Beta Lactams
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2021 ◽  
Vol 8 ◽  
Rutan Zhang ◽  
Ismael A. Barreras Beltran ◽  
Nathaniel K. Ashford ◽  
Kelsi Penewit ◽  
Adam Waalkes ◽  

Methicillin-resistant S. aureus (MRSA) are resistant to beta-lactams, but synergistic activity between beta-lactams and glycopeptides/lipopeptides is common. Many have attributed this synergy to the beta-lactam-glycopeptide seesaw effect; however, this association has not been rigorously tested. The objective of this study was to determine whether the seesaw effect is necessary for synergy and to measure the impact of beta-lactam exposure on lipid metabolism. We selected for three isogenic strains with reduced susceptibility to vancomycin, daptomycin, and dalbavancin by serial passaging the MRSA strain N315. We used whole genome sequencing to identify genetic variants that emerged and tested for synergy between vancomycin, daptomycin, or dalbavancin in combination with 6 beta-lactams with variable affinity for staphylococcal penicillin binding proteins (PBPs), including nafcillin, meropenem, ceftriaxone, ceftaroline, cephalexin, and cefoxitin, using time-kills. We observed that the seesaw effect with each beta-lactam was variable and the emergence of the seesaw effect for a particular beta-lactam was not necessary for synergy between that beta-lactam and vancomycin, daptomycin, or dalbavancin. Synergy was more commonly observed with vancomycin and daptomycin based combinations than dalbavancin in time-kills. Among the beta-lactams, cefoxitin and nafcillin were the most likely to exhibit synergy using the concentrations tested, while cephalexin was the least likely to exhibit synergy. Synergy was more common among the resistant mutants than the parent strain. Interestingly N315-D1 and N315-DAL0.5 both had mutations in vraTSR and walKR despite their differences in the seesaw effect. Lipidomic analysis of all strains exposed to individual beta-lactams at subinhibitory concentrations suggested that in general, the abundance of cardiolipins (CLs) and most free fatty acids (FFAs) positively correlated with the presence of synergistic effects while abundance of phosphatidylglycerols (PGs) and lysylPGs mostly negatively correlated with synergistic effects. In conclusion, the beta-lactam-glycopeptide seesaw effect and beta-lactam-glycopeptide synergy are distinct phenomena. This suggests that the emergence of the seesaw effect may not have clinical importance in terms of predicting synergy. Further work is warranted to characterize strains that don’t exhibit beta-lactam synergy to identify which strains should be targeted with combination therapy and which ones cannot and to further investigate the potential role of CLs in mediating synergy.

Neha Mishra ◽  
Venkata Sai Shashank Mutya ◽  
Irfan Ibrahim K. ◽  
Girish Rai

<p>Actinomyces are commensals of human oropharynx and actinomycosis is considered mainly as an endogenous infection that is triggered by a mucosal lesion. Typically, the disease presents as a slowly progressive painless indurated mass evolving into multiple abscesses with draining sinus tracts sometimes expressing a typical yellow exudate with characteristic sulfur granules. The gold standard of diagnosis is histological examination and bacterial culture of the tissue. Most isolates are susceptible to beta lactams and they are the treatment of choice along with surgical management with drainage of abscesses and excision of recalcitrant fibrotic lesions and debridement of necrotic bone tissue. Here we present a case of 37-year-old male patient who has developed severe COVID-19 infection following which he developed invasive mucormycosis followed by actinomycosis. We postulate that the lymphopenia and the use of immunosuppressants used in treatment of COVID-19 lead to mucormycosis and aggressive debridement used as a strategy in treatment of mucormycosis led to colonization of actinomyces leading to cervicofacial actinomycosis.</p>

2021 ◽  
Vol 21 (1) ◽  
Gabriel Kambale Bunduki ◽  
Eva Heinz ◽  
Vincent Samuel Phiri ◽  
Patrick Noah ◽  
Nicholas Feasey ◽  

Abstract Background Uropathogenic Escherichia coli (UPEC) are amongst the most frequent causes of urinary tract infections. We report a systematic review and meta-analysis of virulence factors and antimicrobial resistance of UPEC isolated from urinary tract infections. Methods A systematic review and meta-analysis were performed using PRISMA guidelines (Research Registry ref. 5874). Data were extracted from PubMed/MEDLINE and ScienceDirect databases for studies published from January 1, 2000 to December 31, 2019. Studies reporting antimicrobial resistance and virulence factors of UPEC isolated in confirmed urinary tract infections (≥105CFU/ml) were eligible. Prevalence of antimicrobial resistance and virulence factors of UPEC were estimated using random-effects meta-analysis model. Estimates with 95% confidence intervals, I-square (I2) statistic, and Cochran’s Q test were computed using the score statistic and the exact binomial method by incorporating the Freeman-Tukey double arcsine transformation of proportions. Results Our search returned 2504 hits, of which 13 studies were included in the meta-analysis, totalling 1888 UPEC isolates. Highest antimicrobial resistance rates were observed among the antibiotic class of tetracycline in 69.1% (498/721), followed by sulphonamides in 59.3% (1119/1888), quinolones in 49.4% (1956/3956), and beta-lactams in 36.9% (4410/11964). Among beta-lactams, high resistance was observed in aminopenicillins in 74.3% (1157/1557) and first generation cephalosporins in 38.8% (370/953). Meanwhile, virulence factors with highest prevalence were immune suppressors (54.1%) followed by adhesins (45.9%). Taken individually, the most observed virulence genes were shiA (92.1%), CSH (80.0%), fimH/MSHA (75.3%), traT (75.1%), sisA (72.2%), iucD (65.7%), iutA (61.8%), kpsMTII (60.6%), and PAI (55.2%). Conclusions The increased antibiotic resistance of UPEC isolates was demonstrated and suggested a need for reassessment of empirical therapies in urinary tract infections treatment caused by this pathogen. In addition, this pathotype exhibited diverse surface and secreted virulence factors.

Isabel Torres‐Rojas ◽  
Diana Pérez‐Alzate ◽  
Maria Luisa Somoza Alvarez ◽  
Elisa Haroun Diaz ◽  
Francisco Javier Ruano Pérez ◽  

A. A. Bhalodi ◽  
N. Oppermann ◽  
S. A. Campeau ◽  
R. M. Humphries

Antimicrobial susceptibility testing for Pseudomonas aeruginosa is critical to determine suitable treatment options. Commercial susceptibility tests are typically calibrated against the reference method, broth microdilution (BMD). Imprecision of minimum inhibitory concentrations (MICs) obtained by BMD for the same isolate on repeat testing is known to exist. Factors that impact the extent of variability include concentration of the inoculum, operator effects, contents of the media, inherent strain properties, and the testing process or materials. We evaluated the variability of BMD for anti-pseudomonal beta-lactams (aztreonam, cefepime, ceftazidime, meropenem, piperacillin-tazobactam, ceftazidime-avibactam, ceftolozane-tazobactam) tested against a collection of P. aeruginosa isolates. Multiple replicate BMD tests were performed and MICs were compared to assess reproducibility, including the impact of the inoculum and operator. Overall, essential agreement (EA) was ≥ 90% for all beta-lactams tested. Absolute agreement (AA) was as low as 70% for some beta-lactams. Variability from the inoculum and operators impacted the reproducibility of MICs. Piperacillin-tazobactam exhibited the highest degree of variability with 74% AA and 94%% EA. The implications of MIC variability are extensive as the MIC is essential for multiple facets of microbiology, such as the development of new compounds and susceptibility tests, dose optimization and pharmacokinetic/pharmacodynamic (PK/PD) targets for individual patients.

2021 ◽  
Vol 45 ◽  
pp. 1
Silvia Boni ◽  
Gustavo H. Marin ◽  
Laura Campaña ◽  
Lupe Marin ◽  
Alejandra Corso ◽  

Objective. To describe bacterial resistance and antimicrobial consumption ratio at the subnational level in Argentina during 2018, considering beta-lactams group as a case-study. Methods. Antimicrobial consumption was expressed as defined daily doses (DDD)/1000 inhabitants. Resistance of Escherichia coli, Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus to beta-lactams was recorded. Resistance/consumption ratio was estimated calculating “R” for each region of Argentina, and this data was compared with other countries. Results. The most widely consumed beta-lactams in Argentina were amoxicillin (3.64) for the penicillin sub-group, cephalexin (0.786) for first generation cephalosporins, cefuroxime (0.022) for second generation; cefixime (0.043) for third generation and cefepime (0.0001) for the fourth generation group. Comparison between beta-lactams consumption and bacterial resistance demonstrated great disparities between the six regions of the country. Conclusions. The case-study of Argentina shows that antimicrobial consumption and resistance of the most common pathogens differed among regions, reflecting different realities within the same country. Because this situation might also be occurring in other countries, this data should be taken into account to target local efforts towards better antimicrobial use, to improve antimicrobial stewardship programs and to propose more suitable sales strategies in order to prevent and control antimicrobial resistance.

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001346
Victor I. Band ◽  
David S. Weiss

Antibiotic resistance is a growing crisis that threatens many aspects of modern healthcare. Dogma is that resistance often develops due to acquisition of a resistance gene or mutation and that when this occurs, all the cells in the bacterial population are phenotypically resistant. In contrast, heteroresistance (HR) is a form of antibiotic resistance where only a subset of cells within a bacterial population are resistant to a given drug. These resistant cells can rapidly replicate in the presence of the antibiotic and cause treatment failures. If and how HR and resistance are related is unclear. Using carbapenem-resistant Enterobacterales (CRE), we provide evidence that HR to beta-lactams develops over years of antibiotic usage and that it is gradually supplanted by resistance. This suggests the possibility that HR may often develop before resistance and frequently be a stage in its progression, potentially representing a major shift in our understanding of the evolution of antibiotic resistance.

2021 ◽  
Vol 9 (7) ◽  
pp. 1505
Claire Roger ◽  
Benjamin Louart

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.

2021 ◽  
Tina Dao ◽  

Streptococcus pneumoniae is a prominent human pathogen that causes both invasive and non-invasive diseases, such as otitis media, pneumonia, meningitis, and bacteremia. Although it is frequently an asymptomatic colonizer of the human nasopharynx, S. pneumoniae is a major cause of morbidity and mortality in the immune compromised population, young children, and the elderly. Up until the 1970s, S. pneumoniae was susceptible to almost all antibiotics. Since then, this pathogen has gained resistance to a variety of antibiotic treatments, including beta-lactams, macrolides, and fluoroquinolones. In the first chapter, we focused on fluoroquinolone resistance in S. pneumoniae. Fluoroquinolones are one of the most frequently prescribed antibiotics, yet fluoroquinolone resistance in S. pneumoniae is still rare compared to other antibiotics resistance, such as beta-lactams. In this study, we investigated the mechanism(s) underlying this intriguing case by assessing the efficiency and fitness costs of horizontal transfer of fluoroquinolone resistance determinants. We hypothesized that the fitness tradeoffs incurred by resistance determinants would define the likelihood of such resistance to emerge in a clinical setting. Clinically relevant fluoroquinolone resistance requires both on-target mutations in topoisomerase IV parC and DNA gyrase gyrA. The wild-type S. pneumoniae TIGR4 was not readily transformed with single mutations in gyrA or parC; however, it was readily transformed with double on-target mutations in gyrA and parC. Compared to the wild type, the single on-target mutants were attenuated, whereas the double on-target mutant was virulent. This suggests that clinically relevant, high-level fluoroquinolone resistance requires the combination of several on-target mutations, which could be acquired via horizontal transfer. The combination of the extremely low probability of acquiring two or more mutations simultaneously from different target genes and the deleterious fitness tradeoffs imposed by individual on-target mutations in gyrA or parC likely result in the infrequent prevalence of fluoroquinolone resistance in S. pneumoniae. Through in vitro serial passaging, we identified a novel mutation (N291D) in the efflux pump patA that facilitated the acquisition of the on-target mutations in parC and gyrA via horizontal transfer with minimal fitness tradeoffs. We also modeled the evolution of fluoroquinolone resistance in a murine host and identified mutation(s) that arose and fixated during in vivo passaging. Interestingly, the experimentally-evolved isolates from the in vivo passaging study did not encode on-target mutations for fluoroquinolone resistance and instead displayed tolerance, which potentially facilitated the subsequent acquisition of fluoroquinolone resistance. In the next chapter, we investigated how fitness tradeoffs and horizontal transfer play a role in the emergence and spread of another mainstay of treatment of pneumococcal infection, beta-lactams- specifically, penicillin, which inhibit wall synthesis. We found that recombination with related viridans species via horizontal transfer may be preferable to de novo on-target mutations in penicillin-binding proteins in S. pneumoniae to acquire resistance more rapidly without initially losing in vivo fitness. Initial recombinants retained virulence in vivo and could readily acquire higher resistance via subsequent transformation. The final recombinants displayed tolerance to penicillin, having reduced kill kinetics compared to the wild type. This suggests that S. pneumoniae might have minimized fitness tradeoffs by developing tolerance via horizonal transfer with related viridans group streptococci, which would serve as a stepping stone for subsequent development of resistance. In the next study, we explored an underlying mechanism of antibiotic tolerance in S. pneumoniae. In our model of the evolution of antibiotic resistance, rny that encodes ribonuclease Y (RNAse Y) was a mutational hotspot across multiple antibiotics. The rny knockout mutant was fully virulent, indicating that deletion of this gene imposed minimal to no fitness tradeoffs. Disruptions in RNA degradation resulted in tolerance to several classes of antibiotics and reduced antibiotic treatment efficacy in vivo. In the final chapter, we investigated whether other phenomena that allow bacteria to withstand antibiotic killing, such as heteroresistance, can affect antibiotic treatment outcomes clinically. We found that vancomycin heteroresistance is associated with treatment failure and poor outcomes in coagulase-negative staphylococci (CoNS) from pediatric leukemia patients. Taken together, this dissertation provides insights into strategies of S. pneumoniae for striking a balance between maximizing resistance potential while minimizing fitness tradeoffs, thereby potentially contributing to the development of more-effective antibiotics for treatment of pneumococcal disease. It also provided insights into the association between heteroresistance in CoNS and clinical outcomes..

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