Treatment Of Community-acquired Bacterial Pneumonia Research Articles

Design, synthesis and structure-activity relationships of novel non-ketolides: 9-Oxime clarithromycin featured with seven-to thirteen-atom-length diamine linkers at 3-OH

We report here on the structure-activity relationships of hybrids combining 3-descladinosyl clarithromycin with quinolones linked by extended diamine connectors. Several hybrids, exemplified by 23Bc, 23Be, 23Bf, 26Be, and 30Bc, not only restored potency against inducibly resistant pathogens but also exhibited significantly enhanced activities against constitutively resistant strains of Staphylococcus pneumoniae and Staphylococcus pyogenes, which express high-level resistance independent of clarithromycin or erythromycin induction. Additionally, the novel hybrids showed susceptibility against Gram-negative Haemophilus influenzae. Notably, hybrid 23Be demonstrated dual modes of action by inhibiting both protein synthesis and DNA replication in vitro and in vivo. Given these promising characteristics, 23Be emerges as a potential candidate for the treatment of community-acquired bacterial pneumonia.

Target attainment of intravenous lefamulin for treatment of acute bacterial skin and skin structure infections.

Lefamulin is a pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). Its spectrum of activity, good penetration into soft tissues and low rates of cross-resistance also make lefamulin a potentially valuable option for treatment of acute bacterial skin and skin structure infections (ABSSSIs). A Phase 2 trial of lefamulin for ABSSSI indicated similar efficacy of 100 and 150 mg q12h IV dosing regimens. In the present study, the potential of lefamulin for this indication was further evaluated from a translational pharmacokinetic/pharmacodynamic perspective. PTA was determined for various dosages using Monte Carlo simulations of a population pharmacokinetic model of lefamulin in ABSSSI patients and preclinical exposure targets associated with bacteriostasis and a 1-log reduction in bacterial count. Overall target attainment against MSSA and MRSA was calculated using lefamulin MIC distributions. Overall attainment of the bacteriostasis target was 94% against MSSA and 84% against MRSA for the IV dosage approved for CABP (150 mg q12h). Using the same target, for the 100 mg q12h regimen, overall target attainment dropped to 68% against MSSA and 50% against MRSA. Using the 1-log reduction target, overall target attainment for both regimens was <40%. Lefamulin at the currently approved IV dosage covers most Staphylococcus aureus isolates when targeting drug exposure associated with bacteriostasis, suggesting potential of lefamulin for the treatment of ABSSSIs. Lefamulin may not be appropriate in ABSSSI when rapid bactericidal activity is warranted.

7-Year (2015-21) longitudinal surveillance of lefamulin in vitro activity against bacterial pathogens collected worldwide from patients with respiratory tract infections including pneumonia and characterization of resistance mechanisms.

Lefamulin (Xenleta™), a pleuromutilin antibiotic, was approved for the oral and IV treatment of community-acquired bacterial pneumonia (CABP) in adults in 2019/2020. This study evaluated the in vitro activity of lefamulin and comparators against 19 584 unique bacterial isolates collected from patients with community-acquired respiratory tract infections and hospitalized patients with pneumonia within the global SENTRY Antimicrobial Surveillance Program during 2015-21. Isolates were susceptibility tested by the CLSI broth microdilution method, and resistance mechanisms were investigated in isolates with elevated lefamulin MICs. Lefamulin exhibited potent antibacterial activity against the most common and typical CABP pathogens tested, including Streptococcus pneumoniae [MIC50/90, 0.06/0.25 mg/L; 99.9% susceptible (S)], Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/L; 99.6% S), Haemophilus influenzae (MIC50/90, 0.5/2 mg/L; 99.1% S) and Moraxella catarrhalis (MIC50/90, 0.06/0.12 mg/L; 100.0% S). Potent activity was also observed against the less common pneumonia pathogens: β-haemolytic (MIC50/90 of 0.03/0.06 mg/L) and viridans group Streptococcus spp. (MIC50/90 of 0.06/0.25 mg/L) and Haemophilus parainfluenzae (MIC50/90 of 1/4 mg/L). Lefamulin's activity was not adversely affected by resistance to macrolides, penicillin, tetracyclines, fluoroquinolones and other resistance phenotypes. Non-susceptibility/resistance to lefamulin was rare and primarily determined by ribosomal protection through vga(A) variants in S. aureus, overexpression of AcrAB-TolC efflux pump in H. influenzae or modifications in L3, L4 and 23SrRNA in Streptococcus spp. Based on the coverage of the most important CABP pathogens and lacking cross-resistance, lefamulin may represent a valuable empirical treatment option for ambulatory and hospitalized patients with CABP, particularly in settings with high prevalence of resistance.

Compatibility of Omadacycline With Select Parenteral Products in Simulated Y-site Administration

Omadacycline is a broad-spectrum intravenous and oral tetracycline antibiotic approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Available information on the compatibility of intravenous omadacycline is limited to sterile water, 0.9% sodium chloride, and 5% dextrose via a dedicated line. The objective of this work was to determine the intravenous compatibility of omadacycline with commonly used intravenous fluids and medications using simulated Y-site administration. Omadacycline was prepared at concentrations consistent with a maintenance dose (1 mg/mL) and a loading dose (2 mg/mL) with 0.9% sodium chloride according to the prescribing information. Compatibility via simulated Y-site administration was assessed with selected crystalloids (lactated Ringer's solution, magnesium sulfate, and normal saline with potassium chloride) and intravenous medications (bumetanide, furosemide, heparin, and insulin). Y-site administration was simulated by mixing 5 mL of omadacycline with 5 mL of each parenteral product prepared at standard concentrations for infusion. Compatibility was assessed by using visual, Tyndall beam, microscopy, and spectrophotometry methods at 0, 30, and 60 minutes. Omadacycline appeared physically compatible with lactated Ringer's solution, magnesium sulfate, normal saline with potassium chloride, bumetanide, heparin, and insulin at standard infusion concentrations. However, although the lower concentrations of omadacycline 1 mg/mL and furosemide 2 mg/mL showed compatibility, higher concentrations of either agent in combination resulted in incompatibility. Omadacycline appeared physically compatible with all products tested and incompatible with furosemide. Simultaneous administration of omadacycline with tested intravenous medications, except furosemide, is suggested to be safe.

Impact of azithromycin, doxycycline and redox-active small molecules on amoxicillin-induced Chlamydia pneumoniae persistence

Amoxicillin is recommended as primary treatment for community-acquired bacterial pneumonia (CABP). 5–10% of CABP cases are caused by Chlamydia pneumoniae, an obligate intracellular bacterium which responds to beta-lactam antibiotics by converting to a persistent phenotype. To support rational pharmacotherapy of C. pneumoniae infections, we investigated how clinically relevant concentrations of azithromycin and doxycycline affect amoxicillin induced C. pneumoniae persistence. Given the known role of redox state alterations in the action of bactericidal antibiotics and widespread use of redox-active dietary supplements when experiencing respiratory symptoms, we also studied how redox active compounds affect the studied antibiotic treatments. Our data demonstrate that clinically applied amoxicillin concentrations (10 and 25 mg/l) fail to eradicate C. pneumoniae infection in respiratory epithelial cells. Transmission electron microscopy (TEM) of amoxicillin-treated C. pneumoniae infected cells reveal aberrant bacterial morphology characteristic of chlamydial stress response. Amoxicillin was also found to significantly limit the antichlamydial effect of azithromycin or doxycycline. However, based on quantitative culture and quantitative PCR data, azithromycin was superior to doxycycline in C. pneumoniae eradication either as monotherapy or in combination with amoxicillin. Amoxicillin was also found to decrease respiratory epithelial cell glutathione (GSH) levels, whereas redox-active dibenzocyclooctadiene lignans increased C. pneumoniae load in amoxicillin-treated cultures up to two-fold. These data highlight the impact of relative administration time on the efficacy of antichlamydial antibiotics and indicate unfavorable interactions between amoxicillin and redox-active small molecules.

Lefamulin - a recently developed antibiotic for treatment of community-acquired bacterial pneumonia (CABP)

Introduction and aim. Nowadays, the increasing resistance of bacteria is a concerning and challenging issue in terms of effective treatment of bacterial infections. The amount of available antibiotics has been quite constant for many years. The search for substances alternative to older classes of drugs, among which resistance is growing, has been ongoing for years. One of the newly introduced available alternatives is lefamulin. The aim of this paper is to present the potential benefits of its use in comunity-acquired bacterial pneumonia (CABP). &#x0D; Material and methods. A review of the available literature was performed by searching the PubMed and GoogleScholar databases using the following key words: lefamulin; BC3781; pleuromutilin; CABP; community acquired pneumonia.&#x0D; Analysis of literature. Lefamulin is a bacteriostatic antibiotic from the group of pleuromutilins, which has a unique mechanism of action consisting in binding to the bacterial 50S ribosomal subunit in the peptidyl transferase center. Thanks to this, it rarely causes resistance among other groups of antibiotics and is characterized by a safe action profile. Its spectrum of action includes bacteria causing CABP. In phase III studies, the efficacy of lefamulin monotherapy was comparable to that of moxifloxacin with or without linezolid in CABP. Thanks to broad spectrum of action its usefulness may also extend to treatment of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and multidrug-resistant organisms associated with sexually transmitted infections, e.g., Neisseria gonorrhoeae, Mycoplasma genitalium, although more additional clinical and pharmacodynamic data is needed.&#x0D; Conclusion. Lefamulin is a promising addition to the antibiotic armamentarium for treating CABP. Its unique mechanism of action, activity against typical and atypical bacteria, flexible dosing options, and favorable safety profile make it a beneficial choice for clinicians.

Evaluation of omadacycline against intracellular Mycobacterium abscessus in an infection model in human macrophages.

Omadacycline is an aminomethylcycline antibiotic in the tetracycline class that was approved by the US FDA in 2018 for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It is available in both IV and oral formulations. Omadacycline has broad-spectrum in vitro activity and clinical efficacy against infections caused by Gram-positive and Gram-negative pathogens. Omadacycline is being evaluated in a 3 month placebo-controlled Phase 2 clinical trial of oral omadacycline versus placebo in adults with non-tuberculous mycobacteria (NTM) pulmonary disease caused by Mycobacterium abscessus (NCT04922554). To determine if omadacycline has intracellular antimicrobial activity against NTM, bacteria that can cause chronic lung disease, in an ex vivo model of intracellular infection. Two strains of M. abscessus were used to infect THP-1 macrophages. Intracellular M. abscessus was then challenged with omadacycline and control antibiotics at multiples of the MIC over time to evaluate intracellular killing. At 16 × the MIC at 72 h, omadacycline treatment of intracellular NTM yielded a log10 reduction in cfu of 1.1 (91.74% reduction in cfu) and 1.6 (97.65% reduction in cfu) consistent with killing observed with tigecycline, whereas amikacin and clarithromycin at 16 × the MIC did not show any reduction in cfu against the intracellular M. abscessus. Omadacycline displayed intracellular activity against M. abscessus within macrophages. The activity was similar to that of tigecycline; as expected, intracellular killing was not observed with clarithromycin and amikacin.

Omadacycline in the treatment of community-acquired bacterial pneumonia in patients with comorbidities: a post-hoc analysis of the phase 3 OPTIC trial.

The 2019 American Thoracic Society/Infectious Disease Society of America guidelines recommend respiratory fluoroquinolones to treat community-acquired bacterial pneumonia (CABP) in adults with comorbidities. Fluoroquinolones are effective against both typical and atypical pathogens. However, fluoroquinolone treatment has a risk of adverse effects, and the Food and Drug Administration has issued black box safety warnings for their use. Inpatient use of fluoroquinolones has reduced as a result; however, most antibiotic courses are completed as outpatients and discharge prescriptions account for the majority of fluoroquinolone use. As such, a new treatment option is needed to replace fluoroquinolones. Omadacycline is an aminomethylcycline antibiotic with a broad spectrum of activity and is available as a once-daily intravenous or bioequivalent oral formulation. This study assessed the safety and clinical efficacy of omadacycline compared with moxifloxacin for the treatment of adult CABP patients with Pneumonia Severity Index (PSI) risk class II/III and ≥1 comorbidity through a post-hoc analysis of the phase 3 OPTIC study (NCT02531438). In total, 239 omadacycline- and 222 moxifloxacin-treated patients were assessed. The median age was similar between groups (omadacycline: 57 years; moxifloxacin: 58 years), with 26.0% and 26.6%, respectively, ≥65 years of age. Early clinical response was 91.6% for patients with ≥1 comorbidity treated with omadacycline and 91.4% for those treated with moxifloxacin. Post-treatment evaluation results for overall response were 89.1% in the omadacycline group and 87.4% in the moxifloxacin group. Safety warnings have reduced inpatient use of fluoroquinolones; however, outpatient and discharge prescriptions account for the majority of fluoroquinolone use. Outpatients with comorbidities need an efficacious alternative to fluoroquinolones. Omadacycline maintains the similar efficacy and benefits of fluoroquinolones as a once-daily, monotherapy, bioequivalent oral option with potent in vitro activity against the most common CABP pathogens, including S. pneumoniae and atypical pathogens, but offers a materially different safety profile consistent with its tetracycline heritage. In conclusion, both omadacycline and moxifloxacin exhibited similar efficacy in patients with PSI risk class II/III and comorbidities. Omadacycline fulfills an unmet need as an oral monotherapy treatment option for adult patients with CABP, which will further reduce the use of fluoroquinolones. https://www.clinicaltrials.gov/study/NCT02531438, identifer: NCT02531438; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004071-13, identifier: EudraCT #2013-004071-13.

Development and validation of a stability-indicating RP-HPLC method for estimation of Lefamulin in pure and pharmaceutical drug products

BackgroundCommonly occurring serious lung parenchymal infection is community-acquired bacterial pneumonia (CABP). Lefamulin acetate drug products are useful for the treatment of community-acquired bacterial pneumonia (CABP). The main objective of the study was the development and validation of a quick reverse-phase high performance liquid chromatographic analytical testing method for Lefamulin in pure and pharmaceutical dosage forms. The C18 column was the stationary phase for reverse-phase high performance liquid chromatographic separation, and the mobile phase consisted of 0.05 M phosphate buffer with a pH adjustment of 2.5 mixed with an equal volume of acetonitrile. A flow rate of 1.0 mL/min, a column temperature of 30 °C, an injection volume of 10 µL, and a detection wavelength of 210 nm were used as optimum conditions.ResultsThe developed method reported that Lefamulin peak’s retention time was 3.1 min, the average theoretical plate count 5000, and the average peak asymmetry 1.12. In both pure and pharmaceutical dosage forms, the method was found to be accurate, precise, specific, linear calibration curve, and robust. Quantitative assay results from laboratory-made formulations showed similarity to existing commercial products of Lefamulin. Lefamulin is stable in acidic and photolytic environmental circumstances, while it degraded in oxidative, basic, and thermal humidity environment, according to the results of stress studies.ConclusionsThe developed analytical method is fast, economic and stability indicating. It is useful for routine pharmaceutical analysis where the Lefamulin is synthesized in pure form, pharmaceutical tablet formulation, and parenteral dosage form, for their quality and safety.

Antibiotic prescribing by age, sex, race, and ethnicity for patients admitted to the hospital with community-acquired bacterial pneumonia (CABP) in the All of Us database.

To assess the proportion of inpatients who received guideline-concordant antibiotics for community-acquired bacterial pneumonia (CABP) in special populations of the All of Us database. CABP contributes significantly to healthcare burden worldwide. The American Thoracic Society and Infectious Disease Society of America jointly published guidelines for the treatment of CABP. Guideline-concordant antibiotics for CABP are associated with better patient and cost outcomes. This was a retrospective cohort study of patients with pneumonia (n = 1608; SNOMED 233604007) from 10/1/2018 to 1/01/22 in the All of Us database. Cases were excluded for treatment setting other than inpatient,prior (within 90 days) pneumonia, receipt of intravenous antibiotics, respiratory isolation of methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa, and/or other non-community-acquired types of pneumonia. Patients were grouped based on patient age, sex, race, and ethnicity. The proportion of patients on guideline-concordant therapy was compared within groups using chi-square statistics. Significant associations were assessed using multivariate logistic regression models. A total of 1608 cases were included, and 45% of these patients received guideline-concordant antibiotics. Non-Hispanic White (NHW) patients vs. Black patients were associated with a 36% higher likelihood for receiving guideline-concordant antibiotics (adjusted OR, 1.36; 95% CI 1.02-1.81), whereas NHW vs. Hispanic patients were associated with a 34% lower likelihood for receiving guideline-concordant antibiotics (aOR 0.66; 0.48-0.91). Black patients with CABP in the All of Us database were less likely to receive guideline-concordant antibiotics, and Hispanic patients were more likely to receive guideline-concordant antibiotics, than NHW patients.

Omadacycline in treating community-based infections: a review and expert perspective

ABSTRACT Introduction Omadacycline is approved for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infection (ABSSSI). The integration of newer agents into clinical use involves understanding the nuances of clinical decision-making. This review will provide an in-depth focus on omadacycline in clinical practice. Areas covered Literature review of omadacycline utilizing PubMed was performed to provide a comprehensive evaluation of omadacycline pharmacology, microbiology, registrational Phase 3 clinical trials, and post-marketing clinical studies. In addition, the immunomodulatory and other attributes of tetracycline class of antibiotics, of which omadacycline is a member, are reviewed, introducing the concept of antibiotic selection with attention to the bacterial pathogen and human host relationship. Expert opinion Omadacycline builds upon the favorable attributes of tetracycline antibiotics and provides very reliable empiric coverage for both Staphylococcus aureus and Streptococcus spp. Clinicians require a more robust understanding of antibiotics, including omadacycline, in order to optimize patient outcomes, streamline care, and reduce medical costs.

2189. Anti-inflammatory Activity of Lefamulin in a Mouse Model of Influenza Virus H1N1 Infection

Abstract Background Lefamulin (LEF) is a pleuromutilin antibiotic approved by the United States (US) FDA for the treatment of community-acquired bacterial pneumonia in adults. In addition to the potent antibacterial activity, LEF has demonstrated anti-inflammatory activity in an LPS induced lung neutrophilia model in mice. We investigated the anti-inflammatory activity of lefamulin in the H1N1 influenza mouse model in comparison to oseltamivir (OTV) and azithromycin (AZM). Methods Infection was performed in BALB/c mice by intranasal challenge ∼70 pfu influenza virus H1N1 A/PR/8/1934 (Day 0). Treatment with drugs at clinically relevant doses started on Day -1 (LEF 70 mg/kg/day and 110/140 mg/kg/day, s.c., AZM 30 mg/kg/day, i,p. and OTV 20 mg/kg/day p.o.) to Day 6. On Days 3 and 6, bronchioalveolar lavage fluid (BALF) was collected to measure infiltrating lung leukocytes and cytokines. Lung immunopathology following infection was evaluated on Day 6 by gross pathology at termination together with hematoxylin and eosin histopathology. Results In untreated vehicle control animals, the influenza infection progressed as expected with bodyweight loss, increased cell infiltration into the lung and increased levels of TNF-α, IL-6 at day 3 and 6. Treatment with LEF significantly decreased the total immune cell infiltration into the lung by day 6 at both doses tested (Figure Left). Cytokine levels in the BALF were significantly reduced on day 3 when the viral load peaked. Furthermore, LEF showed positive effects on lung gross pathology and survival. Oseltamivir and LEF, at both doses, appeared efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin didn’t show reduced pathology (Figure Right). Anti-inflammatory effects of LEF, AZM and OTV in BALF of H1N1 infected mice infected with influenza virus H1N1. Left: Total lung leukocyte infiltrate following infection on day 0. Bars represent mean ± SEM. Right: Day 6 lung inflammation and degeneration histopathology score. Data are presented as mean histopathology score + SEM (n=10). One-way ANOVA, with Dunnett’s multiple comparisons against the vehicle control treatment was run for each timepoint. * represents significance level of p&amp;lt;0.05. ** indicates p&amp;lt;0.01. Conclusion Lefamulin showed anti-inflammatory treatment following acute influenza virus infection. Following influenza infection LEF was able to significantly reduce lung immunopathology and improve clinical outcome in mice. Results from this experiment were consistent with that observed in the LPS induced lung neutrophilia mouse model. Further studies are warranted to evaluate the immunomodulatory potential of Lefamulin. Disclosures Wolfgang W. Wicha, MSc, Nabriva Therapeutics: Grant/Research Support|Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds Sandy Kimber, PhD, Nabriva Therapeutics: Grant/Research Support Charlotte Cumper, BSc, Nabriva Therapeutics: Grant/Research Support Hon S. Lam, MSc, Nabriva Therapeutics: Grant/Research Support Lorena S. Ballesteros, MSc, Nabriva Therapeutics: Grant/Research Support Christopher Kirkham, PhD, Nabriva Therapeutics: Grant/Research Support Claire Richards, PhD, Nabriva Therapeutics: Grant/Research Support Steven P. Gelone, PharmD, Nabriva Therapeutics: Board Member|Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds|Nabriva Therapeutics: Stocks/Bonds Susanne Paukner, PhD, Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds.

1016. Real-World Use of Omadacycline in Physician Office Infusion Centers (POICs)

Abstract Background Omadacycline (OMC) is approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Real-world data on the use of OMC are limited. We present a multicenter observational review of OMC outpatient use in Infectious Disease POICs. Methods Medical records of patients (pts) receiving intravenous OMC from May 2019 to April 2022 from 5 POICs were included in this ongoing study. Data included demographics, diagnosis, medical history, microbiology, OMC regimen, adverse events (AEs), health care utilization and clinical outcomes. Clinical success was defined as complete or partial symptom resolution at completion of OMC with oral antibiotics as needed. Persistent or recurrent infection and premature discontinuation of OMC were deemed non-success. Indeterminate outcomes were excluded in outcome assessment. Chi Square, Fisher’s exact, and t-test were used to identify characteristics associated with clinical outcome. Results Overall, 37 pts (mean age: 61±13 yrs, 65% male) were identified. Infections treated were 62% bone and joint (BJI), 24% complicated skin and skin structure infections (CSSSI), 11% pulmonary nontuberculous mycobacterial (NTM) and 3% diverticulitis. A total of 61 pathogens were identified in 30 pts of which 83% had ≥1 Gram-positive isolate. Polymicrobial pathogens were reported in 13/30 pts (43%). Ten pts (27%) received concomitant IV antibiotics. Median duration of OMC therapy was 38 days (IQR, 21-47). OMC was initiated in the POIC without prior hospitalization in 62% of pts. Overall clinical success was 75% (24/31). Non-success due to persistent infection was reported in 5 pts (3 BJI, 2 CSSSI), of which 4 were hospitalized. Three additional pts were deemed non-successful due to early discontinuations (2 difficulty with administration, 1 AE) (Fig 1). Six pts were non-evaluable for outcome. Ten pts reported 14 AEs, most commonly nausea (4 pts) and elevated liver function tests (3 pts). Figure 1.Clinical outcome of omadacycline by infection type Conclusion These real-world results support the outpatient use of omadacycline in additional, difficult to treat, complicated infections, including bone and joint infections. Disclosures Lucinda J. Van Anglen, PharmD, Merck &amp; Co.: Grant/Research Support|Paratek: Grant/Research Support.

2176. In Vitro Evaluation of Delafloxacin Activity Against Contemporary US Isolates from Cystic Fibrosis Patients Hospitalized with Pneumonia: Results from the SENTRY Antimicrobial Surveillance Program (2019-2021)

Abstract Background Delafloxacin (DLX) is a broad-spectrum fluoroquinolone antibacterial approved in the US for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections. DLX is indicated to treat CABP caused by multiple pathogens, including methicillin-susceptible Staphylococcus aureus (MSSA) and Pseudomonas aeruginosa (PSA). S. aureus (SA) and PSA are common pathogens causing pneumonia in cystic fibrosis (CF) patients. In this study, the in vitro susceptibilities of DLX and comparator quinolones were determined for clinical isolates from US CF patients collected during 2019-2021. Methods Isolates from CF patients hospitalized with pneumonia were consecutively collected at 17 US medical centers participating in the SENTRY Surveillance Program. Sites submitted 1 isolate per patient per infection episode. Isolate identification was determined at each site and confirmed using MALDI-TOF at JMI Laboratories. Susceptibility testing was performed according to CLSI broth microdilution methodology. FDA interpretive criteria were used for DLX, and CLSI (2022) criteria were applied to comparators. Results A total of 115 SA, including 72 MSSA and 67 PSA, were submitted. Susceptibilities (%S) to DLX, levofloxacin (LEV), and moxifloxacin (MOX) for MSSA are shown in the table. As MOX does not have breakpoints for PSA, ciprofloxacin (CIP) was tested. Against all SA, %S was 73.9%, 67.0%, and 67.0% for DLX, LEV, and MOX, respectively. DLX had the highest %S against MSSA (94.4%). The %S to LEV and MOX was 87.5% and 87.5%. DLX was also more active than comparators against PSA, with DLX 68.7%S, while LEV was 43.3%S and CIP was 50.7%S. Conclusion DLX had good activity against recent CF isolates from US hospitals, and had the highest percent susceptibility of the quinolones tested against MSSA and PSA. These in vitro data suggest that DLX could be a useful therapy when coverage of both MSSA and PSA is needed. Disclosures Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Michael D. Huband, BS, AbbVie: Grant/Research Support|Melinta: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

1689. In Vitro Activity of Lefamulin Against Bacterial Pathogens Collected From Pneumonia Patients in United States and Latin America Medical Centers in 2020-2021

Abstract Background Lefamulin is a novel pleuromutilin protein synthesis inhibitor approved in the US, Canada, and Europe for the oral and intravenous treatment of community-acquired bacterial pneumonia (CABP) in adults due to typical and atypical pathogens. This study evaluated the in vitro activity of lefamulin and comparators against bacterial isolates from patients with community-acquired respiratory tract infections and hospitalized patients with pneumonia in the US and Latin America. Methods 1,907 unique isolates were collected within the SENTRY surveillance program from 29 medical centers in the US and 8 medical centers in Latin America (Argentina, Brazil, Chile, Colombia, Mexico, Panama). Isolates were susceptibility tested by CLSI reference broth microdilution methods. CLSI breakpoints (M100, 2022) were applied. Results Lefamulin inhibited 100% of S. pneumoniae isolates at or below its susceptible (S) breakpoint of ≤ 0.5 mg/L, regardless of resistance to other antibiotics used to treat CABP (MIC90 values of 0.12 or 0.25 mg/L, Table). The penicillin-resistant (R; 12.7%), azithromycin-R (43.7%), and tetracycline-R S. pneumoniae (20.4%) displayed reduced susceptibility to the other CABP drugs tested, except moxifloxacin ( &amp;gt; 98.2% S) and lefamulin (100% S). Lefamulin was highly potent against S. aureus, including MRSA, azithromycin-R, and moxifloxacin-R isolates, with 100% of isolates inhibited at or below the lefamulin S breakpoint of ≤ 0.25 mg/L. Susceptibility to azithromycin and moxifloxacin was particularly low for MRSA (13.9% and 25.0%, respectively). The fastidious Gram-negative H. influenzae and M. catarrhalis, of which 24.0% and 98.8%, respectively, were ß-lactamase positive, were S to lefamulin ( &amp;gt; 93%) and the other tested CABP drugs ( &amp;gt; 89%). Table. Susceptibility of pneumonia pathogens from US and Latin America to lefamulin and other CABP drugs Conclusion Lefamulin displayed potent in vitro activity against contemporary CABP pathogens from the US and Latin America. Its activity was unaffected by resistance to other antibiotic classes, including fluoroquinolones, macrolides, β-lactams, and tetracyclines. Lefamulin represents a valuable empiric treatment option for ambulatory and hospitalized patients with CABP, particularly when the causative pathogen is not identified or in settings with high prevalence of resistance. Disclosures Susanne Paukner, PhD, Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support Steven P. Gelone, PharmD, Nabriva Therapeutics: Board Member|Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds|Nabriva Therapeutics: Stocks/Bonds Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support.

Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea using a hollow fiber infection model simulating Neisseria gonorrhoeae infections.

The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is seriously threatening the treatment and control of gonorrhea globally. Novel treatment options are essential, coupled with appropriate methods to pharmacodynamically examine the efficacy and resistance emergence of these novel drugs. Herein, we used our dynamic in vitro hollow fiber infection model (HFIM) to evaluate protein-unbound lefamulin, a semisynthetic pleuromutilin, against N. gonorrhoeae. Dose-range and dose-fractionation experiments with N. gonorrhoeae reference strains: WHO F (susceptible to all relevant antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone resistance), and WHO V (high-level azithromycin resistant, and highest gonococcal MIC of lefamulin (2mg/l) reported), were performed to examine lefamulin gonococcal killing and resistance development during treatment. The dose-range experiments, simulating a single oral dose of lefamulin based on human plasma concentrations, indicated that ≥1.2g, ≥2.8g, and ≥9.6g of lefamulin were required to eradicate WHO F, X, and V, respectively. Dose-fractionation experiments, based on human lefamulin plasma concentrations, showed that WHO X was eradicated with ≥2.8g per day when administered as q12h (1.4g twice a day) and with ≥3.6g per day when administered as q8 h (1.2g thrice a day), both for 7days. However, when simulating the treatment with 5-10 times higher concentrations of free lefamulin in relevant gonorrhea tissues (based on urogenital tissues in a rat model), 600mg every 12h for 5days (approved oral treatment for community-acquired bacterial pneumonia) eradicated all strains, and no lefamulin resistance emerged in the successful treatment arms. In many arms failing single or multiple dose treatments for WHO X, lefamulin-resistant mutants (MIC = 2mg/l), containing an A132V amino acid substitution in ribosomal protein L3, were selected. Nevertheless, these lefamulin-resistant mutants demonstrated an impaired biofitness. In conclusion, a clinical study is warranted to elucidate the clinical potential of lefamulin as a treatment option for uncomplicated gonorrhea (as well as several other bacterial STIs).

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING OF THE COMBINATION OF IVACAFTOR AND LEFAMULIN IN PATIENTS WITH CYSTIC FIBROSIS

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING OF THE COMBINATION OF IVACAFTOR AND LEFAMULIN IN PATIENTS WITH CYSTIC FIBROSIS

Duration of treatment for community-acquired bacterial pneumonia in children

Duration of treatment for community-acquired bacterial pneumonia in children

In vitro activity of lactone ketolide nafithromycin (WCK 4873) against Streptococcus pneumoniae isolates enriched with macrolide-resistance phenotype collected from mainland China.

BackgroundWidespread MDR Streptococcus pneumoniae in China translates clinically into a substantial pneumococcal disease burden and related morbidity and mortality, particularly in the elderly and children. Nafithromycin (WCK 4873), a novel lactone ketolide class of antibiotic designed with a 3 day, once-daily regimen is highly active against resistant pneumococci and other community respiratory pathogens. It is currently in clinical development for the treatment of community-acquired bacterial pneumonia (CABP).ObjectivesTo determine the in vitro activity of nafithromycin against clinical S. pneumoniae isolates collected during 2015–21 from three hospitals in mainland China.MethodsA total of 920 clinical isolates (one isolate per patient), which predominantly with the macrolide- and clindamycin-resistant phenotype were included in this study. The MICs of nafithromycin and other antibiotics tested were determined using the reference broth microdilution method.ResultsClinical S. pneumoniae isolates used in this study showed high macrolide and clindamycin resistance (>95% against erythromycin and azithromycin and 80% against clindamycin) for which nafithromycin showed potent activity (MIC50/90; 0.03/0.06 mg/L) with 100% susceptibility at a proposed pharmacokinetics/pharmacodynamics (PK/PD) breakpoint of 0.25 mg/L. Among other classes of antibiotics tested, moxifloxacin also showed good activity while amoxicillin/clavulanate and ceftriaxone showed lower susceptibility.ConclusionsNafithromycin exhibited therapeutically relevant in vitro antibacterial activity against contemporary highly resistant pneumococci collected from mainland China. This study supports the clinical development of nafithromycin for the management of CABP caused by pneumococci in China.

Tissue Distribution of [14C]-Lefamulin into the Urogenital Tract in Rats.

ABSTRACTLefamulin, a semisynthetic pleuromutilin antibiotic approved in the United States, Canada, and Europe for intravenous and oral treatment of community-acquired bacterial pneumonia, is highly active in vitro against bacterial pathogens that cause sexually transmitted infections (STIs), including multidrug-resistant strains of Neisseria gonorrhoeae, Chlamydia trachomatis, and Mycoplasma genitalium. This nonclinical study used quantitative whole-body autoradiography (QWBA) and qualitative tape-transfer microautoradiography (MARG) to investigate lefamulin distribution into urogenital tract tissues down to a cellular level in male and female rats. A single intravenous dose (30 mg/kg) of [14C]-lefamulin was administered to 3 male and 3 female Sprague-Dawley rats. At 0.5, 6, and 24 h post dose, rats were euthanized and [14C]-lefamulin distribution was investigated using QWBA and MARG of sagittal planes. [14C]-lefamulin was well distributed throughout the carcasses of male and female rats, with the highest concentrations observed in male bulbourethral gland, urethra, prostate in female clitoral gland, uterus (particularly endometrium), and ovary. In these areas, concentrations were similar to or higher than those observed in the lungs. Concentrations peaked at 0.5 h post dose, remaining detectable in the urogenital tract up to 24 h post dose. [14C]-lefamulin in rats showed rapid, homogeneous distribution into urogenital tissues down to a cellular level, with high tissue:blood ratios in tissues relevant to STI treatment. These results, and the potent in vitro activity of lefamulin against multidrug-resistant bacteria known to cause STIs, will help inform further assessment of lefamulin, including potential clinical evaluation for treatment of STIs.