a brief description of lefamulin.

Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms.

Increasing multidrug-resistance to Gram-positive pathogens, particularly to staphylococci, enterococci and streptococci, is a major problem, resulting in significant morbidity, mortality and healthcare costs. In recent years, only a small number of novel antibiotics effective against Gram-positive bacteria has been approved. This review will discuss the current evidence for novel branded antibiotics that are highly effective in the treatment of multidrug-resistant infections by Gram-positive pathogens, namely ceftobiprole, ceftaroline, telavancin, oritavancin, dalbavancin, tedizolid, besifloxacin, delafloxacin, ozenoxacin, and omadacycline. The mechanism of action, pharmacokinetics, microbiological spectrum, efficacy and safety profile will be concisely presented. As for any emerging antibiotic agent, resistance is likely to develop against these highly effective antibiotics. Only through appropriate dosing, utilization and careful resistance development monitoring will these novel antibiotics continue to treat Gram-positive pathogens in the future.

The Role of Minocycline in the Treatment of Nosocomial Infections Caused by Multidrug, Extensively Drug and Pandrug Resistant Acinetobacter baumannii: A Systematic Review of Clinical Evidence.

Treatment options for multidrug resistant Acinetobacter baumannii strains (MDR-AB) are limited. Minocycline has been used alone or in combination in the treatment of infections associated with AB. A systematic review of the clinical use of minocycline in nosocomial infections associated with MDR-AB was performed according to the PRISMA-P guidelines. PubMed-Medline, Scopus and Web of Science TM databases were searched from their inception until March 2019. Additional Google Scholar free searches were performed. Out of 2990 articles, 10 clinical studies (9 retrospective case series and 1 prospective single center trial) met the eligibility criteria. In total, 223 out of 268 (83.2%) evaluated patients received a minocycline-based regimen; and 200 out of 218 (91.7%) patients with available data received minocycline as part of a combination antimicrobial regimen (most frequently colistin or carbapenems). Pneumonia was the most common infection type in the 268 cases (80.6% with 50.4% ventilator-associated pneumonia). The clinical and microbiological success rates following minocycline treatment were 72.6% and 60.2%, respectively. Mortality was 20.9% among 167 patients with relevant data. In this systematic review, minocycline demonstrated promising activity against MDR-AB isolates. This review sets the ground for further studies exploring the role of minocycline in the treatment of MDR-AB associated infections.

New treatments of multidrug-resistant Gram-negative ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) remains an important clinical problem globally, being associated with significant morbidity and mortality. As management of VAP requires adequate and timely antibiotic administration, global emergence of antimicrobial resistance poses serious challenges over our ability to maintain this axiom. Development of antimicrobials against MDR Gram-negative pathogens has therefore emerged as a priority and some new antibiotics have been marketed or approach late stage of development. The aim of this review is to analyse new therapeutic options from the point view of potential treatment of VAP. Among recently developed antimicrobials presented herein, it is obvious that we will have promising therapeutic options against VAP caused by Enterobacteriaceae excluding those producing metallo-ß-lactamases, against which only cefiderocol and aztreonam/avibactam are expected to be active. Against infections caused by carbapenem non-susceptible Pseudomonas aeruginosa, ceftolozane/tazobactam and to a lesser extend ceftazidime/avibactam may cover a proportion of current medical needs, but there still remain a considerable proportion of strains which harbor other resistance mechanisms. Murepavadin and cefiderocol hold promise against this particularly notorious pathogen. Finally, Acinetobacter baummannii remains a treatment-challenge. Eravacycline, cefiderocol and probably plazomicin seem to be the most promising agents against this difficult-to treat pathogen, but we have still a long road ahead, to see their position in clinical practice and particularly in VAP. In summary, despite persisting and increasing unmet medical needs, several newly approved and forthcoming agents hold promise for the treatment of VAP and hopefully will enrich our antimicrobial arsenal in the next few years. Targeted pharmacokinetic and clinical studies in real-life scenario of VAP are important to position these new agents in clinical practice, whereas vigilant use will ensure their longevity in our armamentarium.

Hepatitis C in human immunodeficiency virus co-infected individuals: Is this still a "special population"?

A substantial proportion of individuals with chronic hepatitis C virus (HCV) are co-infected with human immunodeficiency virus (HIV). Co-infected individuals are traditionally considered as one of the "special populations" amongst those with chronic HCV, mainly because of faster progression to end-stage liver disease and suboptimal responses to treatment with pegylated interferon alpha and ribavirin, the benefits of which are often outweighed by toxicity. The advent of the newer direct acting antivirals (DAAs) has given hope that the majority of co-infected individuals can clear HCV. However the "special population" designation may prove an obstacle for those with co-infection to gain access to the new agents, in terms of requirement for separate pre-licensing clinical trials and extensive drug-drug interaction studies. We review the global epidemiology, natural history and pathogenesis of chronic hepatitis C in HIV co-infection. The accelerated course of chronic hepatitis C in HIV co-infection is not adequately offset by successful combination antiretroviral therapy. We also review the treatment trials of chronic hepatitis C in HIV co-infected individuals with DAAs and compare them to trials in the HCV mono-infected. There is convincing evidence that HIV co-infection no longer diminishes the response to treatment against HCV in the new era of DAA-based therapy. The management of HCV co-infection should therefore become a priority in the care of HIV infected individuals, along with public health efforts to prevent new HCV infections, focusing particularly on specific patient groups at risk, such as men who have sex with men and injecting drug users.

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.

Severe Plasmodium vivax malaria complicated with acute respiratory distress syndrome: a case associated with focal autochthonous transmission in Greece.

In 2011, autochthonous Plasmodium vivax malaria emerged in a focal geographical area in Greece after importation by immigrants from the Indian subcontinent. We report the case of complicated P. vivax malaria in a previously healthy 42-year-old Greek female. The patient presented acute respiratory distress syndrome (ARDS), worsening jaundice, and thrombocytopenia after the administration of antimalarial treatment and despite a decreasing burden of parasitemia. She recovered fully after admission in the intensive care unit and support with mechanical ventilation. We discuss the risks potentially associated with the reappearance of P. vivax malaria in a previously malaria-free area.

In vitro activity of fosfomycin in combination with linezolid against clinical isolates of methicillin-resistant Staphylococcus aureus.

The objective of this paper was to investigate the in vitro effects of fosfomycin combined with linezolid against methicillin-resistant Staphylococcus aureus (MRSA). A total of 102 MRSA isolates isolated from clinical specimens of human infections from three hospitals in China were studied. The microdilution checkerboard method was used to determine whether combinations act synergistically against these isolates. The susceptibility results for fosfomycin and linezolid were interpreted according to the guidelines of the Clinical and Laboratory Standards Institute. Synergy and indifference were defined as a fractional inhibitory concentration index of ⩽0.5 and >0.5 but ⩽4, respectively. The combination of fosfomycin and linezolid demonstrated the following interactions: 98.04% (100/102) synergism; 1.96% (2/102) indifference; no antagonism was seen. Thus, the combination between fosfomycin and linezolid shows synergism for most of the MRSA isolates tested in this study. If these findings are confirmed in further in vitro or in vivo studies, the above combination could be tested clinically for difficulty to treat MRSA infections, particularly those warranting prolonged oral therapy.

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.

Drug interactions between antiretrovirals and new or emerging direct-acting antivirals in HIV/hepatitis C virus coinfection.

PURPOSE OF REVIEW: We reviewed the pharmacokinetic interactions between direct-acting antivirals against hepatitis C virus (HCV) and antiretroviral agents. RECENT FINDINGS: Most relevant pharmacokinetic studies involve healthy individuals and refer to the already licensed HCV protease inhibitors, boceprevir and telaprevir. Data from a phase II clinical trial question the clinical relevance of the interactions between boceprevir and HIV protease inhibitors. The use of a higher dose of telaprevir appears to offset the effect of efavirenz on telaprevir metabolism according to another phase II trial. Boceprevir and particularly telaprevir substantially increase the exposure to maraviroc, similarly to other potent CYP3A4 inhibitors. Different dosages of faldaprevir and daclatasvir have been recommended to be used in combination with a boosted HIV protease inhibitor vs. an efavirenz-based antiretroviral regimen. HIV protease inhibitors appear to substantially increase the exposure to simeprevir. The interactions between sofosbuvir and most antiretroviral agents do not appear to be of clinical relevance or to require dosage modifications. SUMMARY: The drug-drug interaction studies for HCV direct-acting antivirals and antiretrovirals are important in determining the appropriate drug combinations and dosages. The clinical implications of these interactions need further assessment in different categories of patients, including those with cirrhosis.

continuous versus conventional infusion of amphotericin B deoxycholate: a meta-analysis.

BACKGROUND: Treatment with Amphotericin B (AmB) deoxycholate, which is still used widely, particularly in low-resource countries, has been challenged due to nephrotoxicity. We sought to study whether continuous infusion of AmB deoxycholate reduces nephrotoxicity retaining, however, the effectiveness of the drug. METHODS: PubMed and Scopus databases were systematically searched to identify studies comparing the outcomes of patients receiving 24-h infusion of AmB ("continuous group") and those receiving 2-6-h infusion of AmB ("conventional group"). Nephrotoxicity and all-cause mortality were the primary outcomes of the review, while treatment failure was the secondary outcome. RESULTS: Five studies met the inclusion criteria; one randomized controlled trial, two prospective cohort studies, and two retrospective cohort studies. The majority of patients were neutropenic with an underlying hematologic malignancy. All 5 studies (392 patients) provided data regarding the development of nephrotoxicity. A non-significant trend towards lower nephrotoxicity was observed for patients receiving continuous infusion of AmB compared with those receiving conventional infusion [RR = 0.61 (95% CI 0.36, 1.02)]. Four studies (365 patients) provided data regarding mortality; no relevant difference was detected between patients receiving continuous and those receiving conventional infusion of AmB [RR = 0.81 (95% CI 0.36, 1.83)]. Data on treatment failure of the two methods of administration was insufficient for meaningful conclusions. CONCLUSION: The available evidence from mainly non-randomized studies suggests that continuous infusion of AmB deoxycholate might offer an advantage over the conventional infusion regarding the development of nephrotoxicity, without compromising patient survival. Further randomized studies are needed to investigate this issue.

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.

MRSA in Africa: filling the global map of antimicrobial resistance.

We sought to assess the prevalence of methicillin-resistance among Staphylococcus aureus isolates in Africa. We included articles published in 2005 or later reporting for the prevalence of MRSA among S. aureus clinical isolates. Thirty-two studies were included. In Tunisia, the prevalence of MRSA increased from 16% to 41% between 2002-2007, while in Libya it was 31% in 2007. In South Africa, the prevalence decreased from 36% in 2006 to 24% during 2007-2011. In Botswana, the prevalence varied from 23-44% between 2000-2007. In Algeria and Egypt, the prevalence was 45% and 52% between 2003-2005, respectively. In Nigeria, the prevalence was greater in the northern than the southern part. In Ethiopia and the Ivory Coast, the prevalence was 55% and 39%, respectively. The prevalence of MRSA was lower than 50% in most of the African countries, although it appears to have risen since 2000 in many African countries, except for South Africa.

A prospective observational study of chronic prostatitis with emphasis on epidemiological and microbiological features.

OBJECTIVES: Despite the progress made in recent years in understanding and diagnosing chronic prostatitis (CP) many cases are still underdiagnosed and undertreated for unknown reasons. The purpose of this study is to investigate the epidemiological data of patients with symptoms of CP and to associate data from medical history and clinical examination with the results of laboratory tests. METHODS: The study population consisted of individuals with reported pelvic discomfort and genital pain with or without lower urinary tract symptoms and sexual dysfunction visiting our department from 03/2009 to 03/2011. Patients underwent Meares-Stamey test (a few cases underwent the two-glass test). Depending on history and specific symptoms, urethral smear and sperm cultures were additionally obtained from several patients. The processes and reading of the samples were performed by a specialist microbiologist, who has not notified the patient record. RESULTS: 114 out of 155 patients who finally enrolled into the study had a medical history, 69 had sexual behavior and 72 sexual habits that predispose to chronic prostatitis. The clinical examination was not diagnostic in 43.8% of cases. The urethral smear and sperm culture diagnosed coexistent urethral infection in 22 cases. 54 out of the 72 positive EPS/VB3/PPM cultures grew one, 11 two to three and 5 cultures grew more than three different organisms. CONCLUSIONS: Findings of this study debate some widely accepted considerations on the etiology and diagnosis of chronic prostatitis and highlight the uncertainties and controversies regarding chronic prostatitis etiology, pathophysiology, presentation and diagnosis.

Extended or continuous versus short-term intravenous infusion of cephalosporins: a meta-analysis.

The authors sought to study whether extended or continuous infusion of cephalosporins is associated with better clinical outcomes than short-term infusion. PubMed and Scopus databases were systematically searched. Studies reporting the clinical outcomes of patients receiving extended or continuous infusion (≥3 or 24 h, respectively) versus short-term infusion (≤1 h) of cephalosporins were considered eligible. Eleven studies (1250 clinically evaluable patients) were included. Clinical cure and mortality were not statistically different between the compared groups (risk ratio: 1.14; 95% CI: 0.94-1.37 and risk ratio: 0.96; 95% CI: 0.80-1.15, respectively). This meta-analysis did not show a difference in clinical cure or mortality regarding extended or continuous versus short-term intravenous infusion of cephalosporins. However, in most of the included studies, patients in the extended/continuous infusion group received a substantially lower total dosage of antibiotic than those in the short-term group for the total duration of treatment.

Impact of antimicrobial multidrug resistance on inpatient care cost: an evaluation of the evidence.

This article evaluates the in-hospital costs attributable to antimicrobial multidrug resistance, defined as the difference in averaged costs of the patients infected with a multidrug-resistant (MDR) versus a non-MDR organism. PubMed and Scopus databases were searched to identify relevant studies. Twenty four studies were included: four on carbapenem-resistant or MDR Gram negative nonfermenters, eight on extended-spectrum b-lactamase-producing Enterobacteriaceae and 12 on methicillin-resistant Staphylococcus aureus. In two studies on carbapenem-resistant nonfermenters, the attributable mean hospital charges were US$58,457 and 85,299, respectively. The attributable mean total costs were US$4484 in a study referring to MDR Acinetobacter baumannii, while that varied from US$1584 to 30,093 among studies on extended-spectrum b-lactamase-producing Enterobacteriaceae. With respect to methicillin-resistant S. aureus, the attributable mean total costs varied from US$1014 to 40,090. The in-hospital costs attributable to multidrug resistance are alarmingly high, justifying the application of strict infection control measures in medical institutions with increased rate of MDR infections.

Severe sepsis and septic shock due to Plasmodium vivax infection.

Plasmodium vivax malaria is typically characterized by a mild and benign clinical course. Organ dysfunction is rarely seen, whereas acute lung injury has been found to occur after starting antimalarial treatment. We present an unusual case of severe sepsis and septic shock due to Plasmodium vivax monoinfection.

The impact of article length on the number of future citations: a bibliometric analysis of general medicine journals.

BACKGROUND: The number of citations received is considered an index of study quality and impact. We aimed to examine the factors associated with the number of citations of published articles, focusing on the article length. METHODS: Original human studies published in the first trimester of 2006 in 5 major General Medicine journals were analyzed with regard to the number of authors and of author-affiliated institutions, title and abstract word count, article length (number of print pages), number of bibliographic references, study design, and 2006 journal impact factor (JIF). A multiple linear regression model was employed to identify the variables independently associated with the number of article citations received through January 2012. RESULTS: On univariate analysis the JIF, number of authors, article length, study design (interventional/observational and prospective/retrospective), title and abstract word count, number of author-affiliated institutions, and number of references were all associated with the number of citations received. On multivariate analysis with the logarithm of citations as the dependent variable, only article length [regression coefficient: 14.64 (95% confidence intervals: (5.76-23.50)] and JIF [3.37 (1.80-4.948)] independently predicted the number of citations. The variance of citations explained by these parameters was 51.2%. CONCLUSION: In a sample of articles published in major General Medicine journals, in addition to journal impact factors, article length and number of authors independently predicted the number of citations. This may reflect a higher complexity level and quality of longer and multi-authored studies.

Weight-adjusted versus fixed dose of linezolid for Chinese healthy volunteers of higher and lower body weight: a Phase I pharmacokinetic and pharmacodynamic study.

OBJECTIVES: The objective was to evaluate the pharmacokinetic and pharmacodynamic properties of a single intravenous fixed dose compared with a weight-adjusted dose of linezolid. METHODS: A Phase I, comparative clinical trial was conducted involving 20 healthy male Chinese volunteers, assigned into low weight (LW) (50 kg < weight ≤ 55 kg) and high weight (HW) (≥ 80 kg) groups. All subjects were administrated single dose of linezolid (600 mg/30 min) and, after 72 h washout period, another single-dose (10 mg/kg/30 min). Plasma linezolid concentrations were measured by liquid chromatography-tandem mass spectrometry. A Monte Carlo simulation was used to evaluate the probability of pharmacodynamic target attainment (PTA). RESULTS: With 600 mg dose, plasma concentrations in LW group were much higher than that in HW group. A persistent serum inhibitory activity was observed in LW group; the inhibitory activity was lower in HW group. The PTA in HW group was lower than in LW group. For 10 mg/kg dose, both HW and LW groups had similar plasma concentrations. The HW and LW groups had similar serum inhibitory effects. The PTA in HW and LW groups also showed no difference. CONCLUSIONS: Our findings suggest that a weight-adjusted, 10 mg/kg regimen of linezolid may be more appropriate than fixed dosing for patients of different body weight.