Antistaphylococcal Antibiotics Research Articles

Exeporfinium chloride (XF-73) nasal gel significantly reduces Staphylococcus aureus nasal carriage in cardiac surgery patients throughout surgery and the early recovery period: results from a randomized placebo-controlled Phase 2 study.

Staphylococcus aureus nasal carriers were randomized (1:1) to XF-73 or placebo nasal gel, administered 5x over ∼24hrs pre-cardiac surgery. S. aureus burden rapidly decreased after 2 doses (-2.2log10 CFU/mL; placebo -0.01log10 CFU/mL) and was maintained to 6 days post-surgery. Among XF-73 patients, 46.5% received post-operative anti-staphylococcal antibiotics versus 70% in placebo (P = 0.045).

Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus

Staphylococcus aureus is responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment. Antibiotic tolerance, the ability of bacteria to persist despite normally lethal doses of antibiotics, contributes to antibiotic treatment failure in S. aureus infections. To understand how antibiotic tolerance is induced, S. aureus biofilms exposed to multiple anti-staphylococcal antibiotics are examined using both quantitative proteomics and transposon sequencing. These screens indicate that arginine metabolism is involved in antibiotic tolerance within a biofilm and support the hypothesis that depletion of arginine within S. aureus communities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation of argH, the final gene in the arginine synthesis pathway, induces antibiotic tolerance. Arginine restriction induces antibiotic tolerance via inhibition of protein synthesis. In murine skin and bone infection models, an argH mutant has enhanced ability to survive antibiotic treatment with vancomycin, highlighting the relationship between arginine metabolism and antibiotic tolerance during S. aureus infection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrant S. aureus infections.

Nafcillin-induced thrombocytopenia: An uncommon complication

Drug-induced thrombocytopenia is a challenging clinical dilemma that is often overlooked. Nafcillin is a beta-lactam anti-staphylococcal penicillin antibiotic used as a first-line treatment for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia and severe infections. Nafcillin has been associated with a higher rate of premature antibiotic discontinuation than cefazolin. Here we report a 58-year-old woman with multiple comorbid conditions who presented with a prosthetic right hip joint infection due to MSSA and was treated with nafcillin but developed profound thrombocytopenia due to a possible nafcillin side effect on the 14th day of therapy. Thrombocytopenia resolved after discontinuation of nafcillin, and the patient was treated successfully with cefazolin. Keywords: Nafcillin-induced thrombocytopenia, drug-induced thrombocytopenia, thrombocytopenia

Antimicrobial Susceptibility of Various MRSA Clinical Isolates and the Impact of Glycopeptide MICs on Clinical and Microbiological Outcomes.

While vancomycin has remained the mainstay of the treatment for methicillin-resistant Staphylococcus aureus (MRSA) infections, there is growing evidence of the clinical impact of increased glycopeptide minimum inhibitory concentrations (MICs) in MRSA isolates. This study aimed to determine the susceptibility of various MRSA isolates to different antibiotics with antistaphylococcal activity and the impact of glycopeptide MICs on clinical and microbiological outcomes. This retrospective cohort study, conducted between 2013 and 2017, evaluated the susceptibility of MRSA strains isolated from various clinical samples to antistaphylococcal antibiotics using the gradient strip method. The clinical and laboratory features of patients infected with MRSA isolates with elevated glycopeptide MICs (>1 mg/L) and with isolates that had low glycopeptide MICs (≤1 mg/L) were compared. A total of 104 patients infected with MRSA strains were included in this study. Male sex (odds ratio [OR]=2.48, 95% confidence interval [CI]=1.01-6.10, p=0.048), two or more comorbidities (OR=2.48, 95% CI=1.03-6.50, p=0.044), history of MRSA infection (OR=4.91, 95% CI=1.70-14.28, p=0.003) and a longer hospital stay prior to MRSA infection (OR=2.32, 95% CI=1.05-7.85, p=0.040) were independent risk factors for high glycopeptide MICs. In MRSA infections with a teicoplanin MIC of >0.75mg/L, the microbiological and treatment failures were 46.2% (p=0.044) and 60.6% (p=0.042), respectively. This study showed that the critical MIC value, which suggested treatment failure as well as microbiological failure in the teicoplanin-treated MRSA infections, was >0.75 mg/L rather than >1 mg/L in our study cohort. The identification of high-risk patients;for treatment failures and mortality considering gradient strip method MIC values is crucial for the effective management of MRSA infections.

Retrospective analysis of a flucloxacillin oral absorption test in patients requiring flucloxacillin therapy: results and determination of factors associated with adequate absorption

ABSTRACT Objectives Flucloxacillin has the most narrow spectrum to treat staphylococcal infections, but has a large variability in bioavailability which hampers its intravenous (iv) to oral switch. To identify patients with adequate absorption, the use of an oral absorption test (OAT) measuring total plasma concentrations of flucloxacillin before and after an oral dose of 1 gram flucloxacillin, was previously published. The current pilot study aims to evaluate the fraction of patients with adequate absorption using a similar OAT; to assess the therapeutic consequences and to identify potential factors associated with adequate absorption. Methods Demographic data of adult patients treated with iv flucloxacillin and requiring prolonged therapy were collected retrospectively between May 2020 and November 2021 at Ghent University Hospital. A previously published OAT protocol was used, with addition of a protocol for intermittent dosing of iv flucloxacillin. Adequate absorption was defined as an increase in plasma concentration of at least 10 mg/L. Results The flucloxacillin OAT was performed in 99 patients, of which 62% were men, with a median age of 58 years and 95% received intermittent dosing of iv flucloxacillin. Of the 99 patients, 55% had a result indicating an adequate absorption and 49% of all patients were switched to oral flucloxacillin afterwards. Inadequate absorption was found to be associated with higher Body Mass Index and higher flucloxacillin baseline concentration, while co-administration of acetylsalicylic acid was associated with an adequate absorption. Conclusions Based on the OAT, 49% of all patients were switched to oral flucloxacillin instead of broader-spectrum anti-staphylococcal antibiotics. This implicates that an OAT could be a valuable antimicrobial stewardship measure by restricting the use of broad-spectrum antibiotics. For each of the associations found, a hypothesis was formulated about the underlying reason or mechanism; these should be confirmed in future studies with prospective and multicentric design.

Real-World Data Study on Risk Factors Associated with Acute Kidney Damage in Patients Treated with Anti-MRSA Antibiotics

The objective was to evaluate the incidence of nephrotoxicity related to vancomycin and other anti-MRSA antibiotics (linezolid and daptomycin). Patients receiving any of these drugs between July 2014 and December 2020 at a tertiary hospital were included. Renal failure was evaluated using the acute renal injury (AKIN) system. Univariate analysis was conducted on the 5806 patients who were included. Among them, 1023 patients (17.62%) developed renal failure. The renal damage incidence was 14.74% (496/3365) for vancomycin, 19.13% (367/1918) for linezolid, and 30.59% (160/523) for daptomycin. Patients with lower basal glomerular filtration had a higher risk of AKIN. In the vancomycin group, the risk factors were high creatinine and urea serum basal values, duration of treatment (DOT), body mass index (BMI), ICU stay, age, and low CKDEPI and albumin levels. In the linezolid group, AKIN was linked to high creatinine and urea levels, BMI, age, and ICU stay and to low CKDEPI levels; for daptomycin, AKIN was associated with low CKDEPI and albumin levels and a long DOT. Patients with AKIN showed higher mortality rates. Vancomycin-associated nephrotoxicity remains a great concern. However, linezolid and daptomycin could also cause nephrotoxicity. Bearing in mind risk factors that may prompt nephrotoxicity in hospitalized patients taking anti-staphylococcal antibiotics will result in better pharmacotherapeutic management.

Staph wars: the antibiotic pipeline strikes back.

Antibiotic chemotherapy is widely regarded as one of the most significant medical advancements in history. However, the continued misuse of antibiotics has contributed to the rapid rise of antimicrobial resistance (AMR) globally. Staphylococcus aureus, a major human pathogen, has become synonymous with multidrug resistance and is a leading antimicrobial-resistant pathogen causing significant morbidity and mortality worldwide. This review focuses on (1) the targets of current anti-staphylococcal antibiotics and the specific mechanisms that confirm resistance; (2) an in-depth analysis of recently licensed antibiotics approved for the treatment of S. aureus infections; and (3) an examination of the pre-clinical pipeline of anti-staphylococcal compounds. In addition, we examine the molecular mechanism of action of novel antimicrobials and derivatives of existing classes of antibiotics, collate data on the emergence of resistance to new compounds and provide an overview of key data from clinical trials evaluating anti-staphylococcal compounds. We present several successful cases in the development of alternative forms of existing antibiotics that have activity against multidrug-resistant S. aureus. Pre-clinical antimicrobials show promise, but more focus and funding are required to develop novel classes of compounds that can curtail the spread of and sustainably control antimicrobial-resistant S. aureus infections.

Comparison of Clindamycin with Other Anti-staphylococcal Antibiotics for the Treatment of Pediatric Staphylococcal Skin-Scaled Syndrome

Background: Staphylococcal scalded skin syndrome (4S) is caused by Staphylococcus aureus exfoliative toxin and is characterized by the separation of the surface layers of skin. Given the existence of conflicting treatment strategies and differences in antibiotic resistance patterns, this study aimed to compare the effectiveness of clindamycin, clindamycin with another anti-staph agent, and antibiotic regimen without clindamycin in the management of pediatric 4S. Objectives: To compare the effectiveness of different treatment strategies in the management of pediatric 4S. Methods: In this cross-sectional study, children with 4S (based on the final documented clinical diagnosis) admitted to the 17th-Shahrivar Hospital of Rasht, Iran, from 2005 to 2021 were enrolled. Exclusion criteria comprised being a neonate, having chronic skin diseases or immunodeficiencies, and incomplete data files. The variables gathered included age, sex, type of antibiotic received, time of fever cessation (if fever existed), recovery time, duration of hospitalization, and complications. The data were entered into SPSS v.24 software and analyzed. Results: This study was conducted on 73 patients with the final diagnosis of 4S. The mean age of the patients was 17.70 ± 15.85 months, and 47.9% of them experienced fever during hospitalization. The mean duration of hospital stay was 6.52 ± 1.90 days. Also, the average duration of recovery in these children was 4.90 ± 1.73 days. There were no differences in terms of sex (P-value = 0.245), age (P-value = 0.383), and duration of fever (P-value = 0.568) between the three groups receiving different antibiotic regimens. Meanwhile, the durations of recovery (P-value = 0.018) and hospitalization (P-value = 0.020) were significantly longer in children who did not receive clindamycin. Moreover, the duration of hospitalization was significantly shorter in the patients who received clindamycin alone compared to those treated with clindamycin plus another antibiotic (P-value = 0.044). There was no significant difference in the occurrence of disease/drug complications between the three groups, and the most common complication in all patients was scaling. Conclusions: Clindamycin (alone or in combination with other anti-staphylococcal agents) could shorten the recovery period, and hospital stay in children with 4S. Besides, it did not have any adverse impact on the occurrence of complications. The patients who received clindamycin alone had a shorter hospital stay than patients who were treated with clindamycin plus another antibiotic. Considering the lower complications, lower costs, and shorter length of hospital stay associated with monotherapy, we recommend using clindamycin alone for treating 4S patients.

Differential response to antibiotic therapy in staphylococcal infective endocarditis: contribution of an ex vivo model.

Staphylococcal infective endocarditis (IE) remains a hard-to-treat infection with high mortality. Both the evaluation of new innovative therapies and research on alternative models mimicking human IE are therefore urgently needed to improve the prognosis of patients with diagnosed IE. Dalbavancin is a novel anti-staphylococcal lipoglycopeptide but there are limited data supporting its efficacy on biofilm infections. This antibiotic could be an alternative to current therapies for the medical treatment of IE but it needs to be further evaluated. Here we developed an original ex vivo model of Staphylococcus aureus IE on human heart valves and assessed biofilm formation on them. After validating the model, the efficacy of two antistaphylococcal antibiotics, vancomycin and dalbavancin, was compared by measuring and visualizing their respective ability to inhibit and eradicate late-formed biofilm. Determination of the minimum biofilm inhibitory (MbIC) and eradicating (MbEC) concentrations in our ex vivo model identified dalbavancin as a promising drug with much lower MbIC and MBEC than vancomycin (respectively <0.01 versus 28 mg/L and 0.03 versus 32 mg/L). These data highlight a strong bactericidal effect of dalbavancin, particularly on an infected heart valve compared with vancomycin. Dalbavancin could be a realistic alternative treatment for the management of staphylococcal IE.

New Antibiotics for Staphylococcus aureus Infection: An Update from the World Association of Infectious Diseases and Immunological Disorders (WAidid) and the Italian Society of Anti-Infective Therapy (SITA).

Staphylococcus aureus is an extremely virulent pathogen that is capable of quickly evolving and developing antibiotic resistance. To overcome this problem, new antibiotics have been developed. Some of these have been licenced for use in clinical practice, mainly for the treatment of adults with acute skin and soft tissue infections, in addition to both community-acquired pneumonia (CAP) and nosocomial pneumonia (hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia). In this paper, the main characteristics and clinical use of new licenced anti-staphylococcal drugs have been discussed. In vitro studies have demonstrated that some new anti-staphylococcal antibiotics have better antimicrobial activity and, at least in certain cases, more favourable pharmacokinetic properties and higher safety and tolerability than the presently available anti-staphylococcal drugs. This suggests that they may have a potential use in reducing the risk of failure of S. aureus therapy. However, an in-depth analysis of microbiological and clinical studies carried out with these new drugs seems to indicate that further studies need to be conducted before the problem of resistance of S. aureus to the antibiotics available today can be completely solved. Considering the overall available research, the drugs that are active against S. aureus appear to present a great therapeutic opportunity for overcoming resistance to traditional therapy. There are advantages in the pharmacokinetic characteristics of some of these drugs and they have the potential to reduce hospital stays and economic costs associated with their use.

Descriptive Study of neonatal sepsis in the Post Graduated Hospital Khost Afghanistan

Introduction: Since neonatal Sepsis are causes a large number of neonatal hospitalizations and considered one of the most common problems of NICUs worldwide, also a large number of neonatal morbidity and mortality occurs in developing and developed countries. 1.6 million to 4 million deaths occur in the world, 40% of newborns in the first week. Diagnosis of the disease in newborns is determined by the level and equipment of the clinic and is based on the detection of antenatal and postnatal risk factors, respiratory and general symptoms, radiological signs, markers of the systemic inflammatory response syndrome / bacterial infections, and the results of etiological diagnosis. The combination of ampicillin with gentamicin is used for initial therapy of early pneumonia in newborns. In case of late neonatal pneumonia that occurred in a hospital, primary therapy must necessarily include anti pseudomonas and anti-staphylococcal antibiotics. Gram-negative antibiotics are given to treat community-acquired pneumonia in newborns.&#x0D; Research Question: What is the frequency and pattern of neonatal sepsis in Khost provincial specialized hospitals?&#x0D; Methodology: Our research is descriptive type that based on a case series, which took place from the first date of hamal 1400 to the last date of hoot, During this year 2311 patients were hospitalized in Khost post graduate Hospital, 821 patients were newborns, out of these 821 patients, 314 patients were diagnosed neonatal sepsis

Woman with facial swelling.

A 68-year-old woman presented to the emergency department (ED) with rapidly progressing left submandibular swelling and inability to tolerate secretions. Her physical examination showed the left submandibular gland was markedly enlarged, firm, and exquisitely tender to palpation. Laboratory tests were remarkable for a white blood cell count of 16.22 k/μL with a neutrophil predominance (81.3%). Computed tomography of the neck was performed and showed markedly dilated, enhancing left submandibular duct that mimicked an abscess, measuring over 1.0 cm in diameter (normal 1–3 mm)1 without visualized obstructing calculus (Figures 1 and 2). Numerous sialoliths were noted within both submandibular glands (Figure 3). In the ED, the patient had rapid worsening of the oral cavity and submandibular edema, and her airway was secured via nasotracheal intubation. She was admitted to the intensive care unit and received intravenous antibiotics and steroids, with resolution of her symptoms within 3 days. She was extubated and discharged home. Sialolithiasis, or salivary stones, may form in any of the salivary glands, but the submandibular gland is the most common site (80%) and forms the largest stones.2 Submandibular stones can be diagnosed on physical examination by palpating the floor of the mouth and pushing the tongue upward and backward to put tension on the papilla.3 Imaging may be necessary if stones are unable to be seen or palpated. Management is usually conservative and includes applying heat packs, massaging the gland, and use of sialagogues to promote saliva production. Anti-staphylococcal antibiotics are administered if there are signs of infection.

The Lysin Exebacase Has a Low Propensity for Resistance Development in Staphylococcus aureus and Suppresses the Emergence of Resistance to Antistaphylococcal Antibiotics.

Exebacase (CF-301) belongs to a novel class of protein-based antibacterial agents, called lysins (peptidoglycan hydrolases). Exebacase exhibits potent antistaphylococcal activity and is the first lysin to initiate clinical trials in the United States. To support clinical development, the potential for resistance development to exebacase was assessed over 28 days of serial daily subculture in the presence of increasing concentrations of the lysin performed in its reference broth medium. Exebacase MICs remained unchanged over serial subculture for three replicates each of methicillin-susceptible Staphylococcus aureus (MSSA) strain ATCC 29213 and methicillin-resistant S. aureus (MRSA) strain MW2. For comparator antibiotics also tested, oxacillin MICs increased by 32-fold with ATCC 29213 and daptomycin and vancomycin MICs increased by 16- and 8-fold, respectively, with MW2. Serial passage was also used to examine the capacity of exebacase to suppress selection for increased oxacillin, daptomycin, and vancomycin MICs when used together in combination, wherein daily exposures to increasing concentrations of antibiotic were performed over 28 days with the added presence of fixed sub-MIC amounts of exebacase. Exebacase suppressed increases in antibiotic MICs over this period. These findings are consistent with a low propensity for resistance to exebacase and an added benefit of reducing the potential for development of antibiotic resistance. IMPORTANCE To guide development of an investigational new antibacterial drug, microbiological data are required to understand the potential for development of resistance to the drug in the target organism(s). Exebacase is a lysin (peptidoglycan hydrolase) that represents a novel antimicrobial modality based on degradation of the cell wall of Staphylococcus aureus. Exebacase resistance was examined here using an in vitro serial passage method that assesses the impact of daily exposures to increasing concentrations of exebacase over 28 days in medium approved for use in exebacase antimicrobial susceptibility testing (AST) by the Clinical and Laboratory Standards Institute (CLSI). No changes in susceptibility to exebacase were observed over the 28-day period for multiple replicates of two S. aureus strains, indicating a low propensity for resistance development. Interestingly, while high-level resistance to commonly used antistaphylococcal antibiotics was readily obtained using the same method, the added presence of exebacase acted to suppress antibiotic resistance development.

Phenotypic Identification and Antibiotics Susceptibility Profile of Staphylococcus aureus from Surgical Equipment and Hospital Environment in Lokoja, Kogi State, Nigeria

Staphylococcus aureus is one of the prominent causes of hospital-acquired bacteremia. Despite the availability of anti-staphylococcal antibiotics, hospital acquired S. aureus bacteremia is still a major problem with considerable morbidity and mortality. Therefore, the aim of this study was to isolate, identify and determine the Antibiotics susceptibility profile of Staphylococcus aureus from the surfaces of surgical equipment and environment of major public and private hospitals in Lokoja, Kogi State, Nigeria using colonial characteristics, microscopy and conventional biochemical techniques. The Antibiotics susceptibility profile of the isolates was determined in accordance with the Guidelines of Clinical and Laboratory Standard Institute (CLSI). A total of three hundred and fifty (350) swab samples comprising of fourty (40) from surgical equipment and three hundred and ten (310) from the environment were collected from three (3) different public and private hospitals within Lokoja metropolis. The results obtained showed that 110(31.4%) of samples from the hospital environment were confirmed positive for Staphylococcus aureus with Hospital A constituting 30(8.6%), Hospital B had 59(16.8%) and Hospital C recorded 21 (6.0%). Of the 19 selected S. aureus isolates for antimicrobial susceptibility screening, 10.52% and 5.26% were intermediately resistant to Norfloxacin and Chloramphenicol respectively. Furthermore, the screened S. aureus isolates showed 100% susceptible to Ciprofloxacin, Gentamicin and Erythromycin; 94.73% susceptible to Chloramphenicol and 89.47% susceptible to Levoflaxin. The result also revealed 100% resistance to Penicillin and 15.78% resistance to Rifampicin. The high presence of Staphylococcus aureus in the hospital environment is a potential threat to the health of the patients and the public as this organism has been implicated in several human diseases, especially hospital- acquired bacteremia. Therefore, improved personal and public hygienic practices within the hospitals are required to reduce the high presence of S. aureus and other pathogenic microorganisms.

1986. Multicenter evaluation of Staphylococcus aureus prosthetic valve infective endocarditis with and without gentamicin treatment: Is it time to revisit?

Abstract Background Staphylococcus aureus prosthetic valve infective endocarditis (SA-PVIE) is associated with high mortality. Gentamicin (GEN) with anti-staphylococcal antibiotics and rifampin are guideline recommendations for SA-PVIE extrapolated from in vitro data. GEN can lead to acute kidney injury (AKI), meanwhile, the clinical benefit on infection-related outcomes remains unclear. Therefore, we evaluated the impact of GEN on outcomes in SA-PVIE. Methods This is a multicenter, retrospective cohort conducted at HonorHealth and UCHealth systems. Adults admitted between January 2014-2022 with definite/possible SA-PVIE by Duke Criteria were included if they received ≥2 days of treatment within 2 days of index culture. Cohorts were stratified by GEN receipt. The primary outcome was 90-day all-cause mortality. The secondary outcomes were treatment failure (change in antimicrobials, abscess development, new indication for cardiac surgery), 30-day all-cause mortality, and incidence of AKI by KDIGO Criteria. Results Overall, 38 patients with definite (40%) and possible SA-PVIE (60%) met inclusion (13 GEN, 25 without GEN [no-GEN]). At baseline, 15 (40%) patients were in an ICU, median Pitt bacteremia score was 2, and methicillin-susceptible S. aureus predominated (71%). A total of 10 (26%) patients had valve surgery; median bacteremia duration was similar between GEN and no-GEN (4 vs 3 days, p = 0.26). Common antibiotics were vancomycin (95%), cefazolin (63%), and nafcillin (21%); rifampin was more common in GEN than no-GEN (20% vs 77%, p &amp;lt; 0.001). Baseline AKI (44% vs 46%) and renal impairment (8% vs 0%) were not different between GEN and no-GEN, respectively. GEN was initiated a median 3 days after index culture, most commonly as intermittent strategy (69%) with 3 mg/kg daily equivalent (84.6%). There was no statistical difference in treatment failure (23% vs 24%, p=0.17), 30-day mortality (20% vs 39%, p=0.22), or 90-day mortality (28% vs 43%, p=0.263) between GEN and no-GEN, respectively. Three in the (23%) GEN group experienced AKI, compared to 10 (40%) in no-GEN. Conclusion We did not find that the addition of GEN to SA-PVIE therapy enhanced mortality benefit, yet patients without GEN may live to experience adverse events. Further studies were warranted. Disclosures All Authors: No reported disclosures.

1827. Comparison of clinical outcomes for glycopeptides and beta-lactams in methicillin-susceptible Staphylococcus aureus bloodstream infections

Abstract Background Several studies demonstrated the inferiority of glycopeptides as definitive antibiotics for MSSA BSI compared to anti-staphylococcal beta-lactam antibiotics. However, almost all of them were retrospective observational studies and no randomized controlled. Therefore, there remains the problem of bias in treatment selection and the possibility of residual confounding factors. In this study, we compare the therapeutic effects of glycopeptides and anti-staphylococcal beta-lactams in the treatment of MSSA BSI using inverse probability of treatment weighting (IPTW) analysis. Methods This is a retrospective cohort study performed in double-center from January 1, 2010 to December 31, 2018. Patients (age ≥18 years) with MSSA identified in the blood culture were included. Patients were classified into two groups according to definite antibiotics used, the beta-lactam (nafcillin or cefazolin) group and the glycopeptide (vancomycin or teicoplanin) group. Figure 1.Flow chart of the study population Results During the study period, 643 patients had MSSA bacteremia. Among them, 203 were treated with beta-lactam group and 156 were treated with glycopeptide group as definite therapy. (Figure 1). Comparison of clinical characteristics of patients between the beta-lactam and glycopeptide groups are shown in Table 1. After IPTW, baseline characteristics of the two groups were well balanced except for the primary focus of bacteremia. Although persistent bacteremia was less common in glycopeptide group (17.9% vs 4.0%; OR, 0.28; 95% CI, 0.14 – 0.60; P &amp;lt; 0.001), the glycopeptide group had higher overall mortality rate (15.9% vs 39.6%, P = 0.024), 7-day mortality rate (2.1% vs 14.1%, P &amp;lt; 0.001), and 28-day mortality rate (7.7% vs 30.9%, P = 0.012) (Table 2) than those of the beta-lactam group. When IPTW was augmented by multivariable logistic regression analyses to minimize remnant confounding, glycopeptide use for the treatment of MSSA BSI was associated with significant risk for 28-day mortality (adjusted OR, 3.37; 95% CI, 1.71–6.61; P &amp;lt; 0.001) (Figure 2). Figure 2.Adjusted ORs and 95% CIs for the primary end point in main analysis and various subgroups Abbreviations: CI, confidence interval; OR, odds ratio; IPTW, inverse probability of treatment weighting. aUnadjusted OR Conclusion Definitive therapy with beta-lactams in patients with MSSA BSI was associated with lower 28-day mortality when compared with definitive therapy with glycopeptides. This study provides compelling evidence of anti-staphylococcal beta-lactam use for MSSA BSI treatment. Disclosures All Authors: No reported disclosures.

127. Antimicrobial Efficacy Against Antibiotic-Tolerant Staphylococcus aureus Depends on the Mechanism of Antibiotic Tolerance

Abstract Background Bacteria can adopt an alternate metabolic state favoring small molecule synthesis over growth. In Staphylococcus aureus this is induced by factors present during infection including nutritional limitation and competition with other bacteria. Isogenic “tolerant” subpopulations have variable responses to antibiotics and can remain viable. Survivors resume growth upon cessation of antibiotics and cause relapse or recurrent infection. In this study we compare the capability of antibiotics to reduce viability of S. aureus made tolerant by different mechanisms. Methods Overnight cultures of S. aureus SH1000 were diluted to 106 cfu/mL. Tolerance was induced with mupirocin or 2-n-heptyl-4-hydroxypuinoline N-oxide (HQNO) simulating nutritional or competitive tolerance, respectively. Tolerant cultures were exposed to ceftaroline, daptomycin, gentamicin, levofloxacin, oritavancin or vancomycin at physiological concentrations and viability assessed by dilution plating. Minimum duration for 3-log viability reduction (“bactericidal activity”, MDK99.9) and 24h viability reduction were calculated independently for each of three biological replicates. Significance (P &amp;lt; 0.05) was determined using Student’s t-test. Results Time to bactericidal activity was prolonged for all antibiotics tested against nutritionally-tolerant S. aureus. Time to bactericidal activity was similarly prolonged against competitively-tolerant S. aureus, although the MDK99.9 of oritavancin was not affected. Viability reduction was mitigated for all antibiotics tested against nutritionally-tolerant S. aureus with the exception of oritavancin. In contrast, 24h viability reduction of competitively-tolerant S. aureus only occurred with ceftaroline, gentamicin and vancomycin while daptomycin, levofloxacin and oritavancin remained equally potent. Conclusion Tolerance can alter both the time to bactericidal effect and the extent of killing. Both the antibiotic and the mechanism of tolerance impact time to bacterial effect and extent of killing. Oritavancin was the only antibiotic that maintained the same extent of killing regardless of tolerance mechanism. Further studies to evaluate additional antistaphylococcal antibiotics and different inducers of tolerance are warranted. Disclosures All Authors: No reported disclosures.

Impact of vancomycin use trend change due to the availability of alternative antibiotics on the prevalence of Staphylococcus aureus with reduced vancomycin susceptibility: a 14-year retrospective study

BackgroundWe investigated the trend change in vancomycin-intermediate Staphylococcus aureus (VISA)/heterogeneous VISA (hVISA) prevalence among methicillin-resistant S. aureus (MRSA) bacteremia strains and antistaphylococcal antibiotic use together with mutation studies of vancomycin resistance-related gene loci to evaluate the impact of changes in antibiotic use after new antistaphylococcal antibiotics became available.MethodsAmong 850 healthcare-associated MRSA isolates from 2006 to 2019 at a tertiary hospital in South Korea, hVISA/VISA was determined by modified PAP/AUC analysis, and the identified hVISA/VISA strains were genotyped. Gene mutations at vraSR, graSR, walKR, and rpoB were studied by full-length sequencing. Antistaphylococcal antibiotic use in 2005–2018 was analyzed.ResultsTwo VISA and 23 hVISA strains were identified. The prevalence rate ratio of hVISA/VISA carrying mutations at the two-component regulatory systems among MRSA was 0.668 (95% CI 0.531–0.841; P = 0.001), and the prevalence rate ratio of hVISA/VISA carrying rpoB gene mutations was 1.293 (95% CI 0.981–1.702; 174 P = 0.068). Annual vancomycin use density analyzed by days of therapy (DOT) per 1,000 patient-days did not decrease significantly, however the annual average length of time analyzed by the number of days vancomycin was administered for each case showed a significantly decreasing trend.ConclusionsDuring the 14-year period when the average length of vancomycin therapy decreased every year with the availability of alternative antibiotics, the prevalence of hVISA/VISA did not decrease significantly. This seems to be because the resistant strains carrying the rpoB mutations increased despite the decrease in the strains carrying the mutations at the two-component regulatory systems.

Role of Staphylococcus aureus in the pathogenesis of folliculitis decalvans

Folliculitis decalvans (FD) is an inflammatory cicatricial alopecia. Its aetiology remains unclear but an imbalance of skin microbiota seems to play a special role in the pathogenesis. The normal subepidermal microbiota resides in hair follicles and protects from opportunistic infections. Previously Staphylococcus aureus (S. aureus) was postulated to play the main role in the pathogenesis of the disease, but recent findings show it is rather opportunistic than a specific pathogen in FD. Staphylococcus aureus colonizing FD does not seem to be more virulent than one isolated from the general population, however, only a partial response to standard anti-staphylococcal antibiotic treatment suggests rather gram-negative aetiology. Antibiotic therapy may prove effective to reduce bacterial load below the threshold that triggers the immune system, but the microbiota found in FD after antibiotic treatment is not entirely restored to normal. Unbalanced microbiota with the reservoir of commensal and opportunistic bacteria in hair follicles may stoke unspecific responses of the immune system, therefore causing chronic inflammation.

Cefadroxil Comparable to Cephalexin: Minimum Inhibitory Concentrations among Methicillin-Susceptible Staphylococcus aureus Isolates from Pediatric Musculoskeletal Infections.

ABSTRACTCephalexin and cefadroxil are oral first-generation cephalosporins used to treat methicillin-susceptible Staphylococcus aureus (MSSA) infections. Despite its shorter half-life, cephalexin is more frequently prescribed, although cefadroxil is an appealing alternative, given its slower clearance and possibility for less frequent dosing. We report comparative MIC distributions for cefadroxil and cephalexin, as well as for oxacillin, cephalothin, ceftaroline, and cefazolin, for 48 unique clinical MSSA isolates from pediatric patients with musculoskeletal infections. Both cefadroxil and cephalexin had MIC50 values of 2 μg/mL and MIC90 values of 4 μg/mL. MIC50s for oxacillin, cephalothin, and ceftaroline were ≤0.25 μg/mL, and cefazolin’s MIC50 was 0.5 μg/mL. While cefadroxil and cephalexin MICs are higher than those for other active agents, the distributions of MICs for cefadroxil and cephalexin are statistically equivalent, suggesting similar in vitro MSSA activities. Cefadroxil should be further considered an alternative agent to cephalexin, although additional work is needed to identify the optimal dose and frequency of these antibiotics for the treatment of serious MSSA infections.IMPORTANCE Cephalexin and cefadroxil are oral antibiotics that are used to treat serious infections due to the bacteria MSSA. While cephalexin is used more commonly, cefadroxil is excreted from the body more slowly; this generally allows patients to take cefadroxil less frequently than cephalexin. In this study, we compared the abilities of cefadroxil, cephalexin, and several other representative intravenous antibiotics to inhibit the growth of MSSA in the laboratory. Bacterial samples were obtained from children with bone, joint, and/or muscle infections caused by MSSA. We found that cefadroxil and cephalexin inhibited the growth of MSSA at similar concentrations, suggesting similar antibacterial potencies. The selected intravenous antistaphylococcal antibiotics generally inhibited bacterial growth with lower antibiotic concentrations. Based on these results, cefadroxil should be further considered an alternative oral antibiotic to cephalexin, although future research is needed to identify the optimal dose and frequency of these antibiotics for serious infections.