scholarly journals Prolonged Antibiotic Treatment Generates a Fluoroquinolone Resistant Gut Microbiome and Collateral Multi-Drug Resistance

2018 ◽  
Author(s):  
Vadim Dubinsky ◽  
Leah Reshef ◽  
Nir Bar ◽  
Keren Rabinowitz ◽  
Lihi Godny ◽  
...  

One Sentence SummaryThe majority of the gut microbiome develops antibiotic resistance via point-mutations in addition to collateral resistance whereas its density is only moderately decreased following long-term antibiotic treatment.ABSTRACTAntibiotic resistance in bacterial pathogens represents a growing threat to modern medicine. Limitation of lengthy and broad-spectrum antibacterial treatment regimens is generally recommended. Nevertheless, some conditions may require prolonged antibiotic treatment. The effects of such treatments on bacterial communities, specifically their resistome, is yet unknown. Here, we followed a unique cohort of patients with ulcerative colitis who underwent total large bowel resection and the formation of an ileal pouch from their normal small bowel. The majority of these patients tend to develop inflammation of this previously normal small bowel, known as “pouchitis”. Pouchitis is commonly treated with repeated or prolonged courses of broad-spectrum antibiotics. By using metagenomics of faecal samples obtained longitudinally from patients treated with antibiotics for prolonged periods, we hereby show that the majority of their gut commensal bacteria develop antibiotic resistance by point-mutations. In addition, some bacterial species had acquired multidrug resistance loci with genes that confer resistance to the drug used in the treatment (ciprofloxacin) but co-localized with genes encoding extended-spectrum β-lactamases and other resistance-conferring enzymes. We further show that bacterial density in faecal samples is only modestly reduced despite the long-term antibiotic treatment, thereby questioning the current rationale that antibiotic efficacy in treating pouch inflammation is due to the reduction of bacterial load. This study reveals the impact and dynamics of prolonged antibiotic treatment on human gut microbiomes and provides insights that may guide the development of future IBD therapies. It also provides novel insights into bacterial community recovery after cessation of such prolonged treatment, and highlights the increased risk of spreading mobile antibiotic resistance.

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Egija Zaura ◽  
Bernd W. Brandt ◽  
M. Joost Teixeira de Mattos ◽  
Mark J. Buijs ◽  
Martien P. M. Caspers ◽  
...  

ABSTRACT Due to the spread of resistance, antibiotic exposure receives increasing attention. Ecological consequences for the different niches of individual microbiomes are, however, largely ignored. Here, we report the effects of widely used antibiotics (clindamycin, ciprofloxacin, amoxicillin, and minocycline) with different modes of action on the ecology of both the gut and the oral microbiomes in 66 healthy adults from the United Kingdom and Sweden in a two-center randomized placebo-controlled clinical trial. Feces and saliva were collected at baseline, immediately after exposure, and 1, 2, 4, and 12 months after administration of antibiotics or placebo. Sequences of 16S rRNA gene amplicons from all samples and metagenomic shotgun sequences from selected baseline and post-antibiotic-treatment sample pairs were analyzed. Additionally, metagenomic predictions based on 16S rRNA gene amplicon data were performed using PICRUSt. The salivary microbiome was found to be significantly more robust, whereas the antibiotics negatively affected the fecal microbiome: in particular, health-associated butyrate-producing species became strongly underrepresented. Additionally, exposure to different antibiotics enriched genes associated with antibiotic resistance. In conclusion, healthy individuals, exposed to a single antibiotic treatment, undergo considerable microbial shifts and enrichment in antibiotic resistance in their feces, while their salivary microbiome composition remains unexpectedly stable. The health-related consequences for the gut microbiome should increase the awareness of the individual risks involved with antibiotic use, especially in a (diseased) population with an already dysregulated microbiome. On the other hand, understanding the mechanisms behind the resilience of the oral microbiome toward ecological collapse might prove useful in combating microbial dysbiosis elsewhere in the body. IMPORTANCE Many health care professionals use antibiotic prophylaxis strategies to prevent infection after surgery. This practice is under debate since it enhances the spread of antibiotic resistance. Another important reason to avoid nonessential use of antibiotics, the impact on our microbiome, has hardly received attention. In this study, we assessed the impact of antibiotics on the human microbial ecology at two niches. We followed the oral and gut microbiomes in 66 individuals from before, immediately after, and up to 12 months after exposure to different antibiotic classes. The salivary microbiome recovered quickly and was surprisingly robust toward antibiotic-induced disturbance. The fecal microbiome was severely affected by most antibiotics: for months, health-associated butyrate-producing species became strongly underrepresented. Additionally, there was an enrichment of genes associated with antibiotic resistance. Clearly, even a single antibiotic treatment in healthy individuals contributes to the risk of resistance development and leads to long-lasting detrimental shifts in the gut microbiome.


2020 ◽  
Vol 41 (10) ◽  
pp. 1162-1168
Author(s):  
Shawn E. Hawken ◽  
Mary K. Hayden ◽  
Karen Lolans ◽  
Rachel D. Yelin ◽  
Robert A. Weinstein ◽  
...  

AbstractObjective:Cohorting patients who are colonized or infected with multidrug-resistant organisms (MDROs) protects uncolonized patients from acquiring MDROs in healthcare settings. The potential for cross transmission within the cohort and the possibility of colonized patients acquiring secondary isolates with additional antibiotic resistance traits is often neglected. We searched for evidence of cross transmission of KPC+ Klebsiella pneumoniae (KPC-Kp) colonization among cohorted patients in a long-term acute-care hospital (LTACH), and we evaluated the impact of secondary acquisitions on resistance potential.Design:Genomic epidemiological investigation.Setting:A high-prevalence LTACH during a bundled intervention that included cohorting KPC-Kp–positive patients.Methods:Whole-genome sequencing (WGS) and location data were analyzed to identify potential cases of cross transmission between cohorted patients.Results:Secondary KPC-Kp isolates from 19 of 28 admission-positive patients were more closely related to another patient’s isolate than to their own admission isolate. Of these 19 cases, 14 showed strong genomic evidence for cross transmission (<10 single nucleotide variants or SNVs), and most of these patients occupied shared cohort floors (12 patients) or rooms (4 patients) at the same time. Of the 14 patients with strong genomic evidence of acquisition, 12 acquired antibiotic resistance genes not found in their primary isolates.Conclusions:Acquisition of secondary KPC-Kp isolates carrying distinct antibiotic resistance genes was detected in nearly half of cohorted patients. These results highlight the importance of healthcare provider adherence to infection prevention protocols within cohort locations, and they indicate the need for future studies to assess whether multiple-strain acquisition increases risk of adverse patient outcomes.


2020 ◽  
Vol 105 (6) ◽  
pp. 563-568
Author(s):  
André Ricardo Araujo da Silva ◽  
Amanda Marques ◽  
Clara Di Biase ◽  
Monique Faitanin ◽  
Indah Murni ◽  
...  

IntroductionAntimicrobial stewardship programmes (ASPs) are recommended to improve antibiotic use in healthcare and reduce antimicrobial resistance (AMR). Our aim was to investigate the effectiveness of ASPs in reducing antibiotic consumption, use of broad-spectrum/restricted antibiotics, antibiotic resistance and healthcare-associated infections (HAIs) in neonates.MethodsWe searched PUBMED, SCIELO, EMBASE and the Cochrane Database (January 2000–April 2019) to identify studies on the effectiveness of ASPs in neonatal wards and/or neonatal intensive care units (NICUs). Outcomes were as follows: reduction of antibiotic consumption overall and of broad-spectrum/target antibiotics, inappropriate antibiotic use, antibiotic resistance and HAIs. ASPs conducted in settings other than acute care hospitals, for children older than 1 month, and ASPs addressing antifungal and antiviral agents, were excluded.ResultsThe initial search identified 53 173 titles and abstracts; following the application of filters and inclusion criteria, a total of six publications were included in the final analysis. All studies, of which one was multi-centre study, were published after 2010. Five studies were conducted exclusively in NICUs. Four articles applied multimodal interventions. Reduction of antibiotic consumption overall and/or inappropriate antibiotic use were reported by four articles; reduction of broad-spectrum/targeted antibiotics were reported by four studies; No article evaluated the impact of ASPs on AMR or the incidence of HAI in neonates.ConclusionASPs can be effectively applied in neonatal settings. Limiting the use of broad-spectrum antibiotics and shorting the duration of antibiotic treatment are the most promising approaches. The impact of ASPs on AMR and HAI needs to be evaluated in long-term studies.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20518-e20518
Author(s):  
Marshall McKenna ◽  
Rena Feinman ◽  
Jaeil Ahn ◽  
Shuqi Wang ◽  
David H. Vesole ◽  
...  

e20518 Background: Gut microbiome dysbiosis is correlated with graft-versus-host disease (GVHD) in allogeneic stem cell transplant (allo-SCT) patients. In the allo-SCT population, antibiotics have been associated with increased risk for GVHD mortality and relapse due to loss of gut obligate anaerobes . It has been shown that antibiotics may negatively impact the efficacy of checkpoint inhibitors for patients with solid tumors. Based on these studies, we performed a retrospective analysis to determine if antibiotic treatment affects outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: This is a single institution retrospective study at Hackensack University Medical Center. A list of consecutive MM patients treated from 1/2012 to 12/2015 was obtained and an electronic medical record review of the first 217 who received ASCT was performed. Baseline characteristics, treatment history, transplant course and antibiotic treatment (including β-lactams, fluoroquinolones, macrolides, metronidazole, and vancomycin) were reviewed. Prophylactic antibiotics were excluded. Response was defined using the IMWG criteria. Median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Log rank tests were used to compare the difference in survival between stratified groups. The LASSO cox regression analysis method was used for multivariate analyses of PFS and OS. Results: Of the 217 patients, 205 patients were available for analysis. Median age at ASCT was 61. β-lactams were associated with decreased median PFS (1.95 vs 4.77 years (yrs), p < 0.01) and decreased median OS (7.51 vs 13.45 yrs, p = 0.01). Multivariate analysis adjusting for lasso-selected age, gender, complete remission (CR) after ASCT, and ISS demonstrated independent progression risk associated with β-lactam use (HR = 2.00, 95% CI, 1.28–3.12, p < 0.01). β-lactams were associated with worse OS in multivariate analysis adjusting for lasso-selected age, gender, CR after ASCT and high risk cytogenetics (HR = 1.89, 95% CI, 1.07–3.40, p = 0.03). Conclusions: In this preliminary study, β-lactams predicted for decreased PFS and OS compared to patients who did not receive β-lactams in MM patients undergoing ASCT. The study was limited by its retrospective nature but demonstrates one of the first evaluations of antibiotic effect on the ASCT population in MM. Prospective studies evaluating the impact of antimicrobials on patient outcomes and the gut microbiome are ongoing.


2020 ◽  
Vol 21 (11) ◽  
Author(s):  
Madiyar Nurgaziyev ◽  
YERMEK AITENOV ◽  
ZHANAGUL KHASSENBEKOVA ◽  
SANIYA AKPANOVA ◽  
KAIRAT RYSBEKOV ◽  
...  

Abstract. Nurgaziyev M, Atenov Y, Khassenbekova Z, Akpanova S, Rysbekov K, Kozhakhmetov S, Nurgozhina A, Sergazy S, Chulenbayeva L, Ospanova Z, Tuyakova A, Mukhambetganov N, Sattybayeva R, Urazova S, Galymgozhina N, Zhumadilova A, Gulyaev A, Kushugulova A. 2020. Effect of mare’s milk prebiotic supplementation on the gut microbiome and the immune system following antibiotic therapy. Biodiversitas 21: 5065-5071. Antibiotic treatment can severely affect the gut microbiome for short-term and long-term consequences. Probiotic and prebiotic supplements are widely prescribed to modulate the composition and function of the human gut microbiome. The current study aims to determine the impacts of mare’s milk prebiotics on the diversity of gut bacterial communities and the local immune system when administered during and after a course of antibiotic therapy. Six children aged 4 to 5 years diagnosed with bilateral bronchopneumonia were prescribed cephalosporin (cefuroxime) antibiotics. During the 60 days of the study, three children consumed mare’s milk prebiotics, while the other three did not. Fecal samples were collected daily during antibiotic therapy and every five days after the last day of antibiotic treatment. Total DNA was isolated, and the taxonomic composition of the gut microbiome was analyzed by sequencing the 16S rRNA gene (V1-V3 region). The MULTIPLEX MAP platform was used to evaluate the local immune status. The relative abundance of 11 genera was reduced and did not recover until the last day of the study. The abundance of Bacteroides was not significantly altered in either group. Christensenella, Rothia, Abiotrophia, Acinetobacter, Anaerotruncus, Holdemania, and Turicibacter numbers were significantly increased on day five and remained at the same level during the study period. Cephalosporin administration also reduced the levels of pro-inflammatory and anti-inflammatory cytokines/chemokines (MIP1α, TNFα, GMCSF, GCSF, sCD40L, FGF2, TGFα, IL1α, and IP10).


2020 ◽  
Author(s):  
Shawn E. Hawken ◽  
Mary K. Hayden ◽  
Karen Lolans ◽  
Rachel D. Yelin ◽  
Robert A. Weinstein ◽  
...  

AbstractObjectiveCohorting patients who are colonized or infected with multidrug-resistant organisms (MDROs) has been demonstrated to protect uncolonized patients from acquiring MDROs in healthcare settings. A neglected aspect of cohorting is the potential for cross-transmission within the cohort and the possibility of colonized patients acquiring secondary isolates with additional antibiotic resistance traits. We searched for evidence of cross-transmission of KPC+ Klebsiella pneumoniae (KPC-Kp) colonization among cohorted patients in a long-term acute care hospital (LTACH), and evaluated the impact of secondary acquisitions on resistance potential.DesignGenomic epidemiological investigationSettingA high-prevalence LTACH during a bundled intervention that included cohorting KPC-Kp-positive patients.MethodsWhole-genome sequencing (WGS) and location data were analyzed to identify potential cases of cross-transmission between cohorted patients.ResultsSecondary KPC-Kp isolates from 19 of 28 admission-positive patients were more closely related to another patient’s isolate than to their own admission isolate. In 14 of these 19 cases there was strong genomic evidence for cross-transmission (<10 SNVs) and the majority of these patients occupied shared cohort floors (12 cases) or rooms (5 cases) at the same time. Of the 14 patients with strong genomic evidence of acquisition, 12 acquired antibiotic resistance genes not found in their primary isolates.ConclusionsAcquisition of secondary KPC-Kp isolates carrying distinct antibiotic resistance genes was detected in nearly half of cohorted patients. These results highlight the importance of healthcare provider adherence to infection prevention protocols within cohort locations, and motivate future studies to assess whether multiple-strain acquisition increases risk of adverse patient outcomes.


2016 ◽  
Vol 60 (7) ◽  
pp. 4264-4273 ◽  
Author(s):  
Jiangwei Yao ◽  
Robert A. Carter ◽  
Grégoire Vuagniaux ◽  
Maryse Barbier ◽  
Jason W. Rosch ◽  
...  

ABSTRACTBroad-spectrum antibiotic therapy decimates the gut microbiome, resulting in a variety of negative health consequences. Debio 1452 is a staphylococcus-selective enoyl-acyl carrier protein reductase (FabI) inhibitor under clinical development and was used to determine whether treatment with pathogen-selective antibiotics would minimize disturbance to the microbiome. The effect of oral Debio 1452 on the microbiota of mice was compared to the effects of four commonly used broad-spectrum oral antibiotics. During the 10 days of oral Debio 1452 treatment, there was minimal disturbance to the gut bacterial abundance and composition, with only the unclassified S24-7 taxon reduced at days 6 and 10. In comparison, broad-spectrum oral antibiotics caused ∼100- to 4,000-fold decreases in gut bacterial abundance and severely altered the microbial composition. The gut bacterial abundance and composition of Debio 1452-treated mice were indistinguishable from those of untreated mice 2 days after the antibiotic treatment was stopped. In contrast, the bacterial abundance in broad-spectrum-antibiotic-treated mice took up to 7 days to recover, and the gut composition of the broad-spectrum-antibiotic-treated mice remained different from that of the control group 20 days after the cessation of antibiotic treatment. These results illustrate that a pathogen-selective approach to antibiotic development will minimize disturbance to the gut microbiome.


Author(s):  
Gaetane Nocturne ◽  
Bineta Ly ◽  
Audrey Paoletti ◽  
Juliette Pascaud ◽  
Raphaele Seror ◽  
...  

The impact of treatment on the risk of lymphoma in patients with rheumatoid arthritis (RA) is unclear. Here, we aimed to assess if the risk of lymphoma differs according to the type of Tumor Necrosis factor inhibitor (TNFi), comparing monoclonal anti-TNF antibodies (Ab) to the soluble TNF receptor. We used BAFF-transgenic (Tg) mice as a model of autoimmunity-associated lymphoma. Six-month aged BAFF-Tg mice were treated with TNFi for 12 months. Histological examination of the spleen, assessment of the cellular composition of the spleen by flow cytometry and assessment of B cell clonality were performed at sacrifice. Crude mortality and incidence of lymphoma were significantly higher in mice treated with monoclonal anti-TNF Ab compared to both controls and mice treated with the soluble TNF receptor, even at high dose. Flow cytometry analysis revealed decreased splenic macrophage infiltration in mice treated with monoclonal anti-TNF Ab. Overall, this study demonstrates, for the first time, that a very prolonged treatment with monoclonal anti-TNF Ab increase the risk of lymphoma in B cell-driven autoimmunity. This data suggests a closer monitoring for lymphoma development in patients suffering from B cell-driven autoimmune disease with long-term exposure to monoclonal anti-TNF Ab.


Author(s):  
Amy L Pakyz ◽  
Christine M Orndahl ◽  
Alicia Johns ◽  
David W Harless ◽  
Daniel J Morgan ◽  
...  

Abstract Background The Centers for Medicare and Medicaid Services (CMS) implemented a core measure sepsis (SEP-1) bundle in 2015. One element was initiation of broad-spectrum antibiotics within 3 hours of diagnosis. The policy has the potential to increase antibiotic use and Clostridioides difficile infection (CDI). We evaluated the impact of SEP-1 implementation on broad-spectrum antibiotic use and CDI occurrence rates. Methods Monthly adult antibiotic data for 4 antibiotic categories (surgical prophylaxis, broad-spectrum for community-acquired infections, broad-spectrum for hospital-onset/multidrug-resistant [MDR] organisms, and anti–methicillin-resistant Staphylococcus aureus [MRSA]) from 111 hospitals participating in the Clinical Data Base Resource Manager were evaluated in periods before (October 2014–September 2015) and after (October 2015–June 2017) policy implementation. Interrupted time series analyses, using negative binomial regression, evaluated changes in antibiotic category use and CDI rates. Results At the hospital level, there was an immediate increase in the level of broad-spectrum agents for hospital-onset/MDR organisms (+2.3%, P = .0375) as well as a long-term increase in trend (+0.4% per month, P = .0273). There was also an immediate increase in level of overall antibiotic use (+1.4%, P = .0293). CDI rates unexpectedly decreased at the time of SEP-1 implementation. When analyses were limited to patients with sepsis, there was a significant level increase in use of all antibiotic categories at the time of SEP-1 implementation. Conclusions SEP-1 implementation was associated with immediate and long-term increases in broad-spectrum hospital-onset/MDR organism antibiotics. Antimicrobial stewardship programs should evaluate sepsis treatment for opportunities to de-escalate broad therapy as indicated.


2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S58-S58
Author(s):  
Da Young Kim ◽  
Dahye kim ◽  
Eunjeong Heo ◽  
Hyung-sook kim ◽  
Ji Young Park ◽  
...  

Abstract Background To reduce unnecessary long-term antibiotic therapies, pharmacist-led intervention followed by the involvement of infectious diseases (ID) specialist was implemented. In addition, a survey for the prescribers was conducted to find the gaps for improvement. Methods The “less is better” intervention was implemented between August 1, 2018 and February 28, 2019, which was focused on those to whom antibiotics had been administered for over 15 days. However, the following patients were excluded: patients having hematologic diseases, patients in the neonatal intensive care units, and patients who were recommended to maintain antibiotics by ID specialist. Treatment duration according to the indications was compared between pre-intervention period (Aug to Sep 2017) and post-intervention period. A questionnaire based on clinical vignettes was distributed among 140 prescribers. Results Among 500 prescriptions assessed as a prolonged treatment, 475 (95%) were stopped after intervention. Over the pre- and post-intervention period, pneumonia was the most common indication of prolonged antibiotic use (43.8 versus 43.0%). The treatment durations decreased from 21.0 (interquartile range [IQR], 27.3-18.0) days pre-intervention to 16.0 (IQR, 20.0-15.0) days post-intervention (p=0.000). The survey response rate was 76.4% (107/140). Regarding community-acquired pneumonia, there was a significant difference between knowledge and practice, showing that 53% were aware of the standard duration, but 72% actually prescribed for a longer duration. There was a similar trend for the treatment of urinary tract infection (30% versus 83%, p=0.024). The reasons why the physicians prescribed antibiotics of a prolonged duration in spite of adequate knowledge were not only the lack of symptom alleviation in patients but also organizational factors. Conclusion The duration of long-term antibiotic treatment was shortened by active participation of pharmacist as well as ID specialists. However, gaps between the knowledge and practice on the duration of antibiotic treatment were also found. Therefore, it is necessary to implement appropriate feedback and education based on clinical scenario in order to improve the physicians’ antibiotic prescription. Disclosures All Authors: No reported disclosures


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