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

Background: 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). Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

Evaluation of Dilution Susceptibility Testing Methods for Aztreonam in Combination with Avibactam against Enterobacterales.

As multidrug and pan-resistance among Enterobacterales continue to increase, there is an urgent need for more therapeutic options to treat these infections. New ß-lactam and ß-lactam inhibitor (BLI) combinations have a broad spectrum of activity, but those currently approved do not provide coverage against isolates harboring metallo-ß-lactamases (MBL). Aztreonam (ATM) and avibactam (AVI) in combination (ATM/AVI; AVI at 4 µg/mL fixed concentration) provides a similarly broad range of activity while maintaining activity against MBL-producing isolates. The in vitro susceptibility testing of ATM/AVI by standard methods was evaluated during development. This study investigated the impact of nonstandard testing conditions on the activity of ATM/AVI as observed during broth microdilution testing as well as the equivalency between agar dilution and broth microdilution MIC values when testing a diverse panel of Enterobacterales (N = 201). Nonstandard test conditions evaluated included inoculum density, atmosphere of incubation, media pH, varied medium cation concentrations, incubation time, varied serum concentrations, testing in pooled urine instead of media, addition of blood to the media, and the presence of surfactant. Generally, apart from low pH and high inoculum density, nonstandard testing parameters did not affect ATM/AVI broth microdilution MIC values. Correlation of MIC values obtained by agar dilution and broth microdilution resulted in an essential agreement of 97.0% for all tested Enterobacterales. Variation of standard testing conditions had little impact on broth microdilution MIC values for ATM/AVI. The correlation between broth microdilution and agar dilution MICs suggests both methods are reliable for determination of ATM/AVI MIC values. IMPORTANCE Increasing antibiotic resistance and emergence of pan-resistant isolates threaten the ability to control infections and to provide many other medical interventions such as surgery and chemotherapy, among others. New therapies are required to control emerging resistance mechanisms, including the increase in metallo-ß-lactamases. Some new antibiotic combinations provide coverage against highly resistant isolates but are unable to target organisms that produce metallo-ß-lactamases. Aztreonam in combination with avibactam provides a broad spectrum of activity against highly resistant isolates that also targets metallo-ß-lactamase-producing organisms. An important part of drug development is the ability for clinical labs to determine the susceptibility of isolates to the antimicrobial. This manuscript investigates the in vitro susceptibility testing of aztreonam/avibactam with nonstandard testing conditions and a correlation study between broth microdilution and agar dilution against clinical isolates encoding a variety of resistance mechanisms. Overall, aztreonam/avibactam was generally unaffected by changes in testing conditions and showed strong agar/broth correlation.

Activity of plazomicin in combination with other antibiotics against multidrug-resistant Enterobacteriaceae.

Plazomicin is a next-generation aminoglycoside that was approved by the US FDA in June 2018 for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis due to Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Proteus mirabilis. Plazomicin is active against multi-drug resistant (MDR) Enterobacteriaceae, where combination therapy is often used to treat infections caused by these pathogens. To determine synergy with other antibiotics, plazomicin was combined with antibiotics in checkerboard assays against MDR Enterobacteriaceae, including isolates with resistance to aminoglycosides and ß-lactams; 10 Escherichia coli isolates, 8 Klebsiella spp. isolates, 10 Enterobacter spp. isolates, and 2 Citrobacter freundii isolates were evaluated. Plazomicin had potent activity against MDR Enterobacteriaceae, including aminoglycoside-resistant strains, with MIC ranges of 0.5 - 2 µg/mL against E. coli isolates, 0.12 - 8 µg/mL against Klebsiella spp. isolates, 0.25 - 2 µg/mL against Enterobacter spp. isolates, and 0.06 - 0.25 µg/mL against C. freundii isolates. Synergy between plazomicin and piperacillin/tazobactam or ceftazidime was observed by checkerboard studies and confirmed by time-kill assays. No combination showed antagonism. These studies indicate that plazomicin has potential as a monotherapy and as combination therapy for treating serious Gram-negative infections caused by MDR Enterobacteriaceae.

Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-Resistant Enterobacteriaceae.

The next-generation aminoglycoside plazomicin, in development for infections due to multidrug-resistant (MDR) Enterobacteriaceae, was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR Enterobacteriaceae isolates with characterized aminoglycoside and ß-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC50/90 of 0.5/4 µg/ml and sustained 3-log10 kill against MDR Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp.

Inflammatory papillary hyperplasia: review of literature and case report involving a 10-year-old child.

Inflammatory papillary hyperplasia is a benign lesion of the palate seen most often in patients with a history of ill-fitting dentures or poor oral hygiene. The specific cause is unknown. Inflammatory papillary hyperplasia can occur at any age. However, it is most often seen in patients in the third to fifth decades. It occurs more frequently in males and whites. The best treatment is surgical removal. The prognosis is excellent, once the lesion is removed. The patient presented in this case report is a 10-year-old black girl without a history of a dental prosthesis. It is conjectured that poor oral hygiene and a habit of mouth breathing contributed to the occurrence of inflammatory papillary hyperplasia in this patient. The lesion was surgically removed, and the patient was followed up for a period of 18 months without recurrence of the lesion.

Complex odontoma: report of case.

This is a case report of a six-year-old boy with a complex odontoma, associated with an unerupted central incisor with a hypoplastic defect in the enamel and a malocclusion. Expedient removal provided an unobstructed path for the eruption of the central incisor.

The psychosocial aspects of adolescent pregnancy: a dental perspective.

This paper presents some of the psychological and social aspects of the adolescent who is pregnant, and how the combination of adolescence and pregnancy affect the dental management of these patients.