Long-term evaluation of clinical success and safety of omadacycline in nontuberculous mycobacteria infections: a retrospective, multicenter cohort of real-world health outcomes

ABSTRACT Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49–67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo (4 – 14), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

functional erm gene, which can be found in MAB, confer inducible macrolide resistance.A recent study found that over 70% (426/607) of tested MAB subspecies abscessus isolates had a functional erm gene (8).Furthermore, macrolide resistance significantly affects clinical outcomes, as only 25% of cases of macrolide-resistant MAB-associated pulmonary disease attained sustained sputum conversion after 1 yr (9).The clinical consequences of macrolide resistance are substantial and could render treatment more complicated.Given that macrolides are accessible in oral form, providing a unique advantage in terms of prescribing and patient acceptance, they are often deemed a fundamental aspect of treatment (2).However, the prospect of their constrained use, owing to escalating resistance, introduces an added dimension of complexity in the management of mycobacterial disease.
This complexity is further amplified by the increasing prevalence of MAB and MAB-associated pulmonary diseases (4)(5)(6).The resilience of this pathogen to conven tional antibiotics, coupled with the necessity for protracted therapy and the lack of effective oral treatment alternatives, highlights the pressing need for the development of new orally administrable therapies that are active against this pathogen (3,6).
Omadacycline (OMC) is a novel first-in-class aminomethylcycline that provides broad-spectrum antimicrobial coverage and is available in both oral and intravenous formulations.It has received approval from the U.S. Food and Drug Administration (FDA) for the treatment of adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and soft tissue infections (ABSSI) (10).Both in vitro and in vivo studies have demonstrated OMC's potency and effectiveness against M. abscessus, Mycobac teroides chelonae (M.chelonae) , and Mycobacterium fortuitum (M.fortuitim) infections (11)(12)(13)(14)(15). Similar to its tetracycline counterparts, OMC functions by binding to the 30S ribosomal subunit, thereby inhibiting protein synthesis (16).However, unlike first-generation tetracyclines, OMC has been deliberately engineered to evade ribosomal protec tion and tetracycline efflux mechanisms.In the context of MAB, the production of a monooxygenase enzyme may degrade tetracyclines, such as minocycline and doxycy cline, but does not affect OMC (17).This feature, in part, revitalizes its activity against recalcitrant MAB and may serve as a deterrent against the development of resistance during treatment (16).Moreover, intolerance during treatment is a frequent reason for drug cessation, especially with tetracyclines, where symptoms such as elevated liver enzymes and gastrointestinal discomfort often necessitate discontinuation (18,19).Emerging evidence suggests that OMC may be more tolerable and potentially less likely than tigecycline (TIG) to cause these issues (10,(18)(19)(20)(21).
OMC has recieved orphan drug status and fast-track designation by the FDA for pulmonary NTM infections and is currently being tested in a phase II trial (ClinicalTri als.govIdentifier: NCT04922554) (22).Despite the increasing use of OMC in the treatment of NTM infections,, there is a paucity of real-world data regarding its outcomes, safety, and treatment-specific factors.Such information can significantly aid clinicians in making informed decisions regarding patient care.Therefore, the primary objective of this study is to evaluate the long-term effectiveness, safety, and tolerability of OMC treatment in patients with both pulmonary and extrapulmonary NTM infections.

MATERIALS AND METHODS
This was a retrospective, cohort study involving 16 U.S. academic medical centers from 1 January 2020 to 30 March 2023.Patients were included if they were ≥18 yr of age, received OMC in any dosage form for≥72h, and were clinically evaluable for≥3 mo with a documented follow-up.Patients were excluded if they were pregnant or nursing mothers, prisoners, or had cystic fibrosis.Any subsequent OMC courses were included only if they were separated by≥60 d.Clinically evaluable durations started from the time of initiation of OMC treatment.The primary outcome was a 3 mo clinical success, defined as a composite of survival, clinician-evaluated clinical improvement at 3 mo, lack of alteration in OMC therapy due to treatment failure or AE, and lack of microbiological recurrence.Secondary outcomes included sputum culture conversion at 12 mo and 6and 12 mo clinical success when available (composites of the components mentioned previously), 3-, 6-, and 12 mo imaging improvement (when applicable), AE, and reasons for OMC utilization.
Culture conversion was defined as ≥2 consecutive negative sputum cultures within 12 mo of OMC initiation, with no further positive cultures, each taken at least 1 mo apart.This definition was applied only to patients who had positive cultures upon the start of OMC therapy.Microbiological recurrence was defined as≥2 consecutive positive cultures for the same pathogen isolated from the index culture following sputum culture conversion (respiratory) or microbiological clearance (non-respiratory).Dissemination was defined as the isolation of the NTM pathogen in ≥2 separate organ sites.Clini cal and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied (when applicable) to interpret mean inhibitory concentration (MIC) values, whereas FDA antibacterial susceptibility interpretive criteria were used when information was unavailable via CLSI (23,24).We characterized combination therapy as the co-administra tion of any antibiotic with OMC for >28 d.While all adverse effects of OMC have been recorded, it is important to mention that they cannot be exclusively ascribed to OMC because of the concurrent use of other treatments.Descriptive statistics were used for analyses.Chi-square or Fisher's exact tests were used for categorical data, and either student's t-test or Mann Whitney U test was used for continuous variables.Bivariate analysis was used to identify the characteristics potentially associated with clinical or safety outcomes.Statistical significance was set at P < 0.05.Statistical analysis was performed using the IBM SPSS software (version 29.0; SPSS, Inc., Chicago, IL, USA).Our study, due to its retrospective design, fell under the category of research exempt from Institutional Review Board (IRB) review.As we only analyzed pre-existing, de-identified data, there was no need for direct patient contact or further consent.

Safety outcomes
Given the protracted nature of therapy for NTM, it is critical to understand the safety and tolerability of OMC.Tetracycline and tetracycline derivatives are known to cause AEs that lead to patient intolerance, particularly over extended durations.AEs were experienced by 32% (24/75) of patients, 9.3% (7/75) discontinued OMC due to intolerance, and 30.7% (23/75) had AE resolution while continuing on OMC (Table 6).Most AEs were gastrointestinal (nausea, vomiting, and diarrhea) (21/75, 28%) or hepatotoxic (AST/ALT elevation 3 × the upper limit of normal) (6/75, 8.0%) in nature.Notably, no specific factor was associated with the occurrence of AEs, and the median (IQR) time to gastrointestinal AE was 28 (10-88) d.

DISCUSSION
To our knowledge, this is one of the largest multicenter observational studies of its kind.
Our investigation provides an in-depth examination of the long-term clinical success, tolerability, and safety of OMC for the treatment of both pulmonary and extrapulmo nary NTM infections.Our findings revealed consistent rates of clinical success, which persisted in patients undergoing clinical follow-up.These outcomes not only reinforce the potential of OMC as a viable treatment approach for NTM infections but also align with the limited but existing data on the clinical success, safety, and tolerability of OMC (26)(27)(28)(29)(30)(31).Although our study showed a greater incidence of gastrointestinal (28%) and hepatotoxic (8.0%) AEs, the overall AE rates were consistent with those reported in previous studies (26)(27)(28)(29)(30)(31).Importantly, most previous studies utilized intravenous OMC, whereas in this study, all patients received the medication orally.As a result, a compar ison of the AEs from the OASIS-2 trial, which evaluated once-daily oral OMC 300mg for ABSSI, may be the most appropriate (31).In our patient population, we reported overall AEs at a rate of 32.0% compared to 54.0% in the OASIS-2 trial.The occurrences of gastrointestinal and hepatotoxic AEs was also different, at 28.0% and 8.0% in our study compared to 37.8% and 10.0% in the OASIS-2 trial, respectively.The authors of the OASIS-2 trial noted that gastrointestinal AEs typically surfaced within the initial 1-2 d, potentially due to the use of loading doses.This may explain the observed diferences in our study, as only 33.0% (25/75) received any type of loading dose.We observed that patients who received oral loading doses had a higher incidence of gastrointestinal AEs a Data reported as n (%), unless otherwise specified; OMC, omadacycline.
(7/18, 38.9%) than those who did not (12/50, 24.0%).Given the concern for GI intoler ance, it may be prudent to prescribe antiemetic medication on initiation to increase tolerability (21).Additionally, we attributed the increased frequency of GI AEs primarily to longer treatment durations, which typically manifested around the 28th day.Despite these concerns, we observed a low OMC discontinuation rate of 9.0%, proving that most AEs were transient in nature.Thus, the importance of treatment tolerability in the management of NTM infections cannot be overstated.Although other tetracyclines, such as TIG and eravacycline (ERV), have shown substantial in vitro activity against NTM, their application has been restricted because of their parenteral-only formulations (ERV and TIG) and their high incidence of side effects (TIG) (18)(19)(20)32).Interestingly, our study detected no discernible relationship between patient baseline or treatment characteristics and the incidence of AEs.However, we did observe that patients who received a loading dose did have a higher proportion of GI AE (P > 0.05).Furthermore, the once-daily oral administration of OMC and higher reported sustained lung penetration may offer an additional advantage over TIG (20,33).Patient adherence and preference for oral medications emerge as crucial considera tions, given the need for long-term NTM treatmen.These factors were key motivators for prescribers' use of OMC in our study.Compared with twice-daily IV alternatives, a once-daily oral regimen could potentially reduce the risk of patient non-adherence and increased costs associated with outpatient parental therapy (34,35).In terms of treatment outcomes, our study observed high culture conversion rates at 12 mo in patients who underwent follow-up cultures, further supporting our composite clinical success outcomes.Although M. abscessus was the primary pathogen isolated during treatment, we also encountered patients with M. avium complex, M. fortuitum, and M. chelonae infections.Several of these pathogens were isolated concomitantly with M. abscessus which may have complicated treatment.
The intrinsic and inducible resistance found in MAB may serve as an area where OMC could become a viable treatment option.Our study found similar clinical success rates, regardless of the presence of a functional erm gene, which highlights the potential of OMC in situations where macrolide resistance or the presence of the erm gene is suspected or detected.Unlike macrolides, OMC is not influenced by functional erm and is less prone to ribosomal protection and efflux pumps, which are common resistance mechanisms that affect many antibiotics, including tetracyclines.Finally, our bivariate analysis helped to identify factors potentially linked to treatment failure.Not surprisingly, patients with NTM-PD, chronic cough, and bronchiectasis had significantly higher rates of clinical failure.
While these findings offer valuable insights, our study has several limitations.First, the retrospective design may have introduced a selection bias, and the lack of standard ization in treatment and follow-up duration could have influenced the results.Second, the inclusion of both pulmonary and extrapulmonary NTM infections in the analysis may complicate comparisons, particularly given the importance of source control in the management of extrapulmonary NTM.Third, the limited availability of susceptibility data for OMC underlines the inadequate application of existing antimicrobial susceptibility testing (AST) techniques for OMC.This emphasizes the importance of integrating OMC into testing panels or examining the possibility of employing TIG MICs as a surrogate for evaluating OMC susceptibility.Lastly, reliance on clinician-evaluated clinical improve ment without predefined criteria may lead to variability in interpretation and potential ambiguity depending on the clinician.
In conclusion, despite its limitations, this study provides a realistic representation of OMC use in outpatient clinical settings, where data completeness is often challeng ing.The practical outcomes and insights from this research can offer significant value to clinicians in their daily practice of treating these infections and shed light on the long-term outcomes and safety profile of OMC to treat NTM infections, an area where existing data are notably sparse.Phase II trials of OMC for the treatment of NTM infections are currently in progress.However, there is still a need for additional data to fully establish the therapeutic potential and role of OMC.This should include studies examining cost-effectiveness in comparison to intravenous treatments, evaluations of outcomes in patients with cystic fibrosis, and translational research that bridges in vitro data with clinical results.

FIG 2
FIG 2 Outcomes of concomitantly administered antibiotics with omadacycline.(A) Frequency and clinical outcomes associated with combined antibiotics with omadacycline in patients with nontuberculous Mycobacterium-pulmonary disease (NTM-PD) represents outcomes for any regimen containing the individual antibiotic; IV, intravenous; INH, inhaled (B) Frequency and clinical outcomes of the most utilized drug regimens combined with OMC in NTM-PD patients (n = 33); INH, inhaled; IV, intravenous; * Did not meet clinical success endpoint.

TABLE 1
Patient baseline characteristics a a Data reported as n (%) unless otherwise specified.Full-Length Text Antimicrobial Agents and Chemotherapy October 2023 Volume 67 Issue 10 10.1128/aac.00824-234

TABLE 3
Distribution of mean inhibitory concentrations for M. abscessus species a Distribution of available MIC data for all Mycobacteroides abscessus species.Some MICs were listed as greater than or equal to and the lesser value was utilized in calculation of the MIC 50 and MIC 90 values.

TABLE 5
Bivariate analysis of factors potentially associated with 3 mo clinical failure a

TABLE 6
Safety outcomes a