The role of inhalational combination therapy when treating carbapenem resistant Pseudomonas aeruginosa and Klebsiella pneumoniae with newer beta-lactam/beta-lactamase inhibitors has not been established. Using a 72 hour in vitro pharmacodynamic chemostat model, we simulated the human exposures achieved in epithelial lining fluid (ELF) following intravenous ceftazidime-avibactam (CZA) 2.5g q8h alone and in combination with inhaled amikacin (AMK) 400mg q12h, a reformulated aminoglycoside designed for inhalational administration, against 3 P. aeruginosa (CZA MICs: 4/4-8/4 μg/ml; AMK-I MICs: 8-64 μg/ml) and 3 K. pneumoniae (CZA: 1/4-8/4 μg/ml; AMK-I: 32-64 μg/ml). Combination therapy resulted in a significant reduction in 72 hour colony forming units (CFU) compared with CZA monotherapy against 2 of 3 P. aeruginosa (-4.14 log10CFU/ml, P= 0.027; -1.42 log10CFU/ml, P=0.020; and -0.4 log10CFU/ml, P= 0.298) and 2 of 3 K. pneumoniae (0.04 log10CFU/ml, P=0.963; -4.34 log10CFU/ml, P < 0.001; and -2.34 log10 CFU/ml, P=0.021). When measured by the area under the bacterial growth curve (AUBC) over 72 hours, significant reductions were observed in favor of the combination regimen against all 6 isolates tested. AMK-I combination therapy successfully suppressed CZA resistance development in one K. pneumoniae harboring blakpc3 that was observed during CZA monotherapy. These studies suggest a beneficial role for combination therapy with intravenous CZA and inhaled AMK when treating pneumonia caused by carbapenem resistant Gram-negative bacteria.

Several diagnostic tests are being developed to detect drug resistance in tuberculosis. In line with previous developments detecting rifampicin and isoniazid resistance using microbead-based systems (spoligoriftyping and TB-SPRINT), we present here an assay called TB-EFI detecting mutations involved in resistance to ethambutol, fluoroquinolones and the three classical injectable drugs (kanamycin, amikacin and capreomycin) in Mycobacterium tuberculosis. The proposed test includes both wild-type and mutant probes for each targeted locus. Basic analysis can be performed manually. An upgraded interpretation is made available in Excel 2016®. Using a reference set of 61 DNA extracts, we show that TB-EFI provides perfect concordance with pyrosequencing. Concordance between genotypic resistance and phenotypic DST was relatively good (72 to 98% concordance), with lower efficiency for fluoroquinolones and ethambutol due to some untargeted mutations. When compared to phenotypical resistance, performances were similar to those obtained with Hain MTBDRsl assay, possibly thanks to the use of automatized processing of data although some mutations involved in fluoroquinolone resistance could not be included. When applied on three uncharacterized sets, phenotype could be predicted for 51% to 98% depending on the setting and the drug investigated, detecting one extensively drug-resistant isolate in each of a Pakistan and a Brazilian set of 91 samples, and 9 XDR among 43 multi-resistant Kazakhstan samples. By allowing high-throughput detection of second-line drugs resistance and of resistance to ethambutol that is often combined to second-line treatments, TB-EFI is a cost-effective assay for large-scale worldwide surveillance of resistant tuberculosis and XDR-TB control.

A 36-year-old man was admitted to the intensive care unit due to diabetic ketoacidosis and pneumonia requiring mechanical ventilation. Three weeks after admission, he developed a refractory bacteremia with Klebsiella pneumoniae carbapenemase-producing bacteria (KPC). He remained febrile and with bacteremia for six weeks despite therapy with polymyxin B, carbapenems, and amikacin. Imaging studies looking for deep-seated infection revealed vertebral L1-L2 diskitis and osteomyelitis with pre-vertebral abscess and bilateral psoas pyomyositis that were not amenable for drainage. In view of the refractory infection and the activity against KPC described in the literature, we decided to switch the patient to ceftazidime/avibactam. After six weeks of therapy, there was complete resolution of the infectious processes. We present an instance of clinical success with ceftazidime/avibactam for the treatment of refractory KPC bacteremia, vertebral diskitis and osteomyelitis with pre-vertebral abscess and bilateral psoas pyomyositis. This experience serves as reference to support treatment with ceftazidime/avibactam in similar complicated cases.

Mitochondrial nonsyndromic hearing loss and deafness is characterized by sensorineural hearing loss (SNHL) of variable onset and severity. Pathogenic variants in MT-RNR1 can be associated with predisposition to aminoglycoside ototoxicity and/or late-onset SNHL. Hearing loss associated with aminoglycoside ototoxicity is bilateral and severe to profound, occurring within a few days to weeks after administration of any amount (even a single dose) of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin. Pathogenic variants in MT-TS1 are usually associated with childhood onset of SNHL that is generally nonsyndromic – although the MT-TS1 substitution m.7445A>G has been found in some families who also have palmoplantar keratoderma (scaling, hyperkeratosis, and honeycomb appearance of the skin of the palms, soles, and heels).