Fluoroquinolone-resistant Bacteria Research Articles

Interactions between Zoliflodacin and Neisseria gonorrhoeae Gyrase and Topoisomerase IV: Enzymological Basis for Cellular Targeting.

Gyrase and topoisomerase IV are the cellular targets for fluoroquinolones, a critically important class of antibacterial agents used to treat a broad spectrum of human infections. Unfortunately, the clinical efficacy of the fluoroquinolones has been curtailed by the emergence of target-mediated resistance. This is especially true for Neisseria gonorrhoeae, the causative pathogen of the sexually transmitted infection gonorrhea. Spiropyrimidinetriones (SPTs), a new class of antibacterials, were developed to combat the growing antibacterial resistance crisis. Zoliflodacin is the most clinically advanced SPT and displays efficacy against uncomplicated urogenital gonorrhea in human trials. Like fluoroquinolones, the primary target of zoliflodacin in N. gonorrhoeae is gyrase, and topoisomerase IV is a secondary target. Because unbalanced gyrase/topoisomerase IV targeting has facilitated the evolution of fluoroquinolone-resistant bacteria, it is important to understand the underlying basis for the differential targeting of zoliflodacin in N. gonorrhoeae. Therefore, we assessed the effects of this SPT on the catalytic and DNA cleavage activities of N. gonorrhoeae gyrase and topoisomerase IV. In all reactions examined, zoliflodacin displayed higher potency against gyrase than topoisomerase IV. Moreover, zoliflodacin generated more DNA cleavage and formed more stable enzyme-cleaved DNA-SPT complexes with gyrase. The SPT also maintained higher activity against fluoroquinolone-resistant gyrase than topoisomerase IV. Finally, when compared to zoliflodacin, the novel SPT H3D-005722 induced more balanced double-stranded DNA cleavage with gyrase and topoisomerase IV from N. gonorrhoeae, Escherichia coli, and Bacillus anthracis. This finding suggests that further development of the SPT class could yield compounds with a more balanced targeting against clinically important bacterial infections.

Discovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria

Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need to identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors of DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates of Escherichia coli. Screening of a small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized via medicinal chemistry efforts to afford the more potent antibacterial LEI-800. Target identification studies, including whole-genome sequencing of in vitro selected mutants with resistance to isoquinoline sulfonamides, unanimously pointed to the DNA gyrase complex, an essential bacterial topoisomerase and an established antibacterial target. Using single-particle cryogenic electron microscopy, we determined the structure of the gyrase–LEI-800–DNA complex. The compound occupies an allosteric, hydrophobic pocket in the GyrA subunit and has a mode of action that is distinct from the clinically used fluoroquinolones or any other gyrase inhibitor reported to date. LEI-800 provides a chemotype suitable for development to counter the increasingly widespread bacterial resistance to fluoroquinolones.

Transperineal Versus Transrectal Magnetic Resonance Imaging–targeted and Systematic Prostate Biopsy to Prevent Infectious Complications: The PREVENT Randomized Trial

Background and objectiveThe transrectal biopsy approach is traditionally used to detect prostate cancer. An alternative transperineal approach is historically performed under general anesthesia, but recent advances enable transperineal biopsy to be performed under local anesthesia. We sought to compare infectious complications of transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis. MethodsWe assigned biopsy-naïve participants to undergo transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis (rectal culture screening for fluoroquinolone-resistant bacteria and antibiotic targeting to culture and sensitivity results) through a multicenter, randomized trial. The primary outcome was post-biopsy infection captured by a prospective medical review and patient report on a 7-d survey. The secondary outcomes included cancer detection, noninfectious complications, and a numerical rating scale (0–10) for biopsy-related pain and discomfort during and 7-d after biopsy. Key findings and limitationsA total of 658 participants were randomized, with zero transperineal versus four (1.4%) transrectal biopsy infections (difference –1.4%; 95% confidence interval [CI] –3.2%, 0.3%; p = 0.059). The rates of other complications were very low and similar. Importantly, detection of clinically significant cancer was similar (53% transperineal vs 50% transrectal, adjusted difference 2.0%; 95% CI –6.0, 10). Participants in the transperineal arm experienced worse periprocedural pain (0.6 adjusted difference [0–10 scale], 95% CI 0.2, 0.9), but the effect was small and resolved by 7-d. Conclusions and clinical implicationsOffice-based transperineal biopsy is tolerable, does not compromise cancer detection, and did not result in infectious complications. Transrectal biopsy with targeted prophylaxis achieved similar infection rates, but requires rectal cultures and careful attention to antibiotic selection and administration. Consideration of these factors and antibiotic stewardship should guide clinical decision-making. Patient summaryIn this multicenter randomized trial, we compare prostate biopsy infectious complications for the transperineal versus transrectal approach. The absence of infectious complications with transperineal biopsy without the use of preventative antibiotics is noteworthy, but not significantly different from transrectal biopsy with targeted antibiotic prophylaxis.

Priorities and Progress in Gram-negative Bacterial Infection Research by the Antibacterial Resistance Leadership Group.

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.

Antimicrobial-Resistant Enterobacterales Recovered from the Environment of Two Zoological Institutions Include Enterobacter cloacae Complex ST171 Producing KPC-4 Carbapenemase.

Environmental surfaces can serve as reservoirs for pathogens and antimicrobial-resistant (AMR) bacteria in healthcare settings. Although active surveillance programs are used in veterinary and human healthcare, unconventional settings like zoological facilities are often overlooked, even though antimicrobials are used to maintain the health of their animal collections. Here, we used electrostatic cloths to conduct active environmental surveillance over a 2-year period at two zoological institutions to determine contamination prevalence of human-only and mixed animal-human touch environments with AMR bacteria. We recovered Enterobacterales isolates that expressed quinolone resistance, an AmpC-like phenotype, and an extended-spectrum β-lactamase phenotype from 144 (39%), 141 (38.2%), and 72 (19.5%) of the environmental samples, respectively. The zoological institutions, areas and exhibits within the zoological facility, and sampling surface type affected the odds of recovering AMR bacteria from the environment. Three carbapenemase-producing Enterobacter cloacae complex ST171 isolates recovered from one zoological facility harbored an IncH12 plasmid with a Tn4401b-KPC-4 transposon conferring multidrug resistance. One isolate maintained three tandem repeats of a Tn4401b-KPC-4 element on an IncHI2 plasmid, although this isolate was susceptible to the four carbapenem drugs tested. These three isolates and their IncH12 plasmids shared significant genomic similarity with two E. cloacae complex isolates recovered from canine patients at a regional veterinary hospital during year 2 of this study. Our results indicated that surface environments at zoological institutions can serve as reservoirs for AMR bacteria and their genes and have implications for animal and public health. IMPORTANCE Environmental surfaces can be a source of antimicrobial-resistant (AMR) bacteria that pose a risk to human and animal health. Zoological institutions are unique environments where exotic animals, staff, and visitors intermingle and antimicrobials are used to maintain animal health. However, zoological environments are often overlooked as reservoirs of AMR bacteria. Here, we show that zoological environments can serve as reservoirs of fluoroquinolone-resistant and extended-spectrum cephalosporin-resistant bacteria. In addition, we isolated three carbapenemase-producing Enterobacter cloacae complex strains carrying blaKPC-4, including one with a unique, tandem triplicate of the Tn4401b-KPC-4 element. Comparative whole genomics of these isolates with two E. cloacae complex isolates from patients at a regional veterinary hospital highlighted the possibility of local KPC-4 spread between animal environments. Our results suggest that environments at zoological institutions serve as reservoirs for AMR bacteria and pose a hypothetical One Health risk to the public, staff, and the wild animal populations in captivity.

Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin

The peptide antibiotic albicidin is a DNA topoisomerase inhibitor with low-nanomolar bactericidal activity towards fluoroquinolone-resistant Gram-negative pathogens. However, its mode of action is poorly understood. We determined a 2.6 Å resolution cryoelectron microscopy structure of a ternary complex between Escherichia coli topoisomerase DNA gyrase, a 217 bp double-stranded DNA fragment and albicidin. Albicidin employs a dual binding mechanism where one end of the molecule obstructs the crucial gyrase dimer interface, while the other intercalates between the fragments of cleaved DNA substrate. Thus, albicidin efficiently locks DNA gyrase, preventing it from religating DNA and completing its catalytic cycle. Two additional structures of this trapped state were determined using synthetic albicidin analogues that demonstrate improved solubility, and activity against a range of gyrase variants and E. coli topoisomerase IV. The extraordinary promiscuity of the DNA-intercalating region of albicidins and their excellent performance against fluoroquinolone-resistant bacteria holds great promise for the development of last-resort antibiotics.

Fluoroquinolone resistance in bacterial isolates from ocular infections: Trend in antibiotic susceptibility patterns between 2005-2020.

To assess the fluoroquinolone resistance pattern and trends among bacterial isolates from ocular infections over a 16-year period and explore alternative antibiotics in fluoroquinolone-resistant strains. In this retrospective, longitudinal study, the microbiology laboratory records of patients with different ocular infections diagnosed at an eye institute in central India from 2005-2020 were reviewed to determine the pattern of fluoroquinolone (ciprofloxacin, ofloxacin, gatifloxacin, and moxifloxacin) resistance. Antibiotic susceptibility testing was done using the Kirby-Bauer disc diffusion method. In 725 Gram-positive bacteria, the resistance of ciprofloxacin, ofloxacin, gatifloxacin, and moxifloxacin was 55.9% (95% confidence interval [CI]: 52.2 - 59.6), 42.7% (95% CI: 39.0 - 46.4), 47.6% (95% CI: 43.9 - 51.3), and 45.6% (95% CI: 41.7-49.5), respectively. In 266 Gram-negative bacteria, the resistance of ciprofloxacin, ofloxacin, gatifloxacin, and moxifloxacin was 57.9% (95% CI: 51.9 - 63.9), 56.0% (95% CI: 49.7 - 62.1), 59.9% (95% CI: 53.8 - 66.0), and 74.3% (95% CI: 68.3 - 80.2), respectively. A declining trend in resistance to ciprofloxacin (P < 0.001), ofloxacin (P < 0.001), and moxifloxacin (P < 0.001) was seen in Gram-positive bacteria, whereas a reduction in resistance to only moxifloxacin (P = 0.04) was seen in Gram-negative bacteria. In fluoroquinolone-resistant Gram-positive bacteria, cefuroxime exhibited the highest susceptibility, whereas in fluoroquinolone-resistant Gram-negative bacteria, colistin exhibited the highest susceptibility. Fluoroquinolone resistance was high among bacteria from ocular infections in central India, but a declining trend in resistance to some of the fluoroquinolones was observed in recent times. Cefuroxime and colistin emerged as alternatives in fluoroquinolone-resistant Gram-positive and Gram-negative bacterial infections, respectively.

Fluoroquinolone Derivatives in the Treatment of Mycobacterium tuberculosis Infection.

Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of multidrug-resistant tuberculosis (MDR TB) cases poses an emergent public health threat. Fluoroquinolones are commonly used in the treatment of both MDR TB and drug-sensitive tuberculosis patients who are intolerant to first-line antitubercular agents. Unfortunately, these drugs have mild side effects, relevant to the prolonged treatment regimens and diminished bioavailability due to binding of metal ions. Moreover, the resistance to fluoroquinolones is also on the rise, a characteristic of extensively drug-resistant TB (XDR TB). Here, we developed esters as prodrugs of the fluoroquinolones levofloxacin and ciprofloxacin, with long-chain fatty alcohols. Both the alcohols and the quinolone have previously shown antimycobacterial activity and the aim was to develop esters with improved lipophilicity and capable of delivering the free acid inside mycobacterial cells. The carboxylic acid group of fluoroquinolones is essential to the mode of action but is also responsible for many of its side effects and metal-chelating properties. The synthesis, stability in biological media, and antibacterial activity were evaluated, the latter not only against Mycobacterium tuberculosis but also against other clinically relevant bacterial species, since the parent compounds display a broad spectrum of activity. The biological results show a reduction in the antitubercular activity of the synthesized derivatives, probably due to deficient activation of the ester prodrug. Despite this, it was found that the derivatives exhibit bioactivity against other fluoroquinolone-resistant bacteria, indicating a different mode of action and suggesting that it may be worthwhile to research further modifications to the carboxylic acid group. This might lead to new compounds that are efficient against resistant strains. This idea that the compounds may act by a different mechanism of action was further supported by a brief computer investigation that demonstrated the potential lack of selectivity of the esters to the fluoroquinolone target.

Is it time for a moratorium on the use of benzalkonium chloride in eyedrops?

Is it time for a moratorium on the use of benzalkonium chloride in eyedrops?

English

BACKGROUND Urinary tract infection (UTI) is a very important reason for increased hospital stay, increased morbidity and mortality in the hospital setting. Annually, about 150 million people are diagnosed with UTI worldwide.1The fluoroquinolones have assumed an important role in the therapy of UTI. But the prevalence of urinary tract infections caused by fluoroquinolone-resistant bacteria has been increasing over the years. The purpose of this study was to evaluate fluoroquinolone resistance pattern among the bacterial pathogens causing urinary tract infections. METHODS This is a cross-sectional descriptive study. A total of 200 urine samples were collected from clinically suspected UTI patients, attending out-patient department (OPDs) and were admitted to various wards of our hospital. The samples were inoculated using the standard loop, incubated aerobically, isolates were identified by standard biochemical reactions and antibiotic susceptibility testing was performed. RESULTS Out of 200 samples, the most common organism isolated was Escherichia coli (57 %), followed by Klebsiella pneumoniae subsp pneumonia (27 %). 93.9 % of Escherichia coli and 100 % of Klebsiella pneumoniae subsp pneumoniae isolates were resistant to ampicillin. The present study also documented high level of fluoroquinolone resistance among almost all common uropathogens. Among Escherichia coli and Klebsiella pneumoniae subsp pneumoniae; ciprofloxacin resistance was 77.2 % and 85.2 % respectively. Quinolone resistance was found to be more common in hospitalised patients and catheterized patients. According to our study, although levofloxacin is far effective than ciprofloxacin for uropathogens, the resistance to both are increasing. CONCLUSIONS The results presented in this study indicate that it is time to reconsider the frequent use of fluoroquinolones. Use of fluoroquinolones to treat patients before getting the sensitivity pattern of the isolate should be stopped. It is mandatory to formulate antimicrobial policy according to the local resistance pattern. Resistance pattern must be assessed in hospital and laboratory-based surveillance studies. KEY WORDS Urinary Tract Infections, Escherichia coli, Antibiotic Sensitivity, Fluoroquinolones

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.

Prevalence of extended-spectrum cephalosporin-, carbapenem-, and fluoroquinolone-resistant members of the family Enterobacteriaceae isolated from the feces of horses and hospital surfaces at two equine specialty hospitals.

To estimate the prevalence of extended-spectrum cephalosporin-, carbapenem-, and fluoroquinolone-resistant bacteria of the family Enterobacteriaceae in the feces of hospitalized horses and on hospital surfaces. Fecal and environmental samples were collected from The Ohio State University Galbreath Equine Center (OSUGEC) and a private referral equine hospital in Kentucky (KYEH). Feces were sampled within 24 hours after hospital admission and after 48 hours and 3 to 7 days of hospitalization. Fecal and environmental samples were enriched, and then selective media were inoculated to support growth of Enterobacteriaceae bacteria that expressed resistance phenotypes to extended-spectrum cephalosporins, carbapenems, and fluoroquinolones. 358 fecal samples were obtained from 143 horses. More samples yielded growth of Enterobacteriaceae bacteria that expressed resistance phenotypes (AmpC β-lactamase, OR = 4.2; extended-spectrum beta-lactamase, OR = 3.2; and fluoroquinolone resistance, OR = 4.0) after 48 hours of hospitalization, versus within 24 hours of hospital admission. Horses hospitalized at KYEH were at greater odds of having fluoroquinolone-resistant bacteria (OR = 2.2). At OSUGEC, 82%, 64%, 0%, and 55% of 164 surfaces had Enterobacteriaceae bacteria with AmpC β-lactamase phenotype, extended-spectrum beta-lactamase phenotype, resistance to carbapenem, and resistance to fluoroquinolones, respectively; prevalences at KYEH were similarly distributed (52%, 32%, 1%, and 35% of 315 surfaces). Results indicated that antimicrobial-resistant Enterobacteriaceae may be isolated from the feces of hospitalized horses and from the hospital environment. Hospitalization may lead to increased fecal carriage of clinically important antimicrobial-resistance genes.

The Profile of Ciprofloxacin-Resistant Bacteria in the Rectum of Patients Undergoing Transrectal Ultrasound-Guided Prostate Biopsy, Its Relation to Post-Biopsy Infection and Alternative Prophylactic Antibiotics

Background: Fluoroquinolone has been routinely given as a prophylactic antibiotic to patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy. Currently, there is no data on the profile of fluoroquinolone-resistant bacteria, its association with post-biopsy sepsis, and alternative prophylactic antibiotics.Methods: A cross-sectional study was conducted in patients undergoing TRUS-guided prostate biopsy at Urology Clinic, Cipto Mangunkusumo National Central General Hospital between August and December 2015. Specimens were taken from rectal swabs prior to biopsy. Gramnegative bacilli and Gram-positive cocci were characterized on the Vitek®2 using GN and GP cards (BioMérieux, USA). Antimicrobial susceptibility testing was done by Kirby Bauer disc diffusion method. Post-biopsy infection was monitored within one week after biopsy by telephone call and diagnosed by clinical examination.Results: A total of 52 patients aged 52-80 years were enrolled. Sixty-six isolates grew from 52 swabs; 14 swabs among them grew 2 isolates. The commonest pathogen was Escherichia coli (78.8%), followed by Klebsiella pneumoniae (13.6%), Enterococcus faecium (3.0%), Acinetobacter haemolyticus, Morganella morganii subsp. morganii, and Enterococcus faecalis (1.5%), respectively. Ciprofloxacin-resistant bacteria were found in 33 (50.0%) isolates which were predominated by E. coli. Meanwhile, 90.4% and 96.2% of isolates were sensitive to amoxicillinclavulanate and ampicillin-sulbactam, respectively. Post-biopsy infection was established in 7 patients requiring no hospitalization.Conclusions: The proportion of ciprofloxacin-resistant bacteria in the rectum among patients undergoing prostate biopsy was 50.0%. Escherichia coli is the commonest resistant pathogen to fluoroquinolone. The recommended alternatives for prophylactic antibiotics are amoxicillinclavulanate and ampicillin-sulbactam. Routine pre-biopsy rectal swab cultures should also be encouraged.

Antibacterial activity of a DNA topoisomerase I inhibitor versus fluoroquinolones in Streptococcus pneumoniae.

The DNA topoisomerase complement of Streptococcus pneumoniae is constituted by two type II enzymes (topoisomerase IV and gyrase), and a single type I enzyme (topoisomerase I). These enzymes maintain the DNA topology, which is essential for replication and transcription. While fluoroquinolones target the type II enzymes, seconeolitsine, a new antimicrobial agent, targets topoisomerase I. We compared for the first time the in vitro effect of inhibition of topoisomerase I by seconeolitsine and of the type II topoisomerases by the fluoroquinolones levofloxacin and moxifloxacin. We used three isogenic non-encapsulated strains and five non-vaccine serotypes isolates belonging to two circulating pneumococcal clones, ST638 (2 strains) and ST1569V (3 strains). Each group contained strains with diverse susceptibility to fluoroquinolones. Minimal inhibitory concentrations, killing curves and postantibiotic effects were determined. Seconeolitsine demonstrated the fastest and highest bactericidal activity against planktonic bacteria and biofilms. When fluoroquinolone-susceptible planktonic bacteria were considered, seconeolitsine induced postantibiotic effects (1.00−1.87 h) similar than levofloxacin (1.00−2.22 h), but longer than moxifloxacin (0.39−1.71 h). The same effect was observed in sessile bacteria forming biofilms. Seconeolitsine induced postantibiotic effects (0.84−2.31 h) that were similar to those of levofloxacin (0.99−3.32 h) but longer than those of moxifloxacin (0.89−1.91 h). The greatest effect was observed in the viability and adherence of bacteria in the postantibiotic phase. Seconeolitsine greatly reduced the thickness of the biofilms formed in comparison with fluoroquinolones: 2.91 ± 0.43 μm (seconeolitsine), 7.18 ± 0.58 μm (levofloxacin), 17.08 ± 1.02 μm (moxifloxacin). When fluoroquinolone-resistant bacteria were considered, postantibiotic effects induced by levofloxacin and moxifloxacin, but not by seconeolitsine, were shorter, decreasing up to 5-fold (levofloxacin) or 2-fold (moxifloxacin) in planktonic cells, and up to 1.7 (levofloxacin) or 1.4-fold (moxifloxacin) during biofilm formation. Therefore, topoisomerase I inhibitors could be an alternative for the treatment of pneumococcal diseases, including those caused by fluoroquinolone-resistant isolates.

Antibiotic Prophylaxis for the Prevention of Infectious Complications following Prostate Biopsy: A Systematic Review and Meta-Analysis.

Infectious complications following prostate biopsy are increasing and fluoroquinolone prophylaxis has recently been banned by the European Commission. In this systematic review we summarize the evidence for different antibiotic prophylaxis regimens. We searched MEDLINE®, Embase® and Cochrane Database for randomized controlled trials (inception to October 2019) assessing antimicrobial interventions in prostate biopsy. Primary outcome was infectious complications. Exclusion criteria were simultaneous interfering interventions. GRADE (Grading of Recommendations, Assessment, Development and Evaluations) was used to assess the certainty of evidence. Protocol was registered with PROSPERO (CRD42015026354). Overall 59 randomized controlled trials (14,153 participants) and 7 different antimicrobial interventions were included. Antibiotic prophylaxis reduced infectious complications compared to no prophylaxis (RR 0.56, 95% CI 0.40-0.77, p=0.0005, I2=15%, participants 1,753, studies 11). A short-term prophylaxis (single shot to 3 days) was inferior to a long-term prophylaxis (1 to 7 days) with fluoroquinolone (RR 1.89, 95% CI 1.37-2.61, p=0.0001, I2=0%, participants 3,999, studies 17). Fosfomycin trometamol was an alternative to fluoroquinolone with reduced rates of infectious complications (RR 0.49, 95 CI 0.27-0.87, p=0.02, I2=54%, participants 1,239, studies 3). Empiric prophylaxis was inferior to targeted prophylaxis (RR 1.81, 95% CI 1.28-2.55, p=0.0008, I2=48%, participants 1,511, studies 6). Standard prophylaxis was inferior to augmented prophylaxis (using multiple rather than single agent) using a fixed model (RR 2.10, 95% CI 1.53-2.88, p <0.0001, I2=71%, participants 2,597, studies 9), but not using a random model (p=0.07). No difference was observed in infectious complications based on route or timing of antimicrobial prophylaxis. The certainty of evidence was rated as low/very low. In countries where fluoroquinolones are allowed as antibiotic prophylaxis, a minimum of a full 1-day administration as well as targeted therapy in case of fluoroquinolone resistance is recommended. In countries with a ban on fluoroquinolones, fosfomycin is a good alternative, as is augmented prophylaxis, although no established standard combination exists to date.

540. The Impact of Diet and Oral Hygiene on the Risk of Multidrug-Resistant Organism Carriage in the Mouth and Gut

BackgroundLittle is known about the relationship between oral hygiene and multidrug-resistant organism in the mouth and gut. We aimed to assess the relationship of oral hygiene and diet with multidrug-resistant organism (MDRO) carriage in the oral cavity and gut.MethodsParticipants were adults over age 18 from the 2016–2017 Survey of the Health of Wisconsin (SHOW) and its ancillary Wisconsin Microbiome Study. SHOW surveys residents of Wisconsin, collecting health determinants including a food frequency questionnaire, oral health, as well as biologic specimens. MDROs were defined as the presence of methicillin-resistant Staphylococcus aureus, Vancomycin-resistant Enterococcus, and Fluoroquinolone-resistant Gram-negative bacteria identified via culture from saliva, oral swabs, and stool samples. Statistical analysis was performed in R v3.5.1. Univariate analyses were conducted for all variables in the data set. Any variable with a P-value < 0.2 in the univariate analysis was considered for the logistic regression. Logistic regression using the glm function was done modeling MDRO carriage in either the saliva, oral swab, saliva and oral samples combined, and stool against diet, oral health, and known confounders.Results876 participants were included in the dataset with all 876 providing oral and stool samples and 784 providing saliva samples. Thirty-three patients were MDRO positive in the saliva (4.2%), 36 were positive in the oral swabs (4.1%), 55 were positive in either the saliva or oral swabs (6.3%), and 103 were positive in the stool (11.8%). In the logistic regression, consumption of whole grains was significantly associated with reduced MDRO carriage in the saliva (P = 0.046) and saliva and oral swab combined (P = 0.036) data sets (Table 1).ConclusionConsuming more whole grains was associated with a lower prevalence of MDRO carriage in the oral cavity. Higher levels of sugar consumption were associated with a higher prevalence of MDRO in the gut. Oral hygiene was not found to be associated with MDRO colonization in the mouth and a higher prevalence in the gut in this cross-sectional study. This may be due to over-reporting of hygiene practices by participants. Being positive for an MDRO in the oral cavity significantly increased the risk of MDRO carriage in the gut. Disclosures All authors: No reported disclosures.

Revisiting Oral Fluoroquinolone and Multivalent Cation Drug-Drug Interactions: Are They Still Relevant?

Fluoroquinolones are a widely-prescribed, broad-spectrum class of antibiotics with several oral formulations notable for their high bioavailability. For certain infections, fluoroquinolones are the first line or only treatment choice. When administered orally, fluoroquinolones require proper administration to ensure adequate systemic absorption and, thereby, protect patients from treatment failure. Oral drug preparations that contain multivalent cations are well known to chelate with fluoroquinolones in the gastrointestinal tract; co-administration may lead to clinically significant decreases in oral fluoroquinolone bioavailability and an overall increase in fluoroquinolone-resistant bacteria. Based on a search and evaluation of the literature, this focused review describes oral fluoroquinolone-multivalent cation drug-drug interactions and their magnitude and offers several clinical management strategies for these potentially clinically significant interactions.

Analysis of fluoroquinolones in dusts from intensive livestock farming and the co-occurrence of fluoroquinolone-resistant Escherichia coli

Fluoroquinolones are important therapeutics in human and veterinary medicine. This study aimed to retrospectively analyse sedimentation dusts from intensive-livestock-farming barns for fluoroquinolones and investigate the association between resistant Escherichia coli and the detected drugs. Sedimentation-dust samples (n = 125) collected (1980–2009) at 14 barns of unknown-treatment status were analysed by HPLC and tandem-mass spectroscopy to detect enrofloxacin, ciprofloxacin, marbofloxacin, and difloxacin. Recent microbiological data were included to investigate the relationship between fluoroquinolone presence and fluoroquinolone-resistant E. coli. Fifty-nine dust samples (47%) from seven barns contained fluoroquinolone residues. Up to three different fluoroquinolones were detected in pig and broiler barns. Fluoroquinolone concentrations ranged from 10-pg/mg to 46-ng/mg dust. Fluoroquinolone-resistant E. coli were isolated from four barns. Of all the dust samples, 22% contained non-susceptible isolates. Non-susceptible isolate presence in the dust was significantly associated (p = 0.0283) with detecting the drugs, while drug detection increased the odds (4-fold) of finding non-susceptible E. coli (odds ratio = 3.9877, 95% CI: 1.2854–12.3712). This retrospective study shows that fluoroquinolone usage leads to dust contamination. We conclude that farmers and animals inhale/swallow fluoroquinolones and fluoroquinolone-resistant bacteria due to drug application. Furthermore, uncontrolled drug emissions via air exhausted from the barns can be assumed.

Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase.

Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI). The compound has successfully completed phase II trials for the treatment of acute bacterial skin/skin structure infections and for the treatment of uncomplicated urogenital gonorrhea. It also displays robust in vitro activity against a range of wild-type and fluoroquinolone-resistant bacteria. Due to the clinical promise of gepotidacin, a detailed understanding of its interactions with its antibacterial targets is essential. Thus, we characterized the mechanism of action of gepotidacin against Staphylococcus aureus gyrase. Gepotidacin was a potent inhibitor of gyrase-catalyzed DNA supercoiling (IC50 ≈ 0.047 μM) and relaxation of positively supercoiled substrates (IC50 ≈ 0.6 μM). Unlike fluoroquinolones, which induce primarily double-stranded DNA breaks, gepotidacin induced high levels of gyrase-mediated single-stranded breaks. No double-stranded breaks were observed even at high gepotidacin concentration, long cleavage times, or in the presence of ATP. Moreover, gepotidacin suppressed the formation of double-stranded breaks. Gepotidacin formed gyrase-DNA cleavage complexes that were stable for >4 h. In vitro competition suggests that gyrase binding by gepotidacin and fluoroquinolones are mutually exclusive. Finally, we determined crystal structures of gepotidacin with the S. aureus gyrase core fusion truncate with nicked (2.31 Å resolution) or intact (uncleaved) DNA (2.37 Å resolution). In both cases, a single gepotidacin molecule was bound midway between the two scissile DNA bonds and in a pocket between the two GyrA subunits. A comparison of the two structures demonstrates conformational flexibility within the central linker of gepotidacin, which may contribute to the activity of the compound.

Correction: Predictors of fluoroquinolone-resistant bacteria in the rectal vault of men undergoing prostate biopsy

The original version of this article contained an error in the name of author Alfredo Mena Lora. This has now been corrected.