An 81-year-old immunocompetent patient with bronchiectasis and refractory Mycobacterium abscessus lung disease was treated for six months with a three-phage cocktail active against the strain. In this case study of phage to lower infectious burden, intravenous administration was safe and reduced the M. abscessus sputum load 10-fold within one month. However, after two months, M. abscessus counts increased as the patient mounted a robust IgM-and IgG-mediated neutralizing antibody response to the phages, which associated with limited therapeutic efficacy.Nontuberculous mycobacteria (NTM)-especially Mycobacterium abscessus infections represent emerging pathogens of increasing clinical importance 1 . There is an urgent need for novel treatments for NTM as outcomes are often poor, particularly with macrolide-resistant strains 2-4 . Bacteriophages offer an innovative therapeutic approach for difficult-to-treat infections 5,6 Recently, a 15-year-old lung transplant recipient with cystic

cAn effective regimen for treatment of tuberculosis (TB) is comprised of multiple drugs that inhibit a range of essential cellular activities in Mycobacterium tuberculosis. The effectiveness of a regimen is further enhanced if constituent drugs act with synergy. Here, we report that faropenem (a penem) or biapenem, doripenem, or meropenem (carbapenems), which belong to the ␤-lactam class of antibiotics, and rifampin, one of the drugs that forms the backbone of TB treatment, act with synergy when combined. One of the reasons (carba)penems are seldom used for treatment of TB is the high dosage levels required, often at the therapeutic limits. The synergistic combination of rifampin and these (carba)penems indicates that (carba)penems can be administered at dosages that are therapeutically relevant. The combination of faropenem and rifampin also limits the frequency of resistant mutants, as we were unable to obtain spontaneous mutants in the presence of these two drugs. The combinations of rifampin and (carba)penems were effective not only against drug-sensitive Mycobacterium tuberculosis but also against drugresistant clinical isolates that are otherwise resistant to rifampin. A combination of doripenem or biapenem and rifampin also exhibited synergistic activity against Mycobacterium abscessus. Although the MICs of these three drugs alone against M. abscessus are too high to be of clinical relevance, their concentrations in combinations are therapeutically relevant; therefore, they warrant further evaluation for clinical utility to treat Mycobacterium abscessus infection, especially in cystic fibrosis patients.

Aim:The objective of this study was to assess if avibactam, a new β-lactamase inhibitor, can restore the potency of carbapenems, a sub-class of β-lactams, against Mycobacterium abscessus clinical isolates. Materials & methods: 28 M. abscessus clinical isolates that are resistant to multiple drugs currently used to treat its infection were included. MIC of carbapenems alone and in combination with avibactam against these strains were determined. Results: Tebipenem, an oral carbapenem, and ertapenem and panipenem exhibited the greatest shift in MIC when supplemented with avibactam. Conclusion: Avibactam restores MICs of tebipenem, ertapenem and panipenem against M. abscessus to therapeutically achievable concentrations and raises the possibility of usefulness of these carbapenems to treat drug-resistant M. abscessus infections. Mycobacterium abscessus is a rapidly growing nontuberculous mycobacterium found widely in soil and water and can cause a spectrum of infections [1]. Prevalence of M. abscessus infections in the lungs of people with chronic conditions, such as cystic fibrosis is significant and can often lead to serious morbidity [2]. A survey revealed that M. abscessus is present in the sputum of approximately 13% of cystic fibrosis patients in the USA [3]. Among nontuberculous mycobacterium lung infections, M. abscessus is one of the prevalent species and often leads to a chronic and incurable disease [4][5][6]. Drug resistance in M. abscessus is steadily rising globally, making it increasingly difficult to manage infections with these strains [7]. Therefore, new drugs and novel regimens are acutely needed to treat infections with M. abscessus. An ideal new drug would inhibit a novel target so that it can be effective against M. abscessus strains that are resistant to currently used drugs.The peptidoglycan is an Achilles' heel of bacteria as agents that inhibit its biosynthesis, namely β-lactams and glycopeptides, comprise some of the most widely used class of antibacterials in modern medicine. β-lactams derive their activity by preventing formation of linkage between peptide side chains by inhibiting the transpeptidases that catalyze this reaction [8]. Recently it was demon strated that majority of the linkages in the peptidoglycan layer of M. abscessus are generated by LD-transpeptidases [9] and that this class of enzyme is selectively more susceptible to the carbapenem class of β-lactams [10][11][12]. Imipenem, a carbapenem, has superior activity compared with For reprint orders, please contact: reprints@futuremedicine.com

Tigecycline is used in multidrug regimens for salvage therapy of Mycobacterium abscessus infections but is often poorly tolerated and has no oral formulation. Here, we report similar in vitro activity of two newly approved tetracycline analogs, omadacycline and eravacycline, against 28 drug-resistant clinical isolates of M. abscessus complex. Since omadacycline and eravacycline appear to be better tolerated than tigecycline and since omadacycline is also formulated for oral dosing, these tetracycline analogs may represent new treatment options for M. abscessus infections.