Oral Beta-lactam Research Articles

Synergistic oral beta-lactam combinations for treating tuberculosis.

The enormous burden of tuberculosis (TB) worldwide is a major challenge to human health, but the costs and risks associated with novel drug discovery have limited treatment options for patients. Repurposing existing antimicrobial drugs offers a promising avenue to expand TB treatment possibilities. This study aimed to explore the activity and synergy of beta-lactams in combination with a beta-lactamase inhibitor, which have been underutilised in TB treatment to date. Based on inhibitory concentration, oral bioavailability and commercial availability, seven beta-lactams (cefadroxil, tebipenem, cephradine, cephalexin, cefdinir, penicillin V, flucloxacillin), two beta-lactamase inhibitors (avibactam and clavulanate), and three second-line TB drugs (moxifloxacin, levofloxacin and linezolid) were selected for combination in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit (CFU) enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index (DRI). The order of activity of beta-lactams was cefadroxil>tebipenem>cephradine>cephalexin>cefdinir>penicillin V>flucloxacillin. The addition of clavulanate improved beta-lactam activity to a greater degree than the addition of avibactam. As a result, avibactam was excluded from further investigations, which focused on clavulanate. Synergy was demonstrated for cefdinir/cephradine, cefadroxil/tebipenem, cefadroxil/penicillin V, cefadroxil/cefdinir, cephalexin/tebipenem, cephalexin/penicillin V, cephalexin/cefdinir, cephalexin/cephradine and cefadroxil/cephalexin, all with clavulanate. However, combining beta-lactams with moxifloxacin, levofloxacin or linezolid resulted in antagonistic effects, except for the combinations of penicillin V/levofloxacin, penicillin V/moxifloxacin and cefdinir/moxifloxacin. Beta-lactam synergy may provide viable combination therapies for the treatment of TB.

Colonisation by multidrug-resistant organisms in health workers in primary care: narrow spectrum oral antimicrobials are a risk factor.

Limited information exists on carriage of multidrug-resistant organisms (MDRO) by health workers (HWs) in primary care settings. This study aims to determine the prevalence of MDRO carriage among HWs in primary care and to identify associated risk factors. A cross-sectional study was conducted across all 12 primary care units in São Caetano do Sul-SP, Brazil, from October to December 2023. Self-collected samples (nasal, oropharyngeal, and inguinal) were obtained. Environment cultures (potable water, sewage and stream water) were evaluated. Stenotrophomonas maltophilia isolates (human and environmental) were typed. The study included 265/288 (92%) of HWs in primary care teams, mostly women with a median age of 47years (IQR 38-57); 78% had no comorbidities. MDRO colonisation was found in 8.7% (23 HWs). The following bacteria were found: S. maltophilia (n = 9; 3.4%) in inguinal swabs; methicillin-resistant Staphylococcus aureus (n = 8; 3%) from all sites; extended-spectrum ß-lactamase-producing bacteria (n = 5; 2%) in inguinal swabs; and vancomycin-resistant enterococci in an inguinal swab (n = 1; 0.4%). Previous antibiotic use was significantly associated with MDRO colonisation (OR 2.91, 95% CI 1.19-7.09, p = 0.018), mainly narrow spectrum oral beta-lactams and macrolides. S. malthophilia was polyclonal and human and environmental isolates differed. Colonisation by MRSA, VRE, and ESBL-producing bacteria was low; however, 4% were surprisingly colonized by polyclonal S. maltophilia. This pathogen may also suggest using narrow-spectrum rather than the expected broad-spectrum antimicrobials. Antibiotic use was the only risk factor found, mainly with oral narrow-spectrum drugs.

Rise of the beta-lactams: a retrospective, comparative cohort of oral beta-lactam antibiotics as step-down therapy for hospitalized adults with acute pyelonephritis

Rise of the beta-lactams: a retrospective, comparative cohort of oral beta-lactam antibiotics as step-down therapy for hospitalized adults with acute pyelonephritis

189. Outcomes of High-dose Oral Beta-lactam Step-down Therapy Compared to Alternative Oral Therapy for Bacteremic Urinary Tract Infections

Abstract Background Pyelonephritis and associated bacteremia are often treated with intravenous antibiotics followed by oral step-down therapy to a fluoroquinolone (FQ) or trimethoprim/sulfamethoxazole (TMP/SMX). Oral beta-lactams were historically utilized less often due to concern for treatment failure. Literature suggests oral beta-lactams are effective, but there are no preferred oral beta-lactam agents or dosing recommendations. This study evaluates outcomes of high-dose oral beta-lactam therapy for Enterobacterales bacteremia due to a urinary tract infection (UTI) compared to alternative therapy. Methods A retrospective, multicenter, observational cohort study was conducted evaluating patients admitted from February 1, 2020, to October 1, 2022, with gram-negative bacteremia from a urinary source. Adult patients were included if they received empiric intravenous antibiotic active against the bacteria isolated and transitioned to appropriately dosed oral cephalexin, amoxicillin, TMP/SMX, or FQ (Table 1). Excluded were patients who received less than 72 hours of oral therapy, had a diagnosis of renal abscess or lobar nephronia, and those who expired during admission. The primary outcome compared the composite of recurrent bacteremia or mortality within 30 days of completing oral therapy. Secondary outcomes included recurrent UTI, emergency department (ED) or hospital readmission, and Clostridioides difficile infections within 30 days of treatment completion. Results There were 194 patients who met inclusion criteria. The primary outcome occurred in 1/75 (1.3%) patients in the oral beta-lactam group and 2/119 (1.7%) patients in the FQ or TMP/SMX group (p=1.0). Two patients in the FQ or TMP/SMX expired within 30 days and 1 patient in the beta-lactam group had a recurrent bacteremia. There were 16 (21.3%) and 14 (11.8%) patients in the beta-lactam and FQ or TMP/SMX group, respectively, treated for recurrent UTI (p=0.073). Twenty (27%) patients in the beta-lactam group required ED re-evaluation or hospital readmission compared to 30 (25%) patients who received a FQ or TMP/SMX (p=0.74). Zero patients had a Clostridioides difficile infection. Conclusion Oral beta-lactams are as effective as oral FQ and TMP/SMX for the treatment of bacteremia from a urinary source. Disclosures All Authors: No reported disclosures

Switch to oral antibiotics in Gram-negative bacteraemia: a randomized, open-label, clinical trial

ObjectivesTo evaluate the safety and efficacy of switching from intravenous (IV) to oral antimicrobial therapy in patients with Enterobacterales bacteraemia, after completion of 3–5 days of microbiologically active IV therapy. MethodsA multicentre, open-label, randomized trial of adults with monomicrobial Enterobacterales bacteraemia caused by a strain susceptible to ≥1 oral beta-lactam, quinolone, or trimethoprim/sulfamethoxazole. Inclusion criteria included completion of 3–5 days of microbiologically active IV therapy, being afebrile and haemodynamically stable for ≥48 hours, and absence of an uncontrolled source of infection. Pregnancy, endocarditis, and neurological infections were exclusion criteria. Randomization, stratified by urinary source of bacteraemia, was to continue IV (IV Group) or to switch to oral therapy (Oral Group). Agents and duration of therapy were determined by the treating physicians. The primary endpoint was treatment failure, defined as death, need for additional antimicrobial therapy, microbiological relapse, or infection-related re-admission within 90 days. Non-inferiority threshold was set at 10% in the 95% CI for the difference in the proportion with treatment failure between the Oral and IV Groups in the modified intention-to-treat population. The protocol was registered at ClinicalTrials.gov (NCT04146922). ResultsIn the modified intention-to-treat population, treatment failure occurred in 21 of 82 (25.6%) in the IV Group, and 18 of 83 (21.7%) in the Oral Group (risk difference –3.7%, 95% CI –16.6% to 9.2%). The proportions of subjects with any adverse events (AE), serious AE, or AE leading to treatment discontinuation were comparable. DiscussionIn patients with Enterobacterales bacteraemia, oral switch, after initial IV antimicrobial therapy, clinical stability, and source control, is non-inferior to continuing IV therapy.

Use of a beta-lactam graded challenge process for inpatients with self-reported penicillin allergies at an academic medical center.

The Antimicrobial Stewardship Program (ASP) at Nebraska Medicine collaborated with a board-certified allergist to develop a penicillin allergy guidance document for treating inpatients with self-reported allergy. This guidance contains an algorithm for evaluating and safely challenging penicillin-allergic patients with beta-lactams without inpatient allergy consults being available. Following multi-disciplinary review, an order set for beta-lactam graded challenges (GC) was implemented in 2018. This contains recommended monitoring and detailed medication orders to challenge patients with various beta-lactam agents. Inpatient orders for GC from 3/2018-6/2022 were retrospectively reviewed to evaluate ordering characteristics, outcomes of the challenge, and whether documentation of the allergy history was updated. All beta-lactam challenges administered to inpatients were included, and descriptive statistics were performed. Overall, 157 GC were administered; 13 with oral amoxicillin and 144 with intravenous (IV) beta-lactams. Ceftriaxone accounted for the most challenges (43%). All oral challenges were recommended by an Infectious Diseases consult service, as were a majority of IV challenges (60%). Less than one in five were administered in an ICU (19%). Almost all (n = 150, 96%) were tolerated without any adverse event. There was one reaction (1%) of hives and six (4%) involving a rash, none of which had persistent effects. Allergy information was updated in the electronic health record after 92% of the challenges. Both intravenous and oral beta-lactam graded challenges were implemented successfully in a hospital without a regular inpatient allergy consult service. They were well-tolerated, administered primarily in non-ICU settings, and were often ordered by non-specialist services. In patients with a self-reported penicillin allergy, these results demonstrate the utility and safety of a broadly adopted beta-lactam GC process.

Oral antimicrobial therapy for cellulitis versus outpatient parenteral antimicrobial therapy: a single-centre audit of cellulitis outcomes.

Cellulitis is a common acute skin and soft tissue infection that causes substantial morbidity and healthcare costs. To audit the impact on cellulitis management, regimen tolerability and outcomes of switching from outpatient parenteral antimicrobial therapy (OPAT) using intravenous (i.v.) cefazolin once daily plus probenecid to oral beta-lactam therapy (OBLT) using oral flucloxacillin plus probenecid. We undertook a retrospective audit on cellulitis management, regimen tolerability and outcomes at the Dunedin Public Hospital Emergency Department (ED) before and after a change of the local outpatient cellulitis treatment pathway from OPAT using i.v. cefazolin once daily plus probenecid to OBLT using oral flucloxacillin plus probenecid. OPAT was used in 97/123 (78.9%) patients with cellulitis before compared to 1/70 (1.4%) after the pathway change (odds ratio (OR), 0.04, P < 0.01). OBLT was used in 26/123 (21.1%) patients with cellulitis before and 69/70 (98.6%) after (OR, 218.8, P < 0.01). Antimicrobial change due to intolerance occurred in 4/123 (3.2%) patients with cellulitis before and 4/70 (5.7%) after (OR, 1.8, P, not significant (NS)) the pathway change. Inpatient admission within 28 days occurred in 15/123 (12.2%) cellulitis patients before and 9/70 (12.9%) after (OR, 1.1, P, NS) the pathway change. Implementation of a change in outpatient cellulitis treatment pathway resulted in a significant change in prescribing practice. Our findings suggest that OBLT was both tolerable and had similar outcomes to OPAT.

The Epidemiology of Antibiotic-Related Adverse Events in the Treatment of Diabetic Foot Infections: A Narrative Review of the Literature.

The use of antibiotics for the treatment of diabetic foot infections (DFIs) over an extended period of time has been shown to be associated with adverse events (AEs), whereas interactions with concomitant patient medications must also be considered. The objective of this narrative review was to summarize the most frequent and most severe AEs reported in prospective trials and observational studies at the global level in DFI. Gastrointestinal intolerances were the most frequent AEs, from 5% to 22% among all therapies; this was more common when prolonged antibiotic administration was combined with oral beta-lactam or clindamycin or a higher dose of tetracyclines. The proportion of symptomatic colitis due to Clostridium difficile was variable depending on the antibiotic used (0.5% to 8%). Noteworthy serious AEs included hepatotoxicity due to beta-lactams (5% to 17%) or quinolones (3%); cytopenia's related to linezolid (5%) and beta-lactams (6%); nausea under rifampicin, and renal failure under cotrimoxazole. Skin rash was found to rarely occur and was commonly associated with the use of penicillins or cotrimoxazole. AEs from prolonged antibiotic use in patients with DFI are costly in terms of longer hospitalization or additional monitoring care and can trigger additional investigations. The best way to prevent AEs is to keep the duration of antibiotic treatment short and with the lowest dose clinically necessary.

Outcomes of high-dose oral beta-lactam definitive therapy compared to fluoroquinolone or trimethoprim-sulfamethoxazole oral therapy for bacteremia secondary to a urinary tract infection.

Compare outcomes of patients receiving high-dose oral beta-lactam versus standard oral therapy for Enterobacterales bacteremia from a urinary tract infection (UTI). Retrospective, multicenter, observational cohort. Three Michigan community teaching hospitals. Adult patients admitted between February 1, 2020, and October 1, 2022, with gram-negative bacteremia from a urinary source were evaluated. Patients receiving active empiric intravenous (IV) antibiotics and transitioned to appropriately dosed oral cephalexin, amoxicillin, fluoroquinolone (FQ), or trimethoprim/sulfamethoxazole (TMP/SMX) were included. Patients receiving less than 72 hours of oral therapy, diagnosed with renal abscess, lobar nephronia, or expired during admission were excluded. Standard oral therapy was defined as FQ or TMP/SMX. The primary outcome compared the composite of recurrent bacteremia or mortality within 30 days of therapy between groups. Secondary outcomes compared recurrent UTI, emergency department or hospital readmission, and Clostridioides difficile within 30 days. 194 patients were included (beta-lactam, n = 75 vs standard therapy, n =119). Patients in both groups were treated for a median of 11 days, with 4 days IV and 7 days oral therapy. There was no difference in the primary outcome between groups (beta-lactam 1.3% vs standard therapy 1.7%, OR 1.27 [95% CI 0.11-14.2]). No patients experienced C. difficile in either group (p = 1.0). Infectious disease consultation was independently associated with standard therapy prescribing (OR 4.4 [95% CI 2.24-8.26]). High-dose oral beta-lactams were as safe and effective as oral FQ or TMP/SMX for the treatment of bacteremia from a urinary source. Most patients received 8-10 days of therapy in both groups.

Comparative-Effectiveness of Oral Beta-Lactams and Fluoroquinolones for Stepdown Therapy in Patients with Enterobacterales Bloodstream Infections: A Retrospective Cohort Study.

Background: This study compares treatment failure for patients who received oral beta-lactams (BLs) and fluoroquinolones (FQs) for stepdown treatment of Enterobacterales bloodstream infections (BSIs). Methods: We conducted a single-center, retrospective, age- and sex-matched, cohort study, at a Veterans Affairs (VA) hospital in South Texas. Eligible patients were at least 18 years of age with a monomicrobial BSI treated with a single oral BL or FQ antibiotic. Treatment failure was defined as recurrence or all-cause mortality within 90 days of documented BSI. Bivariate (chi-square, Fisher's Exact, and Wilcoxon Rank Sum) and multivariate (logistic regression) statistical tests were used to compare groups. Results: A total of 130 patients were included in this study, with 65 patients per group. Groups were well balanced with respect to exact age, sex assigned at birth, Caucasian race, source control, intensive care unit admission, and Charlson Comorbidity Index. Importantly, 60% of patients in the BL group had cultures that were resistant to FQs and 71% were prescribed cefpodoxime. Patients in the BL group had higher median (interquartile range [IQR]) Pitt bacteremia scores than those in the FQ group: 2 (1-4) vs. 1 (1-2), p=0.04. Patients in the BL group also had a higher median (IQR) duration of intravenous (IV) antibiotics than those in the FQ group: 5 (3-7) vs. 4 (3-5), p=0.02. Treatment failure was statistically comparable for patients in the BL and FQ groups: 15% vs. 12%, p=0.61. This finding was consistent in a multivariate logistic regression model with group (BL vs. FQ) as the independent variable, treatment failure as the dependent variable, and Pitt bacteremia score and duration of IV antibiotics as covariates (OR: 0.76, 95% CI: 0.27-2.18). One patient in the FQ group experienced Clostridioides difficile infection. Conclusion: This study suggests that BLs may be as effective as FQs for oral stepdown treatment of Enterobacterales BSI without the potential associated risks. Furthermore, in the setting of FQ-resistant Enterobacterales BSI secondary to urinary source, third generation oral cephalosporins (i.e., cefpodoxime) may be reasonable alternatives.

Oral step-down with β-lactams for uncomplicated Enterobacterales bacteraemia

The preferred definitive treatments for invasive Enterobacterales infections, parenteral antibiotics, oral fluoroquinolones, and oral trimethoprim-sulfamethoxazole, are increasingly limited leading to interest in additional options [1–3]. Oral beta-lactams are a conceptionally attractive option because of their high tolerability and activity against Enterobacterales that do not meaningfully express ampC beta-lactamases, but views on their role are mixed due to concerns for subtherapeutic serum concentrations [1].

1843. Intravenous versus Partial Oral Antibiotic Therapy in the Treatment of Uncomplicated Bloodstream Infection due to Streptococcus species

Abstract Background Effectiveness of oral antibiotics for transition of therapy in uncomplicated bloodstream infections (BSI) due to Streptococcus species remains unclear. This retrospective cohort study examines effectiveness of partial oral antibiotic regimens in patients with uncomplicated BSI due to Streptococcus species compared to standard intravenous (IV) only therapy. Methods Adult patients with uncomplicated BSI due to Streptococcus species from April 2016 through June 2020 in 7 hospitals within Prisma Health in South Carolina were evaluated. Patients who died within 7 days of BSI were excluded to reduce the impact of survival bias. Multivariate Cox proportional hazards regression was used to examine time to treatment failure, defined as a composite of all-cause mortality and BSI recurrence within 90 days. Results A total of 222 patients with Streptococcus species BSI were included in the analysis. Overall, the median age was 62 years, and 116 (52.3%) were men. Beta-hemolytic streptococci (87; 39.2%) were the most common bloodstream isolates, followed by S. pneumoniae (76; 34.2%) and viridans group streptococci (59; 26.6%). Among this cohort, 99 patients received only IV antibiotics, and the remaining 123 received partial oral therapy. The median duration of therapy in both groups was 14 days, and median duration of IV antibiotics prior to oral transition was 4 days. Most patients in the partial oral group were transitioned to either oral beta-lactams (62; 50.4%) or fluoroquinolones (47; 38.2%). Of the IV only group, 46 (46.5%) required outpatient IV antibiotics. Treatment failure rates were 12.0% and 4.4% in the IV only and partial oral therapy groups, respectively (p=0.04). After adjustments for age, chronic comorbidities, and initial response to therapy within the first 72-96 hours, there was no difference in the risk of treatment failure in the partial oral compared to IV only group (hazards ratio 0.55, 95% CI 0.19-1.64; p=0.28). Conclusion Transitioning patients from IV to oral antibiotics may be a reasonable strategy in the management of uncomplicated BSI due to Streptococcus species. Partial oral therapy does not seem to have a higher treatment failure rate than standard IV only therapy and may spare many patients from outpatient IV antibiotics. Disclosures All Authors: No reported disclosures.

2238. Estimating the impact of antibiotic exposure on antibiotic resistance in uncomplicated UTI using machine learning causal inference

Abstract Background Incorporating an antibiotic’s propensity for engendering resistance to itself and other antibiotics is a potentially useful strategy for preventing antimicrobial resistance (AMR), but prospective studies have been difficult to generalize to outpatients and retrospective studies are prone to design errors and model misspecification. To address this gap, we apply causal inference with targeted maximum likelihood estimation (TMLE) using machine learning, to data from the electronic health record to define the antibiotic use-resistance relationship for common outpatient therapies used to treat urinary tract infection (UTI). Methods We estimated the risk of AMR in response to treatment in a cohort of outpatients with uncomplicated UTI in the Mass General Brigham health system between 2016 and 2021. We sought to emulate a randomized controlled trial using the targeted maximum likelihood (TMLE) approach with logistic regression, random forests, multilayer perceptrons, and XGBoost to mitigate confounding by indication and to model the outcome (Figure 1). Potential confounders include demographics, comorbidities and prior microbiology, windowed in time for temporally varying features (Figure 2). We quantified the average treatment effect (ATE) of exposure to nitrofurantoin (NIT, target trial 1) or fluoroquinolones (FQs, target trial 2) to any other antibiotic type on the risk of AMR to NIT, FQs or amoxicillin-clavulanate at 12 months post-exposure. Figure 1:Analytic frameworkFramework for targeted maximum likelihood estimation (TMLE) of causal impacts.Figure 2:Causal diagrama) Conceptual model for the emergence of AMR with observed and unobserved features and b) causal diagram for inference model. Results Our final cohort consisted of 4,573 patients with no baseline AMR or antibiotic exposure in the previous 12 months who were treated with NIT, FQs or oral beta-lactams. XGBoost models significantly outperformed other model types. Compared to other antibiotics, the ATE of NIT exposure to NIT resistance at 12 months was 0.05 (0.04 – 0.07) and for FQ resistance was 0.06 (0.05, 0.08). Exposure to NIT had no impact on the risk of resistance to AMC at 12 months. Exposure to FQs had no impact on resistance to FQs, NIT or AMC at 12 months (Figure 3). Figure 3:Average treatment effectsATEs for the impact of NIT or FQs on the risk of AMR to NIT, FQs or AMC at 12 months using a) logistic regression, b) random forest, c) multilayer perceptron and d) XGBoost models Conclusion Outpatients treated with NIT had a higher risk of AMR at 12 months than those treated with FQs. Future work will focus on including hospital exposures and immunosuppression into models and infer impact using a wider range of treatments. Disclosures Sanjat Kanjilal, MD, MPH, GlaxoSmithKline: Advisor/Consultant|Roche Diagnostics: Honoraria David Sontag, PhD, Adobe: Grant/Research Support|ASAPP: Advisor/Consultant|Cureai Health: Stocks/Bonds|Facebook: Grant/Research Support|Google: Grant/Research Support|IBM: Grant/Research Support|SAP: Grant/Research Support|Takeda: Grant/Research Support.

1822. Clinical Outcomes Associated with Oral Beta-Lactam Therapy versus Oral Fluoroquinolones/TMP-SMX for Uncomplicated Gram-Negative Bacteremia

Abstract Background Agents commonly used as oral step-down therapy in Enterobacterales bacteremia include fluoroquinolones and TMP-SMX. The use of these oral agents have been associated with adverse events. Oral β-lactams are not recommended to treat Enterobacterales bacteremia because of concerns for sub-therapeutic serum concentrations. Given the limited data on clinical effectiveness of oral β-lactams and increased limitations with fluoroquinolones and TMP-SMX, oral β-lactams may be an alternative option. The purpose of this study is to evaluate the clinical effectiveness in patients transitioned to oral β-lactams versus fluoroquinolones or TMP-SMX for the step-down treatment of uncomplicated Enterobacterales bacteremia. Methods A multi-center, retrospective, propensity-score matched, observational cohort study was conducted from July 1, 2017 to December 31, 2020, at 11 Memorial Hermann Health System hospitals among 690 patients with uncomplicated Enterobacterales bacteremia. Patients were included if they received &amp;gt; 1 day of intravenous antibiotic therapy followed by definitive oral step-down therapy with a β-lactam, fluoroquinolone, or TMP-SMX. The primary outcome was treatment failure within 30 days of starting oral antibiotics, defined as at least one of the following: recurrent bacteremia, transition to IV antibiotics, new-onset sepsis, 30-day readmission, or 30-day all-cause mortality. Results After the patients were propensity score matched 1:1, a total of 199 patients with uncomplicated Enterobacterales bacteremia were included in each group. Treatment failure occurred in 8 patients (4%) who received β-lactams and 10 patients (5%) who received fluoroquinolones or TMP-SMX (OR, 0.79 [95% CI, 0.306-2.04] p-value 0.629). Median length of hospital stay was 5 days for both groups (p-value 0.911), and median duration of oral antibiotics was 10 days in the fluoroquinolone or TMP-SMX group and 11 days in the β-lactam group (p-value 0.377). Conclusion Based on the results of this study, no significant difference in treatment failure was seen in patients who were transitioned to β-lactams versus fluoroquinolones or TMP-SMX as oral step-down therapy for uncomplicated Enterobacterales bacteremia. Oral β-lactams appear to be a safe and effective option. Disclosures All Authors: No reported disclosures.

A retrospective review of oral cephalosporins versus fluoroquinolones for the treatment of pyelonephritis.

BackgroundThe current Infectious Diseases Society of America guidelines for the treatment of acute uncomplicated pyelonephritis (AUP) advise caution when using oral beta-lactams due to concern for potentially inferior efficacy compared to fluoroquinolones (FQs) and trimethoprim-sulfamethoxazole; however, studies specifically evaluating the efficacy of oral cephalosporins (CPs) in AUP are limited.ObjectiveTo assess the safety and efficacy of oral CPs versus FQs for the treatment of AUP.Design, setting and participantsThis is a retrospective, chart review study conducted at a single-center, tertiary care hospital.MeasurementsThe primary endpoint was treatment failure within 30 days, defined as a change in antibiotic or return to ED or clinic due to persistent symptoms. Secondary endpoints included adverse drug reactions (ADRs) and C. difficile infection (CDI) within 30 days.ResultsOf the 343 patients included in the study, treatment failure occurred in 54/338 (16.0%) patients and was similar between oral CPs and FQs (35/229 [15.3%] vs. 19/109 [17.4%]). A higher percentage of treatment failures were observed for third generation (3GC) and first generation (1GC) CPs compared to second generation CPs (2GC) (3GC: 15/65 [23.4%]; 1GC: 11/49 [22.4%]; 2GC: 9/115 [7.8%]). Documented ADRs were low (6/343 [1.7%]) and no cases of CDI were documented.ConclusionsOral CPs appear to be as safe and effective as FQs for the treatment of AUP. Fewer treatment failures were noted with 2GCs as compared to 3GCs and 1GCs.

MIC Discrepancies between Parenteral and Oral Anti-Staphylococcal Beta-Lactams among MSSA

Introduction: Recent evidence has shown that oral antibiotic therapy is not inferior to IV antibiotic therapy in the treatment of complicated Staphylococcus aureus infections. Therefore, oral antibiotic therapy is now frequently prescribed in clinical practice due to cost benefit, ease of administration, decreased complication rate, and lack of need for IV access. In vitro susceptibility testing for β-lactam oral antibiotics is not routinely performed as the guidelines provided by the Clinical and Laboratory Standards Institute (CLSI) recommend using oxacillin and cefoxitin as surrogate markers. Hence, oral antibiotic susceptibilities for cephalexin and dicloxacillin are not reported and implied based on oxacillin and cefoxitin. The objective of the current study was to determine whether susceptibilities among S. aureus isolates are predictable when comparing commonly used IV and oral beta-lactams. Methods: Cefazolin, cephalexin, dicloxacillin, and oxacillin broth microdilution minimum inhibitory concentrations (MICs) were determined for 100 clinical isolates of methicillin-sensitive S. aureus by broth microdilution following CLSI guidelines. Results: Among these isolates, median MICs for cephalexin were eight-fold higher than cefazolin MICs and median MICs for dicloxacillin were four-fold less than oxacillin MICs. Ten percent of more strains studied had a major or very major error in its susceptibility reporting when cephalexin was compared to its surrogate marker oxacillin. Discussions/Conclusions: The variations in MICs observed compounded with the dosing and pharmacokinetic differences of oral versus IV β-lactam suggests that establishing breakpoints for oral β-lactam antibiotics is necessary to ensure adequate therapy is selected for the treatment of complex S. aureus infections.

The efficacy of pivmecillinam in oral step-down treatment in hospitalised patients with E. coli bacteremic urinary tract infection; a single-arm, uncontrolled treatment study

BackgroundThe role of oral beta-lactam antibiotics in treating febrile urinary tract infections (UTI) is not yet definite. Today, fluoroquinolones together with trimethoprim–sulfamethoxazole (TMP–MTX) are considered standard of care and often the only available evidence-based oral treatment for febrile UTI. This study clarifies the efficacy and safety of pivmecillinam (PIV) used as step-down therapy for bacteremic urinary tract infection (UTI).MethodsA single-arm, uncontrolled treatment trial was conducted in the period September 2017–March 2020. Candidates for inclusion were men and women suffering from E. coli bacteremia due to UTI and were consecutively included in a Norwegian hospital. Exclusion criteria were among others: other ongoing bacterial infection, septic shock, pyonephrosis/abscess and pregnancy. After 3 days of parenteral antibiotic, the treatment was converted to the study drug; oral PIV 400 mg QID for 1 week. Primary endpoint was a combination of three elements; afebrility, no need for retreatment and improvement in self-reported health status. Test Of Cure (TOC) was 1 week post-treatment. Secondary endpoints included among others microbiological efficacy and CRP value < 30 mg/L.ResultsOf 476 screened subjects, 53 patients were included. Median age was 67 years, 28 (56%) were women. 50 patients were evaluated for per-protocol analysis. 44 of 50 patients (88%) (95% CI [75.7–95.5]) reached the primary endpoint on TOC. 14 of 48 patients (29.2%) had significant growth (> 103 CFU/mL) of E.coli on TOC. CRP-level was strongly associated to treatment outcome, (OR 0.006 [95% CI 0.00–0.11], p < 0.001).ConclusionsThis trial documents that PIV 400 mg QID given for 1 week following 3 days of parenteral antibiotics, is a suitable treatment option in patients suffering from bacteremic UTI due to E. coli. Randomised clinical trials studying the efficacy of PIV vs standard of care of febrile UTI are warranted.Trial registration The trial was registered at ClinicalTrials.gov under the identifier: NCT03282006 13/09/2017 and approved by The Regional Committees for Medical Research Ethics South East Norway (2015/2384/REK sør-øst) and the Norwegian Medicines Agency (SLV; reference No 16/06018-09; EudraCT No 2016-000984-18) before initiation

Risk Factors for Relapse in Acute Bacterial Prostatitis: the Impact of Antibiotic Regimens.

ABSTRACTThe aim of the study was to analyze the risk factors for relapse in patients with acute bacterial prostatitis (ABP), focusing on the impact of different antibiotic regimens. We conducted an observational study of all patients diagnosed with ABP (irritative and/or obstructive urinary symptoms, temperature of >37.8°C, and the presence of bacteriuria in urine culture, in the absence of data suggesting pyelonephritis) from January 2017 to December 2018. The main outcome was relapse. We performed a multivariate analysis to identify the risk factors associated with relapse. A propensity score with inverse weighting was applied to attenuate antibiotic selection bias. We included 410 patients. The mean age was 68 years; 28.8% had diabetes mellitus, and 61.1% benign prostatic hyperplasia. The most common isolated bacteria were Escherichia coli (62.4%) and Klebsiella spp. (10%). The overall resistance rate was 39.5% to quinolones. The mortality rate was 1.2%, and the relapse rate was 6.3%. The only independent risk factor for relapse was inadequate antibiotic therapy (odds ratio [OR] 12.3; 95% confidence interval [95% CI], 3.5 to 43.1). When the antibiotic was modified according to the susceptibility pattern, the rates of relapse were 1.8% in those treated with ciprofloxacin, 3.6% with intravenous beta-lactam, 9.3% with co-trimoxazole, and 9.8% with oral (p.o.) beta-lactam (P = 0.03). Treatment with oral beta-lactam (OR, 5.3; 95% CI, 1.2 to 23.3) and co-trimoxazole (OR, 4.9; 95% CI, 1.1 to 23.2) were associated with a risk of relapse. In this large real-life observational study, a significantly higher relapse rate was observed when antibiotic treatment was inadequate. When the antibiotic was tailored, quinolones and intravenous beta-lactams had a lower relapse rate than co-trimoxazole and oral beta-lactams.IMPORTANCE In the manuscript, we report a large series of acute bacterial prostatitis cases and describe data about the etiology, antibiotic resistance rate, and outcome, specially focused on the risk factors for relapse. We found high rates of resistance to the most frequently used antibiotics and a high relapse rate in patients whose treatment was not adjusted according to their microbiological susceptibility. We did not observe differences, though, in mortality or relapse according to appropriate or inappropriate empirical treatment. What is new in this article is the different relapse rates observed depending upon the definitive adequate antibiotic used. Quinolones and intravenous (i.v.) beta-lactam have lower rates of relapse (1.8% and 3.6%, respectively) compared to co-trimoxazole and oral (p.o.) beta-lactam (3.3% and 9.8%, respectively). Clinicians should carefully choose an adequate antibiotic for definitive ABP treatment depending on the results of microbiological isolation, using quinolones as the first option. Whenever quinolones cannot be administered, i.v. beta-lactams seem to be the second-best option.

Predicting Oral Beta-lactam susceptibilities against Streptococcus pneumoniae

BackgroundOral beta-lactam antimicrobials are not routinely tested against Streptococcus pneumoniae due to presumed susceptibility based upon penicillin minimum inhibitory concentration (MIC) testing. Currently, Clinical and Laboratory Standards Institute provides comments to use penicillin MIC ≤0.06 to predict oral cephalosporin susceptibility. However, no guidance is provided when cefotaxime MIC is known, leading to uncertainty with interpretation. The purpose of this study was to evaluate cefotaxime and penicillin MICs and their respective correlation to oral beta-lactam categorical susceptibility patterns.Methods249 S. pneumoniae isolates were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-ToF) and then tested by broth microdilution method to penicillin, cefotaxime, amoxicillin, cefdinir, cefpodoxime, and cefuroxime.ResultsUsing Clinical and Laboratory Standards Institute (CLSI) non-meningitis breakpoints for cefotaxime, 240/249 isolates were classified as susceptible. Of the cefotaxime susceptible isolates, 23% of the isolates are misrepresented as cefdinir susceptible. Amoxicillin correlated well with penicillin MIC breakpoints with only 1 discordant isolate out of 249.ConclusionThe correlation between amoxicillin and penicillin creates a very reliable predictor to determine categorical susceptibility. However oral cephalosporins were not well predicted by either penicillin or cefotaxime leading to the possible risk of treatment failures. Caution should be used when transitioning to oral cephalosporins in cefotaxime susceptible isolates, especially with higher cefotaxime MICs.

1689. Oral Beta-lactam Step Down in Bacteremic E. coli Urinary Tract Infections

BackgroundLiterature is scarce regarding oral step down to beta-lactams in bacteremic urinary tract infections. Oral fluoroquinolones are an accepted and common step down for bacteremic urinary tract infections; however, their use is associated with mounting safety concerns. We compared clinical cure in patients with E. coli bacteremic urinary tract infections who were stepped down to oral beta-lactams compared to oral fluoroquinolones.MethodsThis multicentre retrospective cohort study included patients with first positive concurrent urine and blood cultures from January 2016 to December 2016. Patients were included if they received empiric intravenous beta-lactam therapy with step down to either oral beta-lactam or fluoroquinolone for treatment completion. The primary outcome was clinical cure. Secondary outcomes were length of hospitalization, all-cause mortality and C. difficile infection. Multivariate analysis and propensity score were used to control for confounding.ResultsA total of 207 patients were identified with bacteremic E.coli urinary tract infections. Clinical cure was achieved in 72/77 (94%) in the oral beta-lactam group versus 127/130 (98%) in the oral fluoroquinolone group (absolute difference -4.2%, 95% confidence interval [CI] -10.3% to 1.9%, p=0.13). The adjusted odds ratio (OR) for clinical cure with oral beta-lactams was 0.31 (95% CI 0.05 – 1.90, p=0.21); propensity score adjusted analysis showed a similar result. There was no statistically significant difference in secondary outcomes.Table 2 Table 3 Table 4 ConclusionOral beta-lactams appear to be a safe and effective step down option in bacteremic E. coli urinary tract infections compared to oral fluoroquinolones.Disclosures All Authors: No reported disclosures