Optimal Treatment Of Infections Research Articles

The CARBA-MAP study: national mapping of carbapenemases in Spain (2014-2018).

Infections caused by carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa, including isolates producing acquired carbapenemases, constitute a prevalent health problem worldwide. The primary objective of this study was to determine the distribution of the different carbapenemases among carbapenemase-producing Enterobacterales (CPE, specifically Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and Klebsiella aerogenes) and carbapenemase-producing P. aeruginosa (CPPA) in Spain from January 2014 to December 2018. A national, retrospective, cross-sectional multicenter study was performed. The study included the first isolate per patient and year obtained from clinical samples and obtained for diagnosis of infection in hospitalized patients. A structured questionnaire was completed by the participating centers using the REDCap platform, and results were analyzed using IBM SPSS Statistics 29.0.0. A total of 2,704 carbapenemase-producing microorganisms were included, for which the type of carbapenemase was determined in 2692 cases: 2280 CPE (84.7%) and 412 CPPA (15.3%), most often using molecular methods and immunochromatographic assays. Globally, the most frequent types of carbapenemase in Enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among Enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). In Enterobacterales, KPC is mainly present in the South and South-East regions of Spain and OXA-48-like in the rest of the country. Regarding P. aeruginosa, VIM is widely distributed all over the country. Globally, an increasing percentage of OXA-48-like enzymes was observed from 2014 to 2017. KPC enzymes were more frequent in 2017-2018 compared to 2014-2016. Data from this study help to understand the situation and evolution of the main species of CPE and CPPA in Spain, with practical implications for control and optimal treatment of infections caused by these multi-drug resistant organisms.

Multi-Omics of Corynebacterium Pseudotuberculosis 12CS0282 and an In Silico Reverse Vaccinology Approach Reveal Novel Vaccine and Drug Targets.

Corynebacterium pseudotuberculosis is an important animal pathogen, which is also able to infect humans. An optimal treatment of infections with this pathogen is not available today and consequently, more research is necessary to understand the infection process. Here, we present a combined -omics and bioinformatics approach to characterize C. pseudotuberculosis 12CS0282. The genome sequence of strain 12CS0282 was determined, analyzed in comparison with the available 130 C. pseudotuberculosis sequences and used as a basis for proteome analyses. In a reverse vaccinology approach, putative vaccine and drug targets for 12CS0208 were identified. Mass spectrometry analyses revealed the presence of multiple virulence factors even without host contact. In macrophage interaction studies, C. pseudotuberculosis 12CS0282 was highly resistant against human phagocytes and even multiplied within human THP-1 cells. Taken together, the data indicate a high pathogenic potential of the strain.

Mortality from infections and malignancies in patients treated with renal replacement therapy: data from the ERA-EDTA registry.

Infections and malignancies are the most common non-cardiovascular causes of death in patients on chronic renal replacement therapy (RRT). Here, we aimed to quantify the mortality risk attributed to infections and malignancies in dialysis patients and kidney transplant recipients when compared with the general population by age group and sex. We followed 168 156 patients included in the ERA-EDTA registry who started RRT in 1993-2007 until 1 January 2012. Age- and cause-specific mortality rates per 1000 person-years (py) and mortality rate ratios (MRRs) compared with the European general population (WHO) were calculated. To identify risk factors, we used Cox regression. Infection-related mortality was increased 82-fold in dialysis patients and 32-fold in transplant recipients compared with the general population. Female sex, diabetes, cancer and multisystem disease were associated with an increased risk of infection-related mortality. The sex difference was most pronounced for dialysis patients aged 0-39 years, with women having a 32% (adjusted HR 1.32 95% CI 1.09-1.60) higher risk of infection-related mortality than men. Mortality from malignancies was 2.9 times higher in dialysis patients and 1.7 times higher in transplant recipients than in the general population. Cancer and multisystem disease as primary causes of end-stage renal disease were associated with higher mortality from malignancies. Infection-related mortality is highly increased in dialysis and kidney transplant patients, while the risk of malignancy-related death is moderately increased. Young women on dialysis may deserve special attention because of their high excess risk of infection-related mortality. Further research into the mechanisms, prevention and optimal treatment of infections in this vulnerable population is required.

Defining multidrug-resistant tuberculosis: correlating GenoType MTBDRplus assay results with minimum inhibitory concentrations

This study correlates MICs of rifampicin (RIF) and isoniazid (INH) with GenoType MTBDRplus assay results for drug-resistant Mycobacterium tuberculosis (MTB) clinical isolates. MICs of RIF and INH were established for 84 and 90 isolates, respectively, testing 7 concentrations of each drug. Genotypic resistance to each drug was determined by GenoType MTBDRplus assay with 50 representative mutations confirmed by pyrosequencing, with mutations in the rpoB gene associated with RIF resistance and mutations in the katG and/or inhA genes associated with INH resistance. Based upon the correlation of MICs with specific genetic profiles, relative resistance levels were established for each isolate. Results indicate that MTB phenotypic resistance, currently based upon the testing of isolate susceptibility to a single drug concentration, may be more accurately profiled via quantitative MICs, and therefore, the correlation of molecular diagnostic results with specific MICs may allow for more optimal treatment of infections.

Management and Outcome of Infections by Klebsiella pneumoniae with Decreased Susceptibility to Carbapenems in Renal Transplant Patients

Introduction: Up to 20% of urinary tract infections (UTI) in renal transplant recipients (RTR) are reported to be caused by ESBL-producing bacteria. Due to their high resistance to ESBL-mediated hydrolysis, carbapenems are the treatment of choice in these cases. The occurrence of infections with carbepenem-resistant Klebsiella pneumoniae (KPC) however is a life-threatening event. Especially since optimal treatment of infections with KPC is not well defined and nephrotoxic agents seem to be required to reduce mortality rates ranging up to 57%. Methods: We report an outbreak of K. pneumoniae with resistance or decreased susceptibility to carbapenems in six RTR of our centre between 05/2010 and 01/2011. Patient age was 65.5±2.9 y. Five patients were de novo transplant recipients (index cultures (IC) 3 to 6 weeks after Tx), one patient was 5 years post transplantation. Immunosuppressive regimens consisted of Basiliximab, MMF, steroids and CsA or Tac according to the local standard protocol. All patients received perioperative antibacterial-prophylaxis with imipenem and longterm PCP-prophylaxis. Antibiotic susceptibilities of isolated K. pneumoniae were determined by Vitek2 and E-test. Genetic relatedness was investigated using Enterobacterial Repetitive Intergenic Consensus (ERIC)- and repetitive sequence based (REP)-PCR. Follow-up is 9.5±2.6 months. All values given as mean±SD. Results: Ertapenem-resistant K. pneumoniae were isolated from rectal swabs, urine or BAL-fluid. All K. pneumoniae were resistant to penicillins, cephalosporins, ertapenem, fluoroquinolones and cotrimoxazol. Some exhibited elevated MICs for meropenem, doripenem or imipenem but remained susceptible. ERIC- and REP-PCR analysis of isolates from 5 of 6 patients showed an identical profile suggesting a clonal spread. One patient was only colonized, three presented with UTI. Two patients, having been treated recently for BPAR or relapsing ITP, were severely ill suffering from pneumonia and/or sepsis due to ertapenem-resistant K. pneumoniae. Antibiotic treatment consisted of high dose meropenem, gentamicin, and inhalative colistin in case of pneumonia, for 19±9 days. In 4 of 5 patients with infection, MMF was transiently withdrawn. Trough-levels [ng/mL] for CsA ((203.3±11.4) vs (194.1±36.7) p=0.82; n=3) and Tac ((12.5±1.2) vs (8.1±0.2) p=0.07; n=2) did not differ significantly before and after IC were obtained. There is no difference in S-Creatinine [mg/dL] at date of IC and at latest follow up ((1.85±0.25) vs (2.1±0.5) p=0.67; n=6). All patients are alive with functioning grafts. Conclusion: In potentially life-threatening infections due to ertapenem resistant K. pneumoniae in RTR, excellent patient and graft survival can be achieved. Early onset combination therapy with gentamicin/high dose meropenem and transient withdrawal of MMF have proved save and efficacious in our cohort.

Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines

Optimal treatment of infections caused by Staphylococcus aureus, Listeria monocytogenes and Legionella pneumophila requires antibiotics with intracellular activity. Linezolid accumulates poorly within cells. Torezolid (TR-700) is a novel methyltetrazolyl oxazolidinone with potentially different cellular pharmacokinetic properties. Our aim was to examine the accumulation and intracellular activities of torezolid in this context. Measurement of torezolid cell content and antibacterial activity in comparison with linezolid using human macrophages (THP-1) and human endothelial cells [human umbilical vein endothelial cells (HUVECs)], applying models allowing for the quantitative evaluation of the pharmacodynamics of antibiotics towards intracellular bacteria. Torezolid accumulated rapidly in THP-1 macrophages, reaching a stable intracellular to extracellular ratio of approximately 10 (compared with approximately 1-2 for linezolid) within 15 min. On a weight concentration basis (mg/L), torezolid was approximately 5- to 10-fold more potent intracellularly (lower concentration needed to achieve a bacteriostatic effect) than linezolid against phagocytosed S. aureus, L. monocytogenes and L. pneumophila, with no change in maximal efficacy (approximately 1 log(10) reduction of the original, post-phagocytosis inoculum). When drugs were compared at equipotent concentrations (multiples of the MIC), no difference was seen between linezolid and torezolid, but the higher potency of torezolid allowed control of intracellular infections caused by linezolid-resistant S. aureus. Torezolid exerts intracellular activity at lower extracellular concentrations than linezolid because of its greater potency independent of its greater intracellular accumulation. This may confer an advantage to torezolid in vivo if the drug can be used at dosages creating serum concentrations similar to those achieved with linezolid.

Efficacy of trovafloxacin in treatment of experimental staphylococcal or streptococcal endocarditis.

The efficacy of trovafloxacin against Staphylococcus aureus and viridans group streptococci was investigated in vitro and in an experimental model of endocarditis. The MICs at which trovafloxacin and ciprofloxacin inhibited 90% of clinical isolates of such bacteria (MIC90s) were (i) 0.03 and 2 mg/liter, respectively, for 30 ciprofloxacin-susceptible S. aureus isolates, (ii) 32 and 128 mg/liter, respectively, for 20 ciprofloxacin-resistant S. aureus isolates, and (iii) 0.25 and 8 mg/liter, respectively, for 28 viridans group streptococci. Rats with aortic vegetations were infected with either of two ciprofloxacin-susceptible but methicillin-resistant S. aureus strains (strains COL and P8), one penicillin-susceptible Streptococcus sanguis strain, or one penicillin-resistant Streptococcus mitis strain. Rats were treated for 3 or 5 days with doses that resulted in kinetics that simulated those achieved in humans with trovafloxacin (200 mg orally once a day), ciprofloxacin (750 mg orally twice a day), vancomycin (1 g intravenously twice a day), or ceftriaxone (2 g intravenously once a day). Against the staphylococci, the activities of both trovafloxacin and ciprofloxacin were equivalent to that of vancomycin, and treatment of endocarditis with these drugs was successful (P < 0.05). However, ciprofloxacin selected for resistant derivatives in vitro and in vivo, whereas trovafloxacin was 10 to 100 times less prone than ciprofloxacin to select for resistance in vitro and did not select for resistance in vivo. Against the two streptococcal isolates, trovafloxacin significantly (P < 0.05) decreased bacterial counts in the vegetations but was less effective than the control drug, ceftriaxone. Thus, a simulated oral dose of trovafloxacin (200 mg per day) was effective against ciprofloxacin-susceptible staphylococci and was less likely than ciprofloxacin to select for resistance. The simulated oral dose of trovafloxacin also had some activity against streptococcal endocarditis, but optimal treatment of infections caused by such organisms might require higher doses of the drug.