scholarly journals Evolutionary route of resistant genes in Staphylococcus aureus

2019 ◽  
Author(s):  
Jiffy John ◽  
Sinumol George ◽  
Sai Ravi Chandra Nori ◽  
Shijulal Nelson-Sathi
Keyword(s):  
Tetracycline Resistance ◽  
Phylogenomic Analysis ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Coagulase Negative Staphylococci ◽  
Resistant Genes ◽  
Depth Analysis ◽  
Frequent Exchange ◽  
Evolutionary Route ◽  
Core Genes

AbstractMulti-drug resistant S. aureus is a leading concern worldwide. Coagulase-Negative Staphylococci (CoNS) are claimed to be the reservoir and source of important resistant elements in S. aureus. However, the origin and evolutionary route of resistant genes in S. aureus are still remaining unknown. Here, we performed a detailed phylogenomic analysis of 152 completely sequenced S. aureus strains in comparison with 7,529 non-S. aureus reference bacterial genomes. Our results reveals that S. aureus has a large open pan-genome where 97 (55%) of its known resistant related genes belonging to its accessory genome. Among these genes, 47 (27%) were located within the Staphylococcal Cassette Chromosome (SCCmec), a transposable element responsible for resistance against major classes of antibiotics including beta-lactams, macrolides and aminoglycosides. However, the physically linked mec-box genes (MecA-MecR-MecI) that are responsible for the maintenance of SCCmec elements is not unique to S. aureus, instead it is widely distributed within Staphylococcaceae family. The phyletic patterns of SCCmec encoded resistant genes in Staphylococcus species are significantly different from that of its core genes indicating frequent exchange of these genes between Staphylococcus species. Our in-depth analysis of SCCmec resistant gene phylogenies reveals that genes such as blaZ, ble, kmA and tetK that are responsible for beta-lactam, bleomycin, kanamycin and tetracycline resistance in S. aureus were laterally transferred from non-Staphylococcus sources. In addition, at least 11 non-SCCmec encoded resistant genes in S. aureus, mostly present in plasmid are laterally acquired from distantly related species. Our study evidently shows that gene transfers played a crucial role in shaping the evolution of antibiotic resistance in S. aureus.

scholarly journals Phylogenomic Analysis Reveals the Evolutionary Route of Resistant Genes in Staphylococcus aureus

2019 ◽  
Vol 11 (10) ◽  
pp. 2917-2926 ◽  
Author(s):  
Jiffy John ◽  
Sinumol George ◽  
Sai Ravi Chandra Nori ◽  
Shijulal Nelson-Sathi
Keyword(s):  
Staphylococcus Aureus ◽  
Tetracycline Resistance ◽  
Multidrug Resistant ◽  
Phylogenomic Analysis ◽  
Beta Lactam ◽  
Coagulase Negative Staphylococci ◽  
Resistant Genes ◽  
Depth Analysis ◽  
Frequent Exchange ◽  
Evolutionary Route

Abstract Multidrug-resistant Staphylococcus aureus is a leading concern worldwide. Coagulase-Negative Staphylococci are claimed to be the reservoir and source of important resistant elements in S. aureus. However, the origin and evolutionary route of resistant genes in S. aureus are still remaining unknown. Here, we performed a detailed phylogenomic analysis of 152 completely sequenced S. aureus strains in comparison with 7,529 non-Staphylococcus aureus reference bacterial genomes. Our results reveal that S. aureus has a large open pan-genome where 97 (55%) of its known resistant-related genes belonging to its accessory genome. Among these genes, 47 (27%) were located within the Staphylococcal Cassette Chromosome mec (SCCmec), a transposable element responsible for resistance against major classes of antibiotics including beta-lactams, macrolides, and aminoglycosides. However, the physically linked mec-box genes (MecA–MecR–MecI) that are responsible for the maintenance of SCCmec elements is not unique to S. aureus, instead it is widely distributed within Staphylococcaceae family. The phyletic patterns of SCCmec-encoded resistant genes in Staphylococcus species are significantly different from that of its core genes indicating frequent exchange of these genes between Staphylococcus species. Our in-depth analysis of SCCmec-resistant gene phylogenies reveals that genes such as blaZ, ble, kmA, and tetK that are responsible for beta-lactam, bleomycin, kanamycin, and tetracycline resistance in S. aureus were laterally transferred from non-Staphylococcus sources. In addition, at least 11 non-SCCmec-encoded resistant genes in S. aureus, were laterally acquired from distantly related species. Our study evidently shows that gene transfers played a crucial role in shaping the evolution of antibiotic resistance in S. aureus.

scholarly journals Beta-Lactams Toxicity in the Intensive Care Unit: An Underestimated Collateral Damage?

2021 ◽  
Vol 9 (7) ◽  
pp. 1505
Author(s):  
Claire Roger ◽  
Benjamin Louart
Keyword(s):  
Risk Factors ◽  
Intensive Care Unit ◽  
Intensive Care ◽  
Clinical Manifestations ◽  
Acute Interstitial Nephritis ◽  
Convulsive Status Epilepticus ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Drug Induced ◽  
Icu Patients

Beta-lactams are the most commonly prescribed antimicrobials in intensive care unit (ICU) settings and remain one of the safest antimicrobials prescribed. However, the misdiagnosis of beta-lactam-related adverse events may alter ICU patient management and impact clinical outcomes. To describe the clinical manifestations, risk factors and beta-lactam-induced neurological and renal adverse effects in the ICU setting, we performed a comprehensive literature review via an electronic search on PubMed up to April 2021 to provide updated clinical data. Beta-lactam neurotoxicity occurs in 10–15% of ICU patients and may be responsible for a large panel of clinical manifestations, ranging from confusion, encephalopathy and hallucinations to myoclonus, convulsions and non-convulsive status epilepticus. Renal impairment, underlying brain abnormalities and advanced age have been recognized as the main risk factors for neurotoxicity. In ICU patients, trough concentrations above 22 mg/L for cefepime, 64 mg/L for meropenem, 125 mg/L for flucloxacillin and 360 mg/L for piperacillin (used without tazobactam) are associated with neurotoxicity in 50% of patients. Even though renal complications (especially severe complications, such as acute interstitial nephritis, renal damage associated with drug induced hemolytic anemia and renal obstruction by crystallization) remain rare, there is compelling evidence of increased nephrotoxicity using well-known nephrotoxic drugs such as vancomycin combined with beta-lactams. Treatment mainly relies on the discontinuation of the offending drug but in the near future, antimicrobial optimal dosing regimens should be defined, not only based on pharmacokinetics/pharmacodynamic (PK/PD) targets associated with clinical and microbiological efficacy, but also on PK/toxicodynamic targets. The use of dosing software may help to achieve these goals.

Confronting the Challenge of Beta-Lactam Allergies: A Quasi-Experimental Study Assessing Impact of Pharmacy-Led Interventions

2017 ◽  
Vol 32 (2) ◽  
pp. 139-146 ◽  
Author(s):  
Steven C. Krey ◽  
Jeff Waise ◽  
Lee P. Skrupky
Keyword(s):  
Guideline Implementation ◽  
Tertiary Care ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Antibiotic Selection ◽  
Reaction Type ◽  
Care Community ◽  
Multidisciplinary Education ◽  
Quasi Experimental ◽  
Pharmacy Technicians

Objective: To improve allergy history documentation and increase the use of beta-lactams when appropriate in patients with a reported beta-lactam allergy. Methods: This pre–post study was conducted at a 167-bed tertiary care community hospital and evaluated multidisciplinary interventions on allergy documentation and antibiotic selection. Interventions included education, creation of local practice guidelines, and modified practices for pharmacists and pharmacy technicians. Inpatients with a reported beta-lactam allergy receiving at least 1 antibiotic for >24 hours were included; first admissions were assessed. Primary outcomes were documentation of reaction type and percentage of patients receiving non-beta-lactam therapy. Secondary outcomes included documentation of previously tolerated beta-lactams, modification of non-beta-lactam therapy, discharge antibiotics, and adverse reactions. Results: A total of 179 patients were included, 91 preintervention and 88 postintervention. No significant differences were observed between the before versus after groups in the percentage of patients with documentation of reaction type (90.1% vs 89.8%, P = .940) or the overall percentage of patients receiving non-beta-lactams (86.8% vs 84.1%, P = .605). However, significantly more patients in the after phase had documentation of previously tolerated beta-lactams (8.8% vs 28.4%, P = .001), and among patients receiving a non-beta-lactam, a greater percentage was subsequently switched to a beta-lactam (11.4% vs 25.7%, P = .022). One allergic reaction was documented during the study, which occurred in the before phase. Conclusion: Multidisciplinary education and local guideline implementation led by pharmacists may improve allergy documentation and antibiotic selection in patients with reported beta-lactam allergies.

scholarly journals Can the Xpert MRSA/SA BC assay be used as an antimicrobial stewardship tool? A prospective assay validation and descriptive impact assessment study in a South African setting

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kessendri Reddy ◽  
Andrew Whitelaw
Keyword(s):  
Bloodstream Infection ◽  
South African ◽  
Antimicrobial Stewardship ◽  
Antibiotic Use ◽  
Rapid Identification ◽  
Western Cape ◽  
Beta Lactams ◽  
Coagulase Negative Staphylococci ◽  
Methicillin Resistant ◽  
Potential Impact

Abstract Background Positive blood cultures showing Gram positive cocci in clusters signifies either Staphylococcus aureus or the less-virulent coagulase-negative staphylococci. Rapid identification and methicillin susceptibility determination with the Xpert MRSA/SA BC assay can improve management of S. aureus bloodstream infection and reduce inappropriate antibiotic use. Methods We prospectively evaluated the Xpert MRSA/SA BC assay in comparison with culture, on samples referred to our laboratory in the Western Cape, South Africa. We interviewed attending clinicians upon culture result availability, to assess antibiotic choices and estimate potential impact of the assay. Results Of the 231 samples included, there was 100% concordance between the Xpert MRSA/SA BC assay and culture (methicillin-resistant S. aureus 15/15, methicillin-susceptible S. aureus 42/42, coagulase-negative staphylococci 170/170). Time to final result could be reduced by approximately 30 h with the assay. Of the 178 patients with adequate antibiotic history, optimisation of antistaphylococcal therapy could have occurred more than 1 day sooner in 68.9% with S. aureus bloodstream infection (31/45, 95% CI 53.2–81.4%). Six of the 11 patients with methicillin-resistant S. aureus bloodstream infection (54.5%) could have received anti-MRSA cover sooner. Fifty-four days of antibiotic therapy could have been spared, equating to 0.3 days (95% CI, 0.2–0.4) saved per patient, driven by broad-spectrum beta-lactams (32 days, in 18.0% of the cohort). Conclusion This assay has potential as an antimicrobial stewardship tool; costing and impact on clinical outcome in patients with S. aureus bloodstream infection should be assessed.

scholarly journals Influence of Reported Penicillin Allergy on Mortality in MSSA Bacteremia

2018 ◽  
Vol 5 (3) ◽  
Author(s):  
Nicholas A Turner ◽  
Rebekah Moehring ◽  
Christina Sarubbi ◽  
Rebekah H Wrenn ◽  
Richard H Drew ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Multivariable Analysis ◽  
Mortality Rates ◽  
Penicillin Allergy ◽  
Care Hospital ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Appropriate Treatment ◽  
Large Tertiary Care ◽  
Multivariable Regression Models

Abstract Background Penicillin allergy frequently impacts antibiotic choice. As beta-lactams are superior to vancomycin in treating methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, we examined the effect of reported penicillin allergy on clinical outcomes in patients with MSSA bacteremia. Methods In this retrospective cohort study of adults with MSSA bacteremia admitted to a large tertiary care hospital, outcomes were examined according to reported penicillin allergy. Primary outcomes included 30-day and 90-day mortality rates. Multivariable regression models were developed to quantify the effect of reported penicillin allergy on mortality while adjusting for potential confounders. Results From 2010 to 2015, 318 patients with MSSA bacteremia were identified. Reported penicillin allergy had no significant effect on adjusted 30-day mortality (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.29–1.84; P = .51). Patients with reported penicillin allergy were more likely to receive vancomycin (38% vs 11%, P < .01), but a large number received cefazolin regardless of reported allergy (29 of 66, 44%). Mortality rates were highest among nonallergic patients receiving vancomycin (22.6% vs 7.4% for those receiving beta-lactams regardless of reported allergy, P < .01). In multivariable analysis, beta-lactam receipt was most strongly associated with survival (OR, 0.26; 95% CI, 0.12–0.54). Conclusions Reported penicillin allergy had no significant effect on 30- or 90-day mortality. Non-penicillin-allergic patients receiving vancomycin for treatment of MSSA bacteremia had the highest mortality rates overall. Receipt of a beta-lactam was the strongest predictor of survival. These results underscore the importance of correct classification of patients with penicillin allergy and appropriate treatment with a beta-lactam when tolerated.

scholarly journals Antipneumococcal activity of BAY 12-8039, a new quinolone, compared with activities of three other quinolones and four oral beta-lactams.

1997 ◽  
Vol 41 (12) ◽  
pp. 2786-2789 ◽  
Author(s):  
M A Visalli ◽  
M R Jacobs ◽  
P C Appelbaum
Keyword(s):  
Beta Lactam ◽  
Beta Lactams ◽  
Agar Dilution ◽  
Resistant Strains

Activities of BAY 12-8039 against 205 pneumococci were tested by agar dilution. MICs (in micrograms per milliliter) at which 50 and 90% of the isolates are inhibited (MIC50s and MIC90s, respectively) were 0.125 and 0.25 (BAY 12-8039), 2.0 and 4.0 (ciprofloxacin and ofloxacin), and 0.25 and 0.5 (sparfloxacin). Beta-lactam MIC50s and MIC90s for penicillin-susceptible, -intermediate, and -resistant strains, in that order, were 0.016 and 0.03, 0.25 and 2.0, and 2.0 and 4.0 (amoxicillin); 0.03 and 0.06, 0.25 and 4.0, and 4.0 and 8.0 (ampicillin); 0.03 and 0.06, 0.5 and 4.0, and 4.0 and 8.0 (cefuroxime); and 0.03 and 0.125, 0.25 and 2.0, and 4.0 and 8.0 (cefpodoxime). At two times their MICs after 24 h, BAY 12-8039, ciprofloxacin, ampicillin, and cefuroxime were uniformly bactericidal (99.9% killing) against 12 strains; other compounds were bactericidal at four times their MICs.

scholarly journals Could Dampening Expression of theNeisseria gonorrhoeaemtrCDE-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Shaochun Chen ◽  
Kristie L. Connolly ◽  
Corinne Rouquette-Loughlin ◽  
Alexander D’Andrea ◽  
Ann E. Jerse ◽  
...  
Keyword(s):  
Genital Tract ◽  
Efflux Pump ◽  
Health Concern ◽  
Third Generation ◽  
Global Public Health ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Genital Tract Infection ◽  
Infected Female ◽  
Content Type

ABSTRACTNeisseria gonorrhoeaehas developed resistance to every antibiotic introduced for treatment of gonorrhea since 1938, and concern now exists that gonorrheal infections may become refractory to all available antibiotics approved for therapy. The current recommended dual antibiotic treatment regimen of ceftriaxone (CRO) and azithromycin (AZM) is threatened with the emergence of gonococcal strains displaying resistance to one or both of these antibiotics. Non-beta-lactamase resistance to penicillin and third-generation cephalosporins, as well as low-level AZM resistance expressed by gonococci, requires overexpression of themtrCDE-encoded efflux pump, which in wild-type (WT) strains is subject to transcriptional repression by MtrR. Since earlier studies showed that loss of MtrCDE renders gonococci hypersusceptible to beta-lactams and macrolides, we hypothesized that transcriptional dampening ofmtrCDEwould render an otherwise resistant strain susceptible to these antibiotics as assessed by antibiotic susceptibility testing and during experimental infection. In order to test this hypothesis, we ectopically expressed a WT copy of themtrRgene, which encodes the repressor of themtrCDEefflux pump operon, inN. gonorrhoeaestrain H041, the first reported gonococcal strain to cause a third-generation-cephalosporin-resistant infection. We now report that MtrR production can repress the expression ofmtrCDE, increase antimicrobial susceptibilityin vitro, and enhance beta-lactam efficacy in eliminating gonococci as assessed in a female mouse model of lower genital tract infection. We propose that strategies that target the MtrCDE efflux pump should be considered to counteract the increasing problem of antibiotic-resistant gonococci.IMPORTANCEThe emergence of gonococcal strains resistant to past or currently used antibiotics is a global public health concern, given the estimated 78 million infections that occur annually. The dearth of new antibiotics to treat gonorrhea demands that alternative curative strategies be considered to counteract antibiotic resistance expressed by gonococci. Herein, we show that decreased expression of a drug efflux pump that participates in gonococcal resistance to antibiotics can increase gonococcal susceptibility to beta-lactams and macrolides under laboratory conditions, as well as improve antibiotic-mediated clearance of gonococci from the genital tract of experimentally infected female mice.

scholarly journals Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening

2018 ◽  
Author(s):  
María Pilar Arenaz Callao ◽  
Rubén González del Río ◽  
Ainhoa Lucía Quintana ◽  
Charles J. Thompson ◽  
Alfonso Mendoza-Losana ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Amoxicillin Clavulanate ◽  
Low Toxicity ◽  
Potential Use ◽  
Ulcer Treatment

ABSTRACTThe potential use of clinically approved beta-lactams for Buruli ulcer (BU) treatment was investigated with representative classes analyzed in vitro for activity against Mycobacterium ulcerans. Beta-lactams tested were effective alone and displayed a strong synergistic profile in combination with antibiotics currently used to treat BU, i.e. rifampicin and clarithromycin; this activity was further potentiated in the presence of the beta-lactamase inhibitor clavulanate. In addition, quadruple combinations of rifampicin, clarithromycin, clavulanate and beta-lactams resulted in multiplicative reductions in their minimal inhibitory concentration (MIC) values. The MIC of amoxicillin against a panel of clinical isolates decreased more than 200-fold within this quadruple combination. Amoxicillin/clavulanate formulations are readily available with clinical pedigree, low toxicity, and orally and pediatric available; thus, supporting its potential inclusion as a new anti-BU drug in current combination therapies.

scholarly journals Species-Specific Sensitivity of Coagulase-Negative Staphylococci to Single Antibiotics and Their Combinations

2011 ◽  
Vol 60 (2) ◽  
pp. 155-161 ◽  
Author(s):  
GRAŻYNA SZYMAŃSKA ◽  
MAGDALENA SZEMRAJ ◽  
ELIGIA M. SZEWCZYK
Keyword(s):  
University Hospital ◽  
Hospital Environment ◽  
Beta Lactam ◽  
Coagulase Negative Staphylococci ◽  
Methicillin Resistant ◽  
Beta Lactam Antibiotics ◽  
Resistant Strains ◽  
Staphylococcus Hominis ◽  
Species Specific

The activity of beta-lactam antibiotics (oxacillin, cloxacillin, cephalotin), vancomycin, gentamicin and rifampicin applied in vitro individually and in combination against 37 nosocomial methicillin-resistant strains of coagulase-negative staphylococci (CNS) was assessed to demonstrate the heterogeneity of this group of bacteria and estimate the chance of the efficacy of such therapy. The strains belonged to four species: Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus cohnii, Staphylococcus hominis. They originated from a hospital environment and from the skin of medical staff of the intensive care unit of a paediatric ward at a university hospital. All strains were methicillin-resistant, according to CLSI standards, but individual strains differed in MIC(ox) values. Susceptibility to other tested antibiotics was also characteristic for the species. The increased susceptibility to antibiotics in combinations, tested by calculating the fractional inhibitory concentration (FIC) index, concerned 26 out of 37 investigated strains and it was a feature of a particular species. Combinations of vancomycin and cephalotin against S. epidermidis and oxacillin with vancomycin were significant, as well as cephalotin and rifampicin in growth inhibition of multiresistant S. haemolyticus strains.

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