The Impact of Carbapenem Resistance on Mortality in Patients With Klebsiella Pneumoniae Bloodstream Infection: An Individual Patient Data Meta-Analysis of 1952 Patients.

INTRODUCTION: Available evidence from observational studies and meta-analyses has highlighted an increased mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) compared with their carbapenem-susceptible (CSKP) counterparts, but the exact reasons for this outcome difference are still to be determined. METHODS: We updated the search of a previous meta-analysis through four databases up to April 2018. A two-stage individual-patient data (IPD) meta-analysis was conducted, building an adjusting model to account for age, comorbidities and activity of empirical and targeted antimicrobial therapy. The protocol was registered on PROSPERO (identifier: CRD42018104256). RESULTS: IPD data were obtained from 14 out of 28 eligible observational studies. A total of 1952 patients were investigated: 1093 in the CRKP group and 859 in the CSKP group. Patients with CRKP-BSI had a twofold risk of death compared with CSKP-infected patients [adjusted odds ratio (aOR) 2.17; 95% confidence interval (CI) 1.56-3.04; I2 = 44.1%]. Mortality was higher in patients with CRKP BSI, in both the subgroup of absent/inactive (aOR 1.75; 95% CI 1.24-2.47; I2 = 0) and of active initial therapy (aOR 2.66; 95% CI 1.70-4.16; I2 = 16%) as well as in case of active targeted therapy (aOR 2.21; 95% CI 1.36-3.59; I2 = 58%). CONCLUSION: Resistance to carbapenem is associated with worse outcome in patients with BSI by Klebsiella pneumoniae even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. This applies to a scenario dominated by colistin-based therapies for CRKP. Further studies are needed to compare the mortality difference between CRKP and CSKP cases in the light of new anti-CRKP antimicrobials.

Trends of Mortality in Greece Prior to and During Its Current Financial Crisis (2009-2015).

OBJECTIVES: To study mortality changes in Greece prior to and during the financial crisis. STUDY DESIGN: Analysis of data by the Hellenic Statistical Authority (1955-2015). RESULTS: During the crisis, mortality increased from 9.76/1000 in 2009 to 10.52/1000 in 2012 and to 11.16/1000 in 2015, driven by an increase in the number of deaths and a decrease in the estimated population. The annual increase of the expected mortality accelerated during the crisis; in contrast, age-adjusted mortality continued to decrease up to 2014 and increased in 2015. The subpopulations that seemed to be affected more during the crisis were the elderly (especially those over 70 years), women, and citizens in southern Greece. The common denominator of all these subgroups was older age. Mortality due to heart diseases continued to decline at an accelerated pace; due to neoplasia continued to increase at an accelerated pace; and stroke mortality reversed (from decline to increment). CONCLUSIONS: The increment of crude mortality during the financial crisis in Greece should be attributed to the increase in deaths, only in part due to the aging population, the reduction in births, and the increase in emigration that contracted the population.

Clinical relevance of in vitro synergistic activity of antibiotics for multidrug-resistant Gram-negative infections: A systematic review.

OBJECTIVES: The aim of this review was to investigate the outcomes of patients infected with multidrug-resistant (MDR) or extensively drug-resistant (XDR) Gram-negative bacteria following synergy-guided antibiotic combination therapy (SGACT). METHODS: A systematic review of PubMed and Scopus databases was performed. Published studies of any design reporting outcomes of patients with MDR Gram-negative bacteria treated with SGACT were included. Two reviewers independently assessed the relevancy and quality of the retrieved articles and extracted the available data. RESULTS: Nineteen reports (530 patients) were included. Eleven case reports/series described 26 cases of systemic infection due to MDR Gram-negative bacteria treated with SGACT. Five deaths were reported, two of which were attributed to the infection. Six studies (including one randomised controlled trial) provided comparative data for patients treated with SGACT and those treated with unguided combination therapy (UCT) or active monotherapy. In the pooled analysis of unadjusted data from these studies (504 patients), there was no difference between SGACT and UCT or monotherapy (OR=0.47, 95% CI 0.21-1.04; I2=52%). Analysis of adjusted data showed that SGACT was significantly associated with survival (OR=0.44, 95% CI 0.20-0.98; I2=54%). CONCLUSION: These limited but promising findings warrant further investigation of SGACT in the outcome of patients with MDR Gram-negative infections in well-designed trials.

Resistance to fosfomycin: Mechanisms, Frequency and Clinical Consequences.

Fosfomycin has been used for the treatment of infections due to susceptible and multidrug-resistant (MDR) bacteria. It inhibits bacterial cell wall synthesis through a unique mechanism of action at a step prior to that inhibited by ß-lactams. Fosfomycin enters the bacterium through membrane channels/transporters and inhibits MurA, which initiates peptidoglycan (PG) biosynthesis of the bacterial cell wall. Several bacteria display inherent resistance to fosfomycin mainly through MurA mutations. Acquired resistance involves, in order of decreasing frequency, modifications of membrane transporters that prevent fosfomycin from entering the bacterial cell, acquisition of plasmid-encoded genes that inactivate fosfomycin, and MurA mutations. Fosfomycin resistance develops readily in vitro but less so in vivo. Mutation frequency is higher among Pseudomonas aeruginosa and Klebsiella spp. compared with Escherichia coli and is associated with fosfomycin concentration. Mutations in cAMP regulators, fosfomycin transporters and MurA seem to be associated with higher biological cost in Enterobacteriaceae but not in Pseudomonas spp. The contribution of fosfomycin inactivating enzymes in emergence and spread of fosfomycin resistance currently seems low-to-moderate, but their presence in transferable plasmids may potentially provide the best means for the spread of fosfomycin resistance in the future. Their co-existence with genes conferring resistance to other antibiotic classes may increase the emergence of MDR strains. Although susceptibility rates vary, rates seem to increase in settings with higher fosfomycin use and among multidrug-resistant pathogens.

An update on adverse drug reactions related to ß-lactam antibiotics.

INTRODUCTION: ß-lactams have been consistently associated with the majority of drug-related adverse events. Generally, these are mild under proper dosing and judicious selection. AREAS COVERED: Immediate hypersensitivity reactions are the most feared adverse events encountered after ß-lactam administration. Emerging evidence shows that immediate reactions are not as common as previously thought. Specialist consultation and testing seems prudent before a patient is officially declared allergic to ß-lactams. The risk of cross-reactions between not only members of the ß-lactam super-family but also between specific classes is also lower than previously thought. Newer studies have shown that cross-reactions are not universal and pertain to specific agents with similar side chains or metabolites of the ß-lactam core. The frequency of severe kidney or liver toxicity, neurotoxicity, cytopenias and Clostiridium difficile infection following ß-lactam administration seem to be agent-specific. EXPERT OPINION: The currently available data denote that in addition to age, gender, co-morbidity, renal or liver function, and co-administered agents, the antibiotic levels rather than the dose itself seem to be associated with the emergence of adverse events. Most of them subside with time after withdrawal of the offending agent, but the number of cases resulting in chronic disabilities or even deaths in not negligible.

Activity of TP-6076 against carbapenem-resistant Acinetobacter baumannii isolates collected from inpatients in Greek hospitals.

TP-6076 is a synthetic fluorocycline antibiotic that inhibits bacterial protein synthesis. In this study, carbapenem-resistant Acinetobacter baumannii clinical isolates from 13 Greek hospitals were tested for susceptibility to TP-6076 and comparator antibiotics. Broth microdilution plates were used to determine minimum inhibitory concentrations (MICs). A total of 121 non-duplicate A. baumannii isolates were tested. The MIC50 and MIC90 values of TP-6076 were 0.03 mg/L and 0.06 mg/L, respectively. Tigecycline was the second most active antibiotic (MIC90, 2 mg/L), followed by minocycline (MIC90, 8 mg/L). TP-6076 exhibited MIC90 values that were one dilution lower against tigecycline- and minocycline-susceptible isolates than against resistant isolates. There was no difference in the MIC90 value for colistin-susceptible or -resistant isolates. In conclusion, TP-6076 exhibited greater antimicrobial activity in vitro against carbapenem-resistant A. baumannii than comparator antibiotics.

Temporal Trends (1999-2015) in the Impact Factor of Biomedical Journals Published by US and EU Scientific Societies.

OBJECTIVE: The impact factor has emerged as the most popular index of scientific journals' resonance. In this study we aimed to examine the impact factor trends of journals published by scientific bodies in the United States of America (USA) and Europe (EU). METHODS: We randomly chose 11 categories of Journal of Citation Reports and created three research classes: clinical medicine, laboratory medicine, and basic science. The impact factor values for the years 1999-2015 were abstracted, and the impact factor of US and EU journals was studied through the years. RESULTS: A total of 265 journals were included in the final analysis. The impact factor of US journals was higher than that of EU journals throughout the study period. In addition, for both US and EU journals the median impact factor increased throughout the study period. The rate of annual change in the impact factor throughout the study period was lower for US than EU journals (1.85% versus 3.55%, P=0.019). A higher median annual increase was seen in the impact factor during the period 1999-2008 compared to the period 2009-2015 for both US (P<0.001) and EU (P=0.001) journals. In fact, during the second period the US median impact factor value did not show significant changes (P=0.31), while the EU median impact factor continued to increase (P<0.001). CONCLUSION: The impact factor of EU journals increased at a significantly higher rate than and approached that of the US journals during the last 16 years.

Intravenous plus inhaled versus intravenous colistin monotherapy for lower respiratory tract infections: A systematic review and meta-analysis.

OBJECTIVE: To evaluate whether intravenous plus inhaled combination (IV/INHCC) compared to intravenous monotherapy (IVCM) was associated with patient outcomes and identify factors influencing study outcomes. METHODS: PubMed and Scopus were searched till November 2016. Studies were included if they evaluated adult patients with lower respiratory tract infections due to MDR/XDR Gram-negative bacteria and reported comparative mortality data (adjusted and unadjusted) for patients receiving IV/INHCC versus IVCM. Random effects meta-analyses were performed. RESULTS: Thirteen studies (11 retrospective, 2 prospective) were included. The overall quality of data was low to very low and characterized by the lack of adjusted data. The majority of the studies were designed to evaluate the outcome of the meta-analysis. Both IV and inhaled colistin were administered at variable doses. There was no difference in mortality between IV/INHCC and IVCM when all studies were combined (13 studies, 1115 patients, risk ratio 0.94, 95% confidence interval 0.81-1.08). Only the analysis that included studies with low-dose IV colistin showed significant difference in favor of IV/INHCC versus IVCM (0.65, 0.45-0.94). CONCLUSIONS: Overall, low quality data suggest that IV/INHCC did not lower mortality in patients with MDR Gram negative infections unless low IV colistin dose was administered.

Inhaled colistin monotherapy for respiratory tract infections in adults without cystic fibrosis: a systematic review and meta-analysis.

BACKGROUND: Inhaled colistin is becoming increasingly popular against respiratory tract infections caused by multidrug resistant (MDR) Gram-negative bacteria because it may overcome the problems associated with intravenous (IV) administration. OBJECTIVE: To investigate the effectiveness and safety of inhaled colistin as monotherapy (without concomitant IV administration of colistin) in the treatment of respiratory tract infections caused by MDR or colistin-only susceptible Gram-negative bacteria. METHODS: PubMed and Scopus databases were searched. A systematic review and meta-analysis were conducted. RESULTS: Twelve studies (373 patients receiving inhaled colistin for respiratory tract infection) were included. Ten studies evaluated patients with pneumonia (including 8 studies with ventilator-associated pneumonia) and 2 studies evaluated patients with ventilator-associated tracheobronchitis. Patients with infections due to MDR Acinetobacter baumannii and Pseudomonas aeruginosa were mainly studied. Daily dose of inhaled colistin and treatment duration varied in the individual studies. The pooled all-cause mortality was 33.8% (95% CI 24.6% - 43.6%), clinical success was 70.4% (58.5% - 81.1%) and eradication of Gram-negative bacteria was shown in 71.3% (57.6% - 83.2%) of cases. CONCLUSIONS: Inhaled colistin monotherapy may deserve further consideration as a mode for colistin administration for the treatment of respiratory tract infections caused by MDR A. baumannii and P. aeruginosa.

Prolonged versus short-term intravenous infusion of antipseudomonal ß-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials.

BACKGROUND: The findings of randomised controlled trials (RCT), observational studies, and meta-analyses vary regarding the effectiveness of prolonged ß-lactam infusion. We aimed to identify the effectiveness of prolonged versus short-term infusion of antipseudomonal ß-lactams in patients with sepsis. METHODS: We did a systematic review and meta-analysis to compare prolonged versus short-term intravenous infusion of antipseudomonal ß-lactams in patients with sepsis. Two authors independently searched PubMed, Scopus, and the Cochrane Library of clinical trials until November, 2016, without date or language restrictions. Any RCT comparing mortality or clinical efficacy of prolonged (continuous or ≥3 h) versus short-term (≤60 min) infusion of antipseudomonal ß-lactams for the treatment of patients with sepsis was eligible. Studies were excluded if they were not RCTs, the antibiotics in the two arms were not the same, neither mortality nor clinical efficacy was reported, only pharmacokinetic or pharmacodynamic outcomes were reported, or if ten or fewer patients were enrolled or randomised. Data were extracted in prespecified forms and we then did a meta-analysis using a Mantel-Haenszel random-effects model. The primary outcome was all-cause mortality at any timepoint. This meta-analysis is registered with the PROSPERO database, number CRD42016051678, and is reported according to PRISMA guidelines. FINDINGS: 2196 articles were identified and screened, and 22 studies (1876 patients) were included in the meta-analysis. According to the Grading of Recommendations Assessment, Development, and Evaluation tool, the quality of evidence for mortality was high. Carbapenems, penicillins, and cephalosporins were studied. Patients with variable age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, severity of sepsis and renal function were enrolled. Prolonged infusion was associated with lower all-cause mortality than short-term infusion (risk ratio [RR] 0·70, 95% CI 0·56-0·87). Heterogeneity was not observed (p=0·93, I2=0%). The funnel plot and the Egger's test (p=0·44) showed no evidence of publication bias. INTERPRETATION: Prolonged infusion of antipseudomonal ß-lactams for the treatment of patients with sepsis was associated with significantly lower mortality than short-term infusion. Further studies in specific subgroups of patients according to age, sepsis severity, degree of renal dysfunction, and immunocompetence are warranted. FUNDING: None.

Intravenous colistin combination antimicrobial treatment vs. monotherapy: a systematic review and meta-analysis.

BACKGROUND: To evaluate whether intravenous colistin in combination with other antibiotics (IVCC) is associated with lower mortality compared with intravenous colistin monotherapy (IVCM), and to identify factors influencing study outcomes. METHODS: PubMed and Scopus were searched up to November 2016. Studies were included if they evaluated adult patients with multi-drug-resistant (MDR) or extensively-drug-resistant Gram-negative infections, and reported comparative mortality data (adjusted and unadjusted) for patients receiving IVCC vs. IVCM. Random effects meta-analyses were performed. FINDINGS: Thirty-two studies (29 observational, three randomized) were included. The overall quality of data was low to very low, and studies were characterized by the lack of adjusted data. The majority of studies were not designed to evaluate the outcome of the meta-analysis, and focused mainly on infections due to Acinetobacter baumannii and Klebsiella pneumoniae. Colistin was administered at variable doses, with or without a loading dose, and in combination with several antibiotics. Overall, IVCC was not associated with lower mortality than IVCM [32 studies, 2328 patients, risk ratio (RR) 0.91, 95% confidence interval (CI) 0.81-1.02, I2 8%]. A significant difference was observed in favour of IVCC when high-dose (>6 million international units) colistin was used (RR 0.80, 95% CI 0.69-0.93), in studies conducted in Asia (RR 0.82, 95% CI 0.71-0.95), in patients with bacteraemia (RR 0.75, 95% CI 0.57-0.98) and in patients with acinetobacter infections (RR 0.88, 95% CI 0.78-1.00). INTERPRETATION: Overall, low-quality data suggest that IVCC did not lower mortality in patients with MDR Gram-negative infections. However, there is some evidence for a benefit observed with high intravenous doses of colistin.

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.

Resistance phenotypes and susceptibility of contemporary Serratia isolates in the university hospital of Crete, Greece.

OBJECTIVE: To study changes in the susceptibility of Serratia spp. in Crete, Greece (2010-2015). METHODS: Non-duplicate isolates were examined using automated systems. Phenotypic confirmatory tests were applied. RESULTS: Three hundred and seventy-eight Serratia spp. were analyzed. Serratia marcescens (88.3%) was the predominant species. Fluoroquinolones (97.9%), carbapenems (97.4%) and fosfomycin (97.4%) were the most active followed by amikacin (95.5%), piperacillin/tazobactam (94.7%), and trimethoprim/sulfamethoxazole (94.4%). The activity of 3rd and 4th generation cephalosporins was 87-88.6%. The distribution of multi-drug resistant (MDR) strains varied, with a trend towards increasing frequency. ESBL (7.9%), carbapenemase (2.9%), AmpC (2.1%) and aminoglycoside modifying enzyme (10.6%) production were the commonest resistant phenotypes. CONCLUSION: The susceptibility of Serratia spp. varied during the study period a trend towards decreasing susceptibility, especially for non-carbapenem ß-lactams and aminoglycosides.

In vitro susceptibility and resistance phenotypes in contemporary Enterobacter isolates in a university hospital in Crete, Greece.

AIM: To study the evolution in the susceptibility of Enterobacter spp. in Crete, Greece from 2010 to 2015. METHODS: Non-duplicate isolates were studied using automated systems. Phenotypic confirmatory tests were applied. RESULTS: A total of 939 Enterobacter isolates were included. Colistin was the most active antibiotic (97.9%) followed by imipenem (96.1%), gentamicin (95.7%), tigecycline (91.8%), cefepime (89.4%), chloramphenicol (85.8%), fosfomycin (85.5%), trimethoprim/sulfamethoxazole (83.3%) and piperacillin/tazobactam (73.3%). Antibiotic resistance did not increase during the study period for most antibiotics. Lower susceptibility was observed among multidrug-resistant strains and carbapenem-nonsusceptible isolates. AmpC was the most common resistant mechanism (21%); carbapenemases (3.7%) and aminoglycoside-modifying enzymes (6.5%) were also detected. CONCLUSION: A significant proportion of Enterobacter spp. was resistant to several antibiotics, most notably ß-lactams.

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.

In vitro susceptibility and resistance phenotypes in contemporary Citrobacter isolates in a University Hospital in Crete, Greece.

BACKGROUND: Data on Citrobacter spp. susceptibility are scarce. We sought to study the evolution in the susceptibility of 385 Citrobacter spp. at the University Hospital of Heraklion, Crete, Greece during a six-year period (2010-2015). METHODS: Non-duplicate strains isolated from inpatients (intensive care unit, oncology, surgery, internal medicine, paediatrics) and outpatients were studied using Vitek 2. Phenotypic confirmatory tests were applied for detection of ß-lactamases and aminoglycoside modifying enzymes. RESULTS: C. freundii (172, 44.7%) and C. koseri (166, 43.1%) were the most commonly isolated species. C. braakii (34), C. amalonaticus (6), C. youngae (6) and C. sedlakii (1) were the remaining isolates. Colistin and fosfomycin were the most active antibiotics (both 99.2%) followed by carbapenems (99%) aminoglycosides (96.6-98.4%), tigecycline (96.1%), cefepime (94.8%), ciprofloxacin (94.3%), tetracycline (92.7%), trimethoprim/sulphamethoxazole (91.4%), chloramphenicol (88.1%), piperacillin/tazobactam (86.5%) and 3rd generation cephalosporins (85.7%). C. freundii were more resistant than C. koseri. Antibiotic resistance did not increase during the study period for most antibiotics. Lower susceptibility to all antibiotics was observed among multi-drug resistant (MDR) strains. AmpC was the most common resistant mechanism (10.9%); carbapenemases (1.3%) and aminoglycoside modifying enzymes (2.9%) were also detected. All AmpC producers were resistant to cephalosporins but not to carbapenems. In all but one isolates aminoglycoside resistance was accompanied by acquired ß-lactamases. CONCLUSIONS: Although Citrobacter species in general were susceptible, antibiotic susceptibility testing is required for the detection of resistant isolates.

Colistin versus polymyxin B for the treatment of patients with multidrug-resistant Gram-negative infections: a systematic review and meta-analysis.

Colistin and polymyxin B (PMB) have different pharmacokinetic profiles and minor differences in antimicrobial activities that may result in discrepancies in mortality and nephrotoxicity. A systematic review and meta-analysis was conducted. PubMed, Scopus and Cochrane Library databases were searched. There was no significant difference in unadjusted mortality between patients treated with colistin and PMB [risk ratio (RR) = 0.71, 95% confidence interval (CI) 0.45-1.13]. Adjusted data were not available. Unadjusted nephrotoxicity was more common in patients treated with colistin than PMB (RR = 1.55, 95% CI 1.36-1.78). According to the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria, there was no difference regarding risk, injury or failure between colistin and PMB. Although episodes of loss of renal function were few in general, they developed primarily in colistin-treated patients (RR = 8.55, 95% CI 1.48-49.49). Colistin was associated with more episodes of nephrotoxicity that also occurred sooner in the analysis of adjusted data (hazard ratio = 2.16, 95% CI 1.43-3.27). Colistin administration was an independent risk factor for nephrotoxicity in two studies. Future studies should evaluate in depth the factors associated with mortality and nephrotoxicity in patients treated with polymyxins and the impact of polymyxin-associated nephrotoxicity on mortality.

Colistin loading dose: evaluation of the published pharmacokinetic and clinical data.

Colistin (polymyxin E) has been widely used since the beginning of the century as a last-option antibiotic for the treatment of patients with multidrug-resistant and extensively-drug resistant bacterial infections. However, colistin dosing is troublesome because each batch of the drug contains a mixture of components and because it is administered as the inactive pro-drug colistimethate sodium (CMS), which has different pharmacokinetic (PK) properties from the active drug. Significant inter-individual and intra-individual variability in colistin plasma concentrations have been observed in all available studies. Low plasma concentrations of the drug during the first hours from initiation of administration suggested that a loading dose would be appropriate. However, other PK studies challenge this approach. Clinical data from randomised controlled trials are not available, whilst data from observational studies do not support higher effectiveness of a loading dose. In this review, we summarise the available data regarding the administration of a loading dose and discuss the issues surrounding the potential advantages and disadvantages as well as the context within which such an approach could be beneficial to patients.

The antibiotic pipeline for multi-drug resistant gram negative bacteria: what can we expect?

INTRODUCTION: A real concern in the medical community is the increasing resistance of bacteria, especially that of Gram-negative types. New antibiotics are currently under clinical development, promising to tackle severe infections caused, especially, by multi-drug resistant (MDR) bacteria and broaden the armamentarium of clinicians. AREAS COVERED: We searched PUBMED and GOOGLE databases. Combinations of already approved ß-lactams or monobactams with new ß-lactamase inhibitors [imipenem-cilastatin/MK-7655 (relebactam), meropenem/RPX7009 (vaborbactam), ceftaroline/avibactam, aztreonam/avibactam], new ß-lactams (S-649266, BAL30072), aminoglycosides (plazomicin), quinolones (finafloxacin) and tetracyclines (eravacycline) were included in the review. Expert commentary: For the majority of the upcoming antibiotics the currently available data is limited to their microbiology and pharmacokinetics. Their effectiveness and safety against infections due to MDR bacteria remain to be proved. Significant issues are also the impact of these antibiotics on the human intestinal microbiota and their possible co-administration with already-known antimicrobial agents in difficult-to-treat-infections; further studies should be conducted for these objectives.