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Sax P, Erlandson K, Lake J, et al.
AbstractBackgroundInitiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation.MethodsWe performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naïve people with HIV (PWH) initiating ART between 2003-2015, comprising over 5,000 participants and 10,000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation.FindingsWeight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4, higher HIV-1 RNA, no injection drug use, female sex and black race. Integrase strand transfer inhibitors (INSTIs) were associated with more weight gain than protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTI), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine.InterpretationWeight gain is ubiquitous in clinical trials of ART initiation, and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens contributing. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.
Duncan R. Cranendonk, Brent C. Opmeer, Michiel A. van Agtmael, Judith Branger, Kees Brinkman, Andy I.M. Hoepelman, Fanny N. Lauw, Jan Jelrik Oosterheert, Annemarie H. Pijlman, Sanjay U.C. Sankatsing, Robin Soetekouw, Jan Veenstra, Peter J. de Vries, Jan M. Prins, W. Joost Wiersinga
Summary: Six days of antibiotic treatment for patients hospitalized for severe cellulitis appeared to be non-inferior to 12 days on the short term, but seemed to result in more frequent relapses by day 90.
Franz Allerberger, Winfried V. Kern
In the clinical microbiology laboratory, blood cultures are a vital technology used to isolate bacteria and fungi. They are the gold standard for diagnosing bloodstream infection and considered a prerequisite for targeted antibiotic treatment [1,2]. Diagnostic with blood cultures can reduce mortality, length of hospital stay and furthermore hospital expense [3,4]. It is not known when exactly the blood culture-technique was “invented”. First practice of microbiologic culture of blood occurred prior 1880, mostly for puerperal fever and endocarditis, and was limited to one drop of blood obtained from the top of finger pricked with a sting.
Fritz S, Shapiro D, Hersh A.
AbstractNationally representative data from 2000-2015 demonstrated a rise in the incidence of outpatient visits for skin infections, peaking in 2010-2013, followed by a plateau. While cephalexin was the most frequently prescribed antibiotic at the beginning, trimethoprim-sulfamethoxazole was the most frequently prescribed antibiotic by the end of the study period.
Household contact tracing of index TB cases has been advocated as a key part of TB control for many years, but has not been widely implemented in many low-resource setting because of the current dearth of high quality evidence for effectiveness. Innovative strategies for earlier, more effective treatment are particularly important in contexts with hyper-endemic levels of HIV, where levels of TB infection remain extremely high.
We present the design of a household cluster-randomised controlled trial of interventions aimed at improving TB-free survival and reducing childhood prevalence of Mycobacterium tuberculosis infection among household contacts of index TB cases diagnosed in two provinces of South Africa. Households of index TB cases will be randomly allocated in a 1:1 ratio to receive either an intensified home screening and linkage for TB and HIV intervention, or enhanced standard of care. The primary outcome will compare between groups the TB-free survival of household contacts over 15 months. All participants, or their next-of-kin, will provide written informed consent to participate.
Evidence from randomised trials is required to identify cost-effective approaches to TB case-finding that can be applied at scale in sub-Saharan Africa.
ISRCTN16006202 (01/02/2017: retrospectively registered) and NHREC4399 (11/04/2016: prospectively registered). Protocol version: 4.0 (date: 18th January 2018).
David S.Y. Ong, Mario Poljak
Point-of-care (POC) tests provide an alternative to traditional laboratory-based diagnostics due to reduced turnaround-times, portability and no need for highly trained laboratory staff. Smartphones can be integrated into POC platforms because of their multifunctionality, enabled by high-quality digital cameras, computer processors, touchscreen interface and wireless data transfer. It is predicted that by 2020 about 80% of the world population will use smartphones.
Daniele Roberto Giacobbe, Tommaso Giani, Matteo Bassetti, Anna Marchese, Claudio Viscoli, Gian Maria Rossolini
Treating severe infections due to multidrug resistant Gram-negative bacteria (MDR-GNB) is one of the most important challenges for clinicians worldwide, partly because resistance may remain unrecognized until identification of the causative agent and/or antimicrobial susceptibility testing (AST). Recently, some novel rapid test for identification and/or AST of MDR-GNB from positive blood cultures or the blood of patients with bloodstream infections (BSI) have become available.
Lorenzo Subissi, Caroline Rodeghiero, Helena Martini, Amber Litzroth, Kris Huygen, Geert Leroux-Roels, Denis Piérard, Isabelle Desombere
Quantifying IgG antibodies to pertussis toxin (PT) is the most specific and sensitive method to serodiagnose a Bordetella pertussis infection. Since PT is a component of acellular pertussis vaccines, anti-PT IgG is also induced by vaccination, precluding pertussis serodiagnosis exclusively based on anti-PT IgG in recently vaccinated subjects. Here, we aim to identify additional B. pertussis-specific serological markers that can discriminate between infection and recent vaccination.
Marks M, Bell L, Jones I, et al.
AbstractThe OVIVA study demonstrated non-inferiority for managing bone and joint infections (BJI) with oral antibiotics. We report that 79.7% of OPAT patients being treated for BJI at our centre would be eligible for oral antibiotics, saving median 19.5 IV antibiotic days (IQR 8.5-37) and GBP 1,234 (IQR 569-2,594) per patient.
The following error appeared in the corrected proof publication of this article [Drain PK, Kubiak RW, Siriprakaisil O, et al. confUrine Tenofovir Concentrations Correlate with Plasma and Relates to TDF Adherence: A Randomized Directly-observed Pharmacokinetic Trial (TARGET Study). Clin Infect Dis https://doi.org/10.1093/cid/ciz645].
Helminthic and protozoan infections are common, particularly in low- or middle-income countries. Although an association between parasite carriage and markers of poor growth have been shown in some studies, systematic reviews have suggested only a modest impact of clearing carriage. The prevalence of these pathogens and the effect that they have on growth in preschool children has never been investigated in Malawi.
One hundred ninety-three children aged 0–72 months were randomly recruited from rural villages in the Mangochi district of Malawi. Formol-ether concentration was performed on stool and the samples examined with a light microscope. Anthropometric data was taken for each child and the haemoglobin measured with a point of care test.
The mean age of the children was 2 years 4 months. Overall prevalence of intestinal parasite infection was 37.3%. Protozoa were found in 28.5% of children, while helminths were found in 8.8%. The most commonly found organisms were Giardia lambia (12.4%), Entamoeba coli (10.4%) and Hookworm species (3.6%). Stunting was seen in 47.8% of children, 12.9% were underweight and 5.0% were wasted. No significant association was found between markers of poor growth and infection with any intestinal parasite.
We found that prevalence of helminth infection was low in preschool children living in the Mangochi district compared to international standards. However a significant proportion of the preschool population are infected with protozoa, particularly Giardia lambia. In this cohort, despite a significant prevalence of stunting, helminth infection was not significantly associated with any markers of poor growth. The significance of protozoal carriage and contribution to growth restriction in this context creates further avenues for future research.
Tuberculosis (TB) is a major public health problem in developing countries like Bangladesh. Female sex workers (FSWs) and their clients are active sources for spreading TB. The purpose of this study was to assess the knowledge of TB among FSWs in Rajshahi city, Bangladesh.
It was a cross-sectional study with a sample size of 225 FSWs. The knowledge on TB was measured by six different questions. Chi-square test and multinomial logistic regression model were used in this study to find the associated factors of lack of general knowledge on TB among FSWs.
Out of 225 FSWs, 43.1, 34.7 and 22.2% came from urban, rural and slum areas respectively. More than 41% FSWs perceived that TB is a non-communicable disease. A large number of FSWs (76.4%) did not know the spread of TB. It was found that more than 90% FSWs did not have knowledge on latent TB. The χ2-test demonstrated that FSWs’ education, monthly family income, age, currently marital status and sex trading place were significantly associated with their knowledge on TB. A remarkable number of FWSs (42.2%) had poor knowledge on TB. It was found that comparatively higher educated FWSs were more likely to have good or fair knowledge on TB than lower educated ones (p
Increasing number of hospitalized children with community acquired pneumonia (CAP) is co-detected with Mycoplasma pneumoniae (Mp). The clinical characteristics and impact of Mp co-detected with other bacterial and/or viral pathogens remain poorly understood. The purpose of this study was to evaluate the demographic and clinical features of CAP children with Mp mono-detection and Mp co-detection.
A total of 4148 hospitalized children with CAP were recruited from January to December 2017 at the Children’s Hospital of Hebei Province, affiliated to Hebei Medical University. A variety of respiratory viruses, bacteria and Mp were detected using multiple modalities. The demographic and clinical features of CAP children with Mp mono-detection and Mp co-detection were recorded and analyzed.
Among the 110 CAP children with Mp positive, 42 (38.18%) of them were co-detected with at least one other pathogen. Co-detection was more common among children aged ≤3 years. No significant differences were found in most clinical symptoms, complications, underlying conditions and disease severity parameters among various etiological groups, with the following exceptions. First, prolonged duration of fever, lack of appetite and runny nose were more prevalent among CAP children with Mp-virus co-detection. Second, Mp-virus (excluding HRV) co-detected patients were more likely to present with prolonged duration of fever. Third, patients co-detected with Mp-bacteria were more likely to have abnormal blood gases. Additionally, CAP children with Mp-HRV co-detection were significantly more likely to report severe runny nose compared to those with Mp mono-detection.
Mp co-detection with viral and/or bacterial pathogens is common in clinical practice. However, there are no apparent differences between Mp mono-detection and Mp co-detections in terms of clinical features and disease severity.
Moraxella nonliquefaciens is a usually non-pathogenic biofilm-producing Gram-negative coccobacillus which may colonize the upper respiratory tract, rarely causing invasive disease. Although very rare, bloodstream infections caused by this organism have been described, showing often a fatal outcome. Here, we report the case of a pediatric cancer patient with bloodstream infection and sepsis due to M. nonliquefaciens showing full recovery after appropriate antibiotic treatment.
A three-year-old boy with stage IV neuroblastoma was admitted for high-dose chemotherapy with autologous stem cell rescue after standard neuroblastoma treatment. Despite receiving antimicrobial prophylaxis with trimethoprim/sulfamethoxazole, acyclovir and amphothericin B, the patient presented with fever of up to 39.5 °C and neutropenia. Besides a chemotherapy-related mucositis and an indwelling Broviac catheter (removed), no infection focus was identified on physical examination. Moraxella nonliquafaciens was identified in blood cultures. After antibiotic treatment and neutrophil recovery, the patient was fit for discharge.
The case described highlights the importance of an otherwise non-pathogenic microorganism, especially in immunosupressed cancer patients. It should be kept in mind that, although very infrequently, Moraxella nonliquefaciens may cause bloodstream infections that can be successfully treated with prompt focus identification and antibiotic therapy.
Xiao Chen, Yinghui Li, Wenqing Yao, Tao Wu, Qiaoyun Zhu, Yanjun Zhang, Hongyan Ye, Ruonan Wang, Shufa Zheng, Fei Yu, Weiwei Chen, Zhaoqin Zhu, Lingling Mao, Qinghua Hu, Zhen Tang, Haili Chen, Yanchao Liu, Yu Chen
During surveillance, we found a new type of Vibrio parahaemolyticus that agglutinated with O4 serum but not with K serum, and the recA gene was affected by a large insertion. We named this strain “O4:KUT-recAin”.
Tenofovir alafenamide (TAF)-containing combinations were introduced in Switzerland after October 2016 and are recommended over tenofovir disoproxil fumarate (TDF) in patients with osteoporosis or impaired renal function.
We included all participants of the Swiss HIV Cohort Study on TDF-containing antiretroviral therapy with follow-up visits after January 2016. We determined the proportion of switches from TDF to TAF overall, and among patients with risk factors for TDF toxicity, including osteoporosis, impaired renal function or marked proteinuria. We used multivariable logistic regression to explore predictors of switching from TDF to TAF.
We included 5′012 patients, of whom 652 (13.0%) had risk factors for TDF toxicity. A switch from TDF to TAF was undertaken in 2′796 (55.8%) individuals overall, and in 465 (71.3%) with risk factors. Predictors of switching to TAF were male sex (adjusted odds ratio 1.27, 95% confidence interval 1.07–1.50), age > 50 years (1.43, 1.23–1.66) and the presence of risk factors for TDF toxicity (2.21, 1.77–2.75). In contrast, patients with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-pill regimen (0.11, 0.09–0.13), those treated in non-tertiary care centers (0.56, 0.46–0.70), as well as those with CD4 cell counts below 500/μL (0.77, 0.66–0.90) and with chronic hepatitis C infection (0.66, 0.54–0.80) were most likely to stay on TDF.
Over 50% of patients on TDF-containing therapy, including the majority of patients at risk for TDF toxicity, were switched to TAF within two years of its introduction in Switzerland. Individuals on NNRTI-based single-pill regimens were most likely to remain on TDF.
Kimmel S, Walley A, Linas B, et al.
AbstractBackgroundInjection drug use–associated infective endocarditis (IDU-IE) is rising and valve surgery is frequently indicated. The effect of initiating public outcomes reporting for aortic valve surgery on rates of valve surgery and in-hospital mortality for endocarditis is not known.MethodsFor an interrupted time series analysis, we used data from the National Inpatient Sample, a representative sample of United States inpatient hospitalizations, from January 2010 to September 2015. We included individuals aged 18–65 with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis of endocarditis. We defined IDU-IE using a validated combination of ICD-9 codes. We used segmented logistic regression to assess for changes in valve replacement and in-hospital mortality rates after the public reporting initiation in January 2013.ResultsWe identified 7322 hospitalizations for IDU-IE and 23 997 for non–IDU-IE in the sample, representing 36 452 national IDU-IE admissions and 119 316 non-IDU admissions, respectively. Following the implementation of public reporting in 2013, relative to baseline trends, the odds of valve replacement decreased by 4.0% per quarter (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.93–0.99), with no difference by IDU status. The odds of an in-patient death decreased by 2.0% per quarter for both IDU-IE and non–IDU-IE cases following reporting (OR 0.98, 95% CI 0.97–0.99).ConclusionsInitiating public reporting was associated with a significant decrease in valve surgery for all IE cases, regardless of IDU status, and a reduction in-hospital mortality for patients with IE. Patients with IE may have less access to surgery as a consequence of public reporting. To understand how reduced valve surgery impacts overall mortality, future studies should examine the postdischarge mortality rate.
Li K, Xu Y, Liu L, et al.
Manuello Roxane, Ruimy Raymond, Boileau Pascal, Trojani Christophe, Courjon Johan
We red with a great interest the review of Depypere et al. on pathogenesis and management of fracture-related infection (FRI) , Enterobacteriaceae are described as the third microorganisms involved in FRI and the prevention section of the paper report the protective effect of early antibiotic prophylaxis administration. The second international consensus meeting on musculoskeletal infections mentioned that additional coverage for gram-negative organisms should be considered for patients with high-energy open fractures but does not recommend any specific drug .
Schimmel J, Haessler S, Imrey P, et al.
AbstractBackgroundThe Infectious Disease Society of America recommends pneumococcal urinary antigen testing (UAT) when identifying pneumococcal infection would allow for antibiotic de-escalation. However, the frequencies of UAT and subsequent antibiotic de-escalation are unknown.MethodsWe conducted a retrospective cohort study of adult patients admitted with community-acquired or healthcare-associated pneumonia to 170 US hospitals in the Premier database from 2010-2015, to describe variation in UAT use, associations of UAT results with antibiotic de-escalation, and associations of de-escalation with outcomes.ResultsAmong 159,894 eligible admissions, 24,757 (15.5%) included UAT performed (18.4% of ICU and 15.3% of non-ICU patients). Among hospitals with ≥100 eligible patients, UAT testing proportions ranged from 0%-69%. Compared to patients with negative UAT, 7.2% with positive UAT more often had a positive S. pneumoniae culture (25.4% vs. 1.9%, p
In their interrupted time series analysis of a sample of US inpatient hospitalizations of injection drug use (IDU) related infectious endocarditis (IE) (IDU-IE) and non-IDU IE before and after public reporting of aortic valve (AV) surgery outcomes was instituted in 2013, Kimmel SD et al’s current study published in this issue of Clinical Infectious Diseases identified some important findings that have relevant implications from a public health standpoint. In this evaluation, hospital admissions for IE, AV surgeries, and in-hospital mortality among persons hospitalized with IDU-IE were compared to those with non-IDU IE in a time period before (2010–2012) the national reporting system was instituted in 2013 to after this policy was enacted (August of 2013–2015). This study utilized International Classification of Diseases, 9th Revision (ICD-9) coding data from the National Inpatient Sample (NIS) database. The importance of undertaking this analysis is underscored by dramatic increases in IDU-related infections  in the setting of ever-worsening epidemics of opioid [2, 3] and non-opioid overdoses  in the United States. As highlighted by Kimmel et al, concern has been raised in the medical community that because of a rise in bacterial and fungal infective endocarditis diagnoses among persons who use drugs (PWUD) [5, 6], surgeons may be less inclined to perform surgery due to concern for ongoing drug use and risk of reinfection after valve surgery and other biases [7, 8]. Thus evaluating the potential negative impact of public reporting of IDU-IE on the ability to obtain life-saving valve surgery is important to understand.
van De Ven N, Pozniak A, Levi J, et al.
AbstractBackgroundThe Botswana Tsepamo study reported neural tube defects (NTDs) in 4 of 426 (0.94%) infants of women receiving preconception dolutegravir (DTG) antiretroviral therapy (ART) vs 14 of 11 300 (0.12%) receiving preconception non-DTG ART. Data are needed to investigate this potential safety signal. Clinicians, patients, and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance databases. Data from ADRs reported to various pharmacovigilance databases were searched for NTDs.MethodsFour pharmacovigilance databases (World Health Organization [WHO] VigiAccess; United Kingdom Medicines Health Regulatory Authority [UK MHRA]; European Medicines Agency [EMA] EudraVigilance; US Food and Drug Administration Adverse Event Reporting System [FAERS]) with online data availability were analyzed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz). Reports in the system organ class “congenital or familial disorders” were searched for NTDs.ResultsNTDs have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases (WHO VigiAccess, 116 reactions; UK MHRA, 8 cases; EMA EudraVigilance, 20 cases; FAERS, 44 cases). Six NTDs were identified for DTG across the pharmacovigilance databases. Cases were very hard to interpret, given the lack of clear denominators.ConclusionsPharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.Neural tube defects have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases. Safety reports were inconsistent between databases and very hard to interpret
Hidalgo, L., de Been, M., Rogers, M. R. C., Schürch, A. C., Scharringa, J., van der Zee, A., Bonten, M. J. M., Fluit, A. C.
Objectives. A large OXA-48 outbreak in the Netherlands involved the spread of OXA-48producing Enterobacteriaceae among at least 118 patients, suggesting horizontal transfer of this resistance gene through one or more plasmids. Elucidating transmission dynamics of resistance plasmids is hampered by the low resolution of classic typing methods. This study aimed to investigate the molecular epidemiology of plasmids carrying OXA-48 carbapenemase using a next-generation sequencing approach.Methods. A total of 68 OXA-48-producing Enterobacteriaceae isolated from the hospital outbreak, as well as 22 non-outbreak related OXA-48-producing Enterobacteriaceae from the Netherlands, Libya and Turkey were selected. Plasmids were sequenced using the Illumina Miseq platform, and read sets were assembled and analysed.Results. In all plasmids blaOXA-48 was embedded in transposon Tn1999.2 and located on a ca. 62 kb IncL/M conjugative plasmid in 14 different species. There were a maximum of 2 SNPs (single nucleotide polymorphisms) between the core sequence alignment of all plasmids. Closely related sequence variants of this plasmid were detected in non-outbreak isolates from the Netherlands and other countries. Thirty-one of 89 OXA-48-producing isolates also harboured blaCTX-M-15, which was not located on the blaOXA-48-carrying plasmid. Sequencing of four plasmids harbouring blaCTX-M15 revealed extensive plasmid heterogeneity.Conclusions. A ca. 62 kb plasmid was responsible for the OXA-48 outbreak in a Dutch hospital. Our findings provide strong evidence for both within-host inter-species and between host dissemination of plasmid-based OXA-48 during a nosocomial outbreak. These findings exemplify the complex epidemiology of carbapenemase producing Enterobacteriaceae (CPE).
Kempker, R. R., Alghamdi, W. A., Al-Shaer, M. H., Burch, G., Peloquin, C. A.
Tuberculosis (TB) and hepatitis C virus (HCV) infection are both major public health problems. Despite high rates of co-infection there is scarce literature addressing the convergence of the two diseases. One particularly unexplored area is the potential for simultaneous treatment of TB and HCV which would allow for leveraging an extensive global TB treatment infrastructure to help scale up HCV treatment. We review the drug metabolism of anti-TB and HCV drugs and the known and potential drug-drug interactions between recommended HCV regimens and individual anti-TB drugs. Rifampin is the only anti-TB drug to have been formally studied for potential drug interactions with anti-HCV direct-acting antivirals (DAAs) and existing data precludes these combinations. However, based on known pathways of drug metabolism and enzyme effects, the combination of HCV DAA regimens with all other anti-TB drugs may be feasible. Pharmacokinetic studies are needed next to help move co treatment regimens forward for clinical use among patients coinfected with TB and HCV.
Chen, C., Wu, X.-T., He, Q., Chen, L., Cui, C.-Y., Zhang, Y., Chen, S.-H., Liao, X.-P., Liu, Y.-H., Sun, J.
Recently, a novel plasmid-mediated tigecycline resistance mechanism, Tet(X4), has raised a global antimicrobial resistance concern (1, 2)....
Bidaud, A. L., Botterel, F., Chowdhary, A., Dannaoui, E.
Candida auris is an emerging, multidrug resistant pathogen, responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-Candida drug, but which cannot be used as a monotherapy because of the risk of development of resistant mutants during treatment. It is therefore noteworthy to test possible combinations with flucytosine that may have a synergistic interaction. In this study, we determined the in vitro interaction between flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15 C. auris isolates. The MIC range (Gmean) of flucytosine, amphotericin B, micafungin and voriconazole were 0.125 to 1 μg/mL (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml) and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01 and 0.5 to 1.06 for the combination of flucytosine with amphotericin B, micafungin and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. Combination of flucytosine with amphotericin B or micafungin may be relevant for the treatment of C. auris infections.
Snow, D. M., Riling, K., Kimbler, A., Espinoza, Y., Wong, D., Pham, K., Martinez, Z., Kraus, C. N., Conrad, F., Garcia-Rodriguez, C., Cobb, R. R., Marks, J. D., Tomic, M. T.
Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as Tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A-G), which differ between 35% to 68% in amino acid sequence, necessitates the development of serotype specific countermeasures. We present results of a Phase 1 clinical study of an anti-toxin to BoNT serotypes C and D, NTM-1634, which consists of an equimolar mixture of four fully human IgG1 monoclonal antibodies (mAbs), each binding to non-overlapping epitopes on BoNT serotypes C and D resulting in potent toxin neutralization in rodents. This first-in-human study evaluated the safety and pharmacokinetics of escalating doses of NTM-1634 administered intravenously to healthy adults (NCT03046550). Three cohorts of eight healthy subjects received a single intravenous dose of NTM-1634 or placebo at 0.33 mg/kg, 0.66 mg/kg or 1 mg/kg. Follow-up examinations and pharmacokinetic evaluations were continued up to 121 days post-infusion. Subjects were monitored using physical examinations, hematology and chemistry blood tests, and electrocardiograms. Pharmacokinetic parameters were estimated using noncompartmental methods. The results demonstrated that the materials were safe and well-tolerated with the expected half-lives for human mAbs and with minimal anti-drug antibodies detected over the dose ranges and duration of the study.
Iwanowski, P., Bhatia, A., Gupta, M., Patel, A., Chavan, R., Yeole, R., Friedland, D.
Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, Phase 1 studies. In the first-in-human study, single-ascending oral doses of nafithromycin (100 to 1200 mg) were administered to subjects under fasted or fed condition, with effects of food on bioavailability of nafithromycin studied at the dose levels of 400 and 800 mg. In the second study, multiple-ascending oral doses of 600, 800, or 1000 mg of nafithromycin were administered once daily for 7 days under a fed condition. Nafithromycin was generally well tolerated at all doses. No serious or severe adverse events were observed. The mean maximum plasma concentration (Cmax) ranged from 0.099 to 1.742 mg/L, and the area under the concentration-time curve from time zero to time t (AUC0–t) ranged from 0.54 to 22.53 h⋅mg/L. Nafithromycin plasma AUC0-t increased approximately 1.2-fold under fed compared to fasted condition. In the multiple-dose study, the Day 7 nafithromycin Cmax ranged from 1.340 to 2.987 mg/L and the AUC over the final dosing interval (AUC0-24) ranged from 13.48 to 43.46 h⋅mg/L. The steady state was achieved after 3 days for the 600 mg and 800 mg dose cohorts and after 4 days for the 1000 mg cohort. Under both single- and multiple-dosing regimens, plasma exposure to nafithromycin appeared to increase more than dose-proportionally. Nafithromycin showed moderate accumulation on Day 7 of dosing. The human pharmacokinetic profile, safety and tolerability data support further development of nafithromycin.
Berthaud, R., Benaboud, S., Hirt, D., Genuini, M., Oualha, M., Castelle, M., Briand, C., Artru, S., Norsa, L., Boyer, O., Foissac, F., Bouazza, N., Treluyer, J.-M.
Methicillin-resistant staphylococcal infections are a global burden. Area under the serum concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio is the pharmacokinetic (PK) parameter that best predicts vancomycin efficacy. Its therapeutic range is narrow, difficult to achieve because of a wide intersubject variability, especially in children, and is not routinely targeted since the AUC is rarely available. We investigated if an early Bayesian dose adjustment would increase the rate of vancomycin target attainment, in the first 24 hours of treatment (H24), in children.We conducted a single-centre randomized controlled trial in 4 pediatric departments of Necker-Enfants Malades hospital (Paris, France). Patients aged 3 months to 17 years for whom intravenous vancomycin was started were eligible and randomized in a 1:1 ratio: routine care were compared with an early vancomycin therapeutic drug monitoring (3h after treatment initiation) followed by an early Bayesian dose adjustment using a previously published population-based PK model that included age, bodyweight and serum creatinine as covariates. The primary outcome was the proportion of patients of each group achieving vancomycin therapeutic range at H24, defined by AUC0-24/MIC≥400 and AUC0-24 ≤800mg-h/L.Ninety-nine patients were enrolled: 49 were randomized to the Bayesian group and 50 to the control group. Modified intention-to-treat analysis included 82 patients: 85% of Bayesian group patients achieved H24 vancomycin target versus 57% of control group patients (p=0.007) with no difference regarding iatrogenic events. Early Bayesian dose adjustment increased the proportion of children achieving vancomycin target at H24, which may improve clinical outcomes of methicillin-resistant staphylococcal infections.
Alamiri, F., Riesbeck, K., Hakansson, A. P.
HAMLET is a protein-lipid complex derived from human milk that was first described for its tumoricidal activity. Later studies showed that HAMLET also has direct bactericidal activity against select species of bacteria, with highest activity against Streptococcus pneumoniae. Additionally, HAMLET in combination with various antimicrobial agents can make a broader range of antibiotic-resistant bacterial species sensitive to antibiotics. Here, we show that HAMLET has direct antibacterial activity not only against pneumococci, but also against Streptococcus pyogenes (GAS) and Streptococcus agalactiae (GBS). Analogous to pneumococci, HAMLET-treatment of GAS and GBS resulted in depolarization of the bacterial membrane followed by membrane permeabilization and death that could be inhibited by calcium and sodium transport inhibitors. Treatment of clinical antibiotic-resistant isolates of S. pneumoniae, GAS, and GBS with sublethal concentrations of HAMLET in combination with antibiotics decreased the minimal inhibitory concentrations of the respective antibiotic into the sensitive range. This effect could also be blocked by ion transport inhibitors, suggesting that HAMLET's bactericidal and combination treatment effects used similar mechanisms. Finally, we show that HAMLET potentiated the effects of erythromycin against erythromycin-resistant bacteria more effectively than it potentiated killing by penicillin G of bacteria resistant to penicillin G. These results show for the first time that HAMLET effectively kills three different species of pathogenic Streptococci using similar mechanisms and also potentiate the activity of macrolides and lincosamides more effectively than combination treatment with beta-lactams. These findings suggest a potential therapeutic role for HAMLET in repurposing antibiotics currently causing treatment failures in patients.
Clarke, R. S., Bruderer, M. S., Ha, K. P., Edwards, A. M.
Co-trimoxazole (SXT) is a combination therapeutic that consists of sulfamethoxazole and trimethoprim that is increasingly used to treat skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the use of SXT is limited to the treatment of low-burden, superficial S. aureus infections and its therapeutic value is compromised by the frequent emergence of resistance. As a first step towards the identification of approaches to enhance the efficacy of SXT, we examined the role of bacterial DNA repair in antibiotic susceptibility and mutagenesis. We found that mutants lacking the DNA repair complex RexAB had a modest 2-fold lower SXT MIC than wild-type strains but were killed 50-5000-fold more efficiently by the combination antibiotic at the breakpoint concentration. SXT-mediated DNA damage occurred via both thymidine limitation and the generation of reactive oxygen species, and triggered induction of the SOS response in a RexAB-dependent manner. SOS induction was associated with a 50% increase in the mutation rate, which may contribute to emergence of resistant strains during SXT therapy. In summary, this work determined that SXT caused DNA damage in S. aureus via both thymidine limitation and oxidative stress, which was repaired by the RexAB complex, leading to induction of the mutagenic SOS response. Small molecule inhibitors of RexAB could therefore have therapeutic value by increasing the efficacy of SXT and decreasing the emergence of drug-resistance during treatment of infections caused by S. aureus.
Wamae, K., Okanda, D., Ndwiga, L., Osoti, V., Kimenyi, K. M., Abdi, A. I., Bejon, P., Sutherland, C., Ochola-Oyier, L. I.
Antimalarial drug resistance is a substantial impediment to malaria control. The spread of resistance has been described using genetic markers which are important epidemiological tools. We carried out a temporal analysis of changes in allele frequencies of 12 drug resistance markers over two decades of changing antimalarial drug policy in Kenya. We did not detect any of the validated kelch 13 (k13) artemisinin resistance markers, nonetheless, a single k13 allele, K189T, was maintained at a stable high frequency (>10%) over time. There was a distinct shift from chloroquine resistant transporter (crt)-76, multi-drug resistant gene 1 (mdr1)-86 and mdr1-1246 chloroquine (CQ) resistance alleles to a 99% prevalence of CQ sensitive alleles in the population, following the withdrawal of CQ from routine use. In contrast, the dihydropteroate synthetase (dhps) double mutant (437G and 540E) associated with sulfadoxine-pyrimethamine (SP) resistance was maintained at a high frequency (>75%), after a change from SP to artemisinin combination therapies (ACTs). The novel cysteine desulfurase (nfs) K65 allele, implicated in resistance to lumefantrine in a West African study, showed a gradual significant decline in allele frequency pre- and post-ACT introduction (from 38% to 20%), suggesting evidence of directional selection in Kenya, potentially not due to lumefantrine. The high frequency of CQ-sensitive parasites circulating in the population suggests that the re-introduction of CQ in combination therapy for the treatment of malaria can be considered in the future. However, the risk of a re-emergence of CQ resistant parasites circulating below detectable levels or being reintroduced from other regions remains.
Nagy, T. A., Quintana, J. L. J., Reens, A. L., Crooks, A. L., Detweiler, C. S.
Salmonella enterica are natural bacterial pathogens of humans and animals that cause systemic infection or gastroenteritis. During systemic infection, Salmonella generally reside within professional phagocytes, typically macrophages, whereas gastroenteritis is caused by infection of epithelial cells. We are only beginning to understand which host pathways contribute to Salmonella survival in particular cell types. We therefore sought to identify compounds that perturb Salmonella-host interactions using a chemical genetics approach. We found one small molecule, D61, that reduces Salmonella load in cell-line and primary macrophages but has no effect on Salmonella growth in epithelial cells or rich medium. We determined that in macrophages D61 induces LC3II, a marker of the autophagy pathway, and promotes aggregation of LC3II near Salmonella. We found that D61 antibacterial activity depends on the VPS34 complex and on ATG5. D61 also reduced Salmonella load in the spleens and livers of infected mice. Lastly, we demonstrate that D61 antibacterial activity in macrophages is synergistic with the antibiotic chloramphenicol, but that this synergy is largely independent of the known autophagy-stimulating activity of chloramphenicol. Thus, a small molecule has anti-bacterial activity specifically in macrophages and mice based on the promotion of bacterial degradation by autophagy.Importance Autophagy is a conserved cellular response to metabolic stress and to invading pathogens. For many pathogens, including Salmonella, autophagy can play a detrimental or beneficial role during infection depending on the cellular context. We combined chemical genetics with single cell analyses and murine infection to dissect host-pathogen interactions. We identified a small molecule that reduces bacterial load in macrophages by increasing autophagic flux. This compound also reduces bacterial colonization of tissues in infected mice. These observations demonstrate the potential therapeutic utility of stimulating autophagy in cells and animals to curb infection.
Petraitis, V., Petraitiene, R., Valdez, J. M., Pyrgos, V., Lizak, M. J., Klaunberg, B. A., Kalasauskas, D., Basevicius, A., Bacher, J. D., Benjamin, D. K., Hope, W. W., Walsh, T. J.
Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeability and low cerebrospinal fluid (CSF) concentrations, but is effective in treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro BBB model was serially infected with C. albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml were then provided, vascular and CNS compartments were sampled 4h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB 1 mg/kg or LAMB 5 mg/kg, and were euthanized after 1, 3, 6 and 24h. Evans blue solution (2%) 2 ml/kg administered IV one hour prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using UPLC. For selected rabbits, MRI scans performed on days 1-7 postinoculation were acquired before and after IV bolus Gd-DTPA at 15min intervals through 2h post-injection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24h of exposure (P=0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue (P≤0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low CSF concentrations.
Lepak, A. J., Zhao, M., Andes, D. R.
WCK 5222 is a combination of cefepime and the novel β-lactam enhancer (BLE) zidebactam. Zidebactam has a dual mechanism of action involving high-affinity penicillin binding protein (PBP) 2 binding as well as inhibition of Ambler class A, and C, enzymes. In the current study, we evaluated the effect of zidebactam on the cefepime pharmacodynamic target time above MIC (T>MIC) exposure required for efficacy against a diverse group of carbapenem-resistant Enterobacteriaceae (CRE) secondary to MBL-production. Plasma and ELF pharmacokinetic (PK) studies were performed for both cefepime (6.25, 25, and 100 mg/kg) and zidebactam (3.125, 12.5, and 50 mg/kg) after subcutaneous administration to mice. Only total drug was considered as protein binding is MIC. The results were modelled to evaluate the relationship between cefepime T>MIC, when zidebactam was co-administered, and therapeutic effect. The results revealed a strong association between T>MIC and effect (R2 0.82). Net stasis in organism burden occurred at cefepime T>MIC exposures of only 18%. A 1-log kill endpoint was demonstrated for the group of organisms at approximately 31% T>MIC. These target exposures for stasis and 1-log kill are much lower than previously observed cephalosporin monotherapy PK/PD targets.
Samodelov, S. L., Visentin, M., Gai, Z., Häusler, S., Kullak-Ublick, G. A.
The polymixin colistin represents a last resort antibiotic for multidrug resistant infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during colistin treatment in order to pinpoint early signs of injury and minimise long-term renal dysfunction. To facilitate this, a mouse model of colistin-induced nephrotoxicity was used to uncover novel early markers of colistin-induced DIKI. Increased urinary levels of kidney injury molecule 1 (Kim-1) as well as glycosuria were observed in colistin-treated mice, where alterations of established clinical markers of acute kidney injury (serum creatinine and albuminuria) and emerging markers such as cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of colistin with renal glucose reabsorption was ruled out by a cis-inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and protein quantification by western blotting showed a marked reduction in the protein amount of sodium-glucose transporter 2 (Sglt2), the main kidney glucose transporter, in renal tissue from colistin-treated mice in comparison to control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in ex vivo glucose uptake when compared to BBMV isolated from control kidneys. These findings support pathology observations of colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of glycosuria as a sensitive, specific, and accessible marker of DIKI during colistin therapy.
Clancy, C. J., Nguyen, M. H.
New antibiotics with activity against carbapenem-resistant Enterobacteriaceae (CRE) improve outcomes of CRE-infected patients. However, companies developing these drugs have faced financial difficulties. Sales of ceftazidime-avibactam, meropenem-vaborbactam and plazomicin in the United States (US) totaled $101 million from February 2018-January 2019. We estimate the current annual US market for new anti-CRE antibiotics is $289 million (range: $169-$439 million). Without new antibiotic development models and/or reimbursement reform, the majority of anti-CRE drugs will be commercially inviable.
Kordalewska, M., Lee, A., Zhao, Y., Perlin, D. S.
Accurate and rapid assessment of Candida auris antifungal drug resistance is crucial for effective infection prevention and control actions, and patient management. Here, performance of a molecular diagnostic platform, enabling rapid identification of FKS1 and ERG11 mutations conferring echinocandin and azole resistance, respectively, was evaluated on a panel of clinical skin swabs. Gene sequencing and antifungal susceptibility testing were used as "gold standard". All swabs were correctly categorized as harboring wild-type or mutant C. auris.
Chen, I. H., Kidd, J. M., Abdelraouf, K., Nicolau, D. P.
Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of β-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (2 g Q8H 3 h infusion) and ceftazidime (2 g Q8H 2 h infusion) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/mL and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; mean bacterial reduction at 24 h was -2.67 ± 0.68 log10CFU/thigh with ≥ 2 log-reduction achieved in 21 isolates (87.5%) and ≥ 1 log-reduction achieved in the remaining three isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced mean bacterial reduction of -1.38 ± 1.49 log10CFU/thigh among 10 ceftazidime-susceptible isolates and mean bacterial growth of 0.64 ± 0.79 log10CFU/thigh among 14 ceftazidime-non-susceptible isolates. While ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-non-susceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.
Kalligeros, M., Karageorgos, S. A., Shehadeh, F., Zacharioudakis, I. M., Mylonakis, E.
Concomitant use of vancomycin plus piperacillin/tazobactam (TZP) has been associated with increased risk of acute kidney injury (AKI) in hospitalized adults. In this systematic review and meta-analysis, we searched PubMed and EMBASE for pediatric studies examining this hypothesis, with reference to vancomycin monotherapy or in combination with another beta-lactam antibiotic. Out of 1381 non-duplicate studies, 10 met our inclusion criteria. We performed a random effects meta-analysis, based on crude odds ratios, and we accounted for both quality of included studies and publication bias. In primary analysis, concomitant vancomycin and TZP use yielded a statistically significant association with the development of AKI. More specifically, children with AKI had higher odds to have been exposed to vancomycin plus TZP, in comparison with vancomycin monotherapy (OR 8.15; 95% CI: 3.49-18.99), or vancomycin plus any other beta-lactam antibiotic (OR 3.48; 95% CI: 2.71-4.46). Based on the results of the Newcastle Ottawa Scale quality assessment, a secondary analysis including only higher quality studies (6 out of 10 studies) yielded again higher odds of exposure to vancomycin plus TZP, compared to vancomycin plus another beta-lactam antibiotic (OR 3.76; 95% CI: 2.56-5.51). Notably, even after controlling for possible publication bias our results remained statistically significant (OR 3.09; 95% CI: 2.30-4.14). In conclusion, the concomitant use of vancomycin and TZP could be associated with AKI development and the clinical significance of this potential association needs to be studied further in the pediatric population.
Belveyre, T., Guerci, P., Pape, E., Thilly, N., Hosseini, K., Brunaud, L., Gambier, N., Meistelman, C., Losser, M.-R., Birckener, J., Scala-Bertola, J., Novy, E.
Background: The optimal dose of cefoxitin for antibiotic prophylaxis in obese patients remains uncertain. We evaluated the adequacy of a 4-gram dosing regimen of cefoxitin against the most frequent pathogens that infect patients undergoing bariatric surgery.Methods: This observational prospective study included obese patients who required bariatric surgery and a 4-gram dose of cefoxitin as an antibiotic prophylaxis. Serum concentrations were measured during surgery (incision, wound closure and in case of reinjection). The pharmacokinetic/pharmacodynamic (PK/PD) target was to obtain free cefoxitin concentrations above 4x MIC, from incision to wound closure (100% fT>4xMIC). The targeted MIC was based on the worst-case scenario (the highest ECOFF value of Staphylococcus aureus, Enterobacteriaceae and anaerobic bacteria). The secondary outcomes were the factors related to underdosage.Results: Two hundred patients were included. The mean age of the patients was 46 (±12) years-old, and the mean BMI was 45.8 (±6.9) kg/m2. Bypass surgery was the preferred technique (84%). The percentages of patients who met the PK/PD target (100% fT>4xMIC) of cefoxitin were 37.3%, 1.1% and 0% for S. aureus, Enterobacteriaceae and anaerobic bacteria, respectively. BMIs below 50 kg/m2 (OR 0.29, 95% CI [0.11-0.75], P = 0.0107) and a shorter duration of surgery (OR 0.97, 95% CI [0.95-0.99], P = 0.004) were associated with reaching the target concentrations.Conclusions: In obese patients undergoing bariatric surgery, a regimen of 4 grams of cefoxitin led to an inadequate coverage for most common pathogens. A longer surgery duration and BMI over 50 kg/m2 increase the risk of underdosage.
Jade Feller, Brian.C. Lund, Eli.N. Perencevich, Bruce Alexander, Brett Heintz, Brice Beck, Rajeshwari Nair, Michihiko Goto, Daniel.J. Livorsi
Antimicrobial stewardship programs have focused on reducing inappropriate inpatient antimicrobial prescribing, but several small studies have found a large portion of antimicrobial exposure occurs immediately after hospital discharge. In this study, we describe the prescribing of oral antimicrobials at hospital discharge across an integrated national healthcare system. At the hospital-level, we also compare total inpatient antimicrobial use and post-discharge oral antimicrobial use.
Intestinal schistosomiasis is highly endemic in Tanzania and mass drug administration (MDA) using praziquantel is the mainstay of the control program. However, the MDA program covers only school aged children and does not include neither adult individuals nor other public health measures. The Ijinga schistosomiasis project examines the impact of an intensified treatment protocol with praziquantel MDA in combination with additional public health interventions. It aims to investigate the feasibility of eliminating intestinal schistosomiasis in a highly endemic African setting using an integrated community-based approach. In preparation of this project, we report about baseline data on S.mansoni prevalence, intensity of infection, related hepatosplenic morbidities and their associated factors.
A cross sectional study was conducted among 930 individuals aged 1–95 years living at Ijinga Island, north-western Tanzania in September 2016. Single stool and urine samples were collected from each study participant and processed using Kato Katz (KK) technique and point-of-care Circulating Cathodic (POC-CCA) antigen test for detection of S.mansoni eggs and antigen respectively. Ultrasonographical examination for S.mansoni hepatosplenic morbidities was done to all participants. For statistical analyses Fisher’s exact test, chi-square test, student-t-test, ANOVA and linear regression were used where applicable.
Overall based on KK technique and POC-CCA test, 68.9% (95%CI: 65.8–71.8) and 94.5% (95%CI: 92.8–95.8) were infected with S.mansoni. The overall geometrical mean eggs per gram (GMepg) of faeces was 85.7epg (95%CI: 77.5–94.8). A total of 27.1, 31.2 and 51.9% of the study participants had periportal fibrosis (PPF-grade C-F), splenomegaly and hepatomegaly. Risk factors for PPF were being male (aRR = 1.08, 95%CI: 1.02–1.16, P
Acinetobacter baumannii is an increasingly worrying organism in the healthcare setting, due to its multidrug resistance and persistence. Prolonged hospitalisation, immunocompromised patients and excessive antibiotic exposure all contribute to increasing the risk of A. baumannii infections, which makes cancer patients a significant risk group. This study aims to investigate the dissemination of A. baumannii at the National Cancer Institute (NCI) in Cairo – Egypt.
All bacterial isolates were typed using Multi-locus Sequence Typing (MLST) to characterise the epidemiology of isolates. The intrinsic OXA-51-like, and the acquired carbapanemases OXA-23, − 24/40, − 58, NDM, IMP, and VIM were also amplified and sequenced to genetically identify mechanisms of carbapenem resistance.
MLST results show a high degree of multi-clonal dissemination, with 18 different Sequence Types (STs) identified, including 5 novel. The majority of isolates belonged to International Clone (IC) 2, and carbapenem resistance was detected in 93% of isolates and mediated by blaOXA-23, blaOXA-58, blaNDM-1 and blaVIM-1. We also report the presence of a resistant ST732 (OXA-378) which has been previously identified in migratory birds.
Multiple highly resistant clones were identified in a Cancer hospital in Cairo. It is vital that clinicians and healthcare workers are aware of the population of A. baumannii present in order to have appropriate treatment and infection control practices.
Whether past history of solid stage I/II inactive cancer has an impact on 28-day mortality of sepsis remains unclear. We aimed to determine the impact of history of stage I or II solid tumor malignancy in complete remission the last 3 years on sepsis outcome.
Using the database of the Hellenic Sepsis Study Group from 1553 patients with sepsis admitted in the ICU, 83 patients with sepsis by Sepsis-3 definition with past-history of stage I/II inactive solid malignancy the last 3 years were depicted. A comparator group of 83 patients fully matched for age, severity, type of infection and comorbidities was selected by propensity score matching.
Mortality after 28 days was 37.3% in the comparator group and 54.2% in the solid tumor stage I/II group (odds ratio for death 1.98; p: 0.030). Following step-wise forward Cox regression analysis, septic shock (hazard ratio 1.80), acute renal injury (hazard ratio 2.06), history of coronary heart disease (hazard ratio 0.36) and history of stage I/II solid tumor malignancy (hazard ratio 1.79) were the only independent variables associated with 28-day mortality. Serum levels of procalcitonin and of soluble urokinase plasminogen activator receptor were similar between the two groups of comparisons.
Past history of stage I/II solid malignancy is an independent risk factor for unfavorable outcome from sepsis the first 28 days.
Many gaps in the burden of resistant pathogens exist in endemic areas of low- and middle-income economies, especially those endemic for carbapenem resistance. The aim of this study is to evaluate risk factors for carbapenem-resistance, to estimate the association between carbapenem-resistance and all-cause 30-day mortality and to examine whether mortality is mediated by inappropriate therapy.
A case-control and a cohort study were conducted in one tertiary-care hospital in Medellín, Colombia from 2014 to 2015. Phenotypic and genotypic characterization of isolates was performed. In the case-control study, cases were defined as patients infected with carbapenem-resistant K. pneumoniae (CRKP) and controls as patients infected with carbapenem-susceptible K. pneumoniae (CSKP). A risk factor analysis was conducted using logistic regression models. In the cohort study, the exposed group was defined as patients infected with CRKP and the non-exposed group as patients infected with CSKP. A survival analysis using an accelerated failure time model with a lognormal distribution was performed to estimate the association between carbapenem resistance and all-cause 30-day-mortality and to examine whether mortality is mediated by inappropriate therapy.
A total of 338 patients were enrolled; 49 were infected with CRKP and 289 with CSKP. Among CRKP isolates CG258 (n = 29), ST25 (n = 5) and ST307 (n = 4) were detected. Of importance, every day of meropenem (OR 1.18, 95%CI 1.10–1.28) and cefepime (OR 1.22, 95%CI 1.03–1.49) use increase the risk of carbapenem resistance. Additional risk factors were previous use of ciprofloxacin (OR 2.37, 95%CI 1.00–5.35) and urinary catheter (OR 2.60, 95%CI 1.25–5.37). Furthermore, a significant lower survival time was estimated for patients infected with CRKP compared to CSKP (Relative Times 0.44, 95%CI 0.24–0.82). The strength of association was reduced when appropriate therapy was included in the model (RT = 0.81 95%CI 0.48–1.37).
Short antibiotic courses had the potential to reduce the selection and transmission of CRKP. A high burden in mortality occurred in patients infected with CRKP in a KPC endemic setting and CRKP leads to increased mortality via inappropriate antibiotic treatment. Furthermore, dissemination of recognized hypervirulent clones could add to the list of challenges for antibiotic resistance control.
International Congress on Infectious Diseases (ICID) 2020
Kuala Lumpur, Malaysia
20.02.2020 - 23.02.2020
Dansk Selskab for Intern Medicin (DSIM) årsmøde og overrækkelse af Hagedorn prisen 2020
Novo Nordisk Fonden, Tuborg Havnevej 19, 2900 Hellerup
Conference on Retroviruses and Opportunistic Infections (CROI) 2020
Boston, Massachusetts, USA
8.03.2020 - 11.03.2020
Når CROI går i fisk - med transmissioner fra CROI 2020
10.03.2020 - 11.03.2020
World TB day 2020
National handlingsplan for antibiotika til mennesker (2017)
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Sustained reduction in third-generation cephalosporin usage in adult inpatients following introduction of an antimicrobial stewardship program in a large urban hospital in Malawi
15.02.2020Clinical Infectious Diseases Advance Access
Septoplasty for nasal obstruction
Complicit silence in medical malpractice
Preventing teenage pregnancies in Brazil
Appropriate care for pregnant women in Ebola outbreaks
Hvad tænker Professor Jens Lundgren om"Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV."?
Hvad mener Professor Troels Lillebæk om artiklen"The global prevalence of latent tuberculosis: a systematic review and meta-analysis."?
Hvad tænker Professor Lars Østergaard om"Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial."?
Hvad mener Professor Thomas Benfield om artiklen"Oral versus Intravenous Antibiotics for Bone and Joint Infection."?
Hvorfor synes Professor Niels Obel, at du bør læse"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
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