Streptococcus pneumoniae is becoming increasingly antibiotic resistant worldwide, and thus new antimicrobials are badly needed. We report the use of Cpl-1, the lytic enzyme of a pneumococcal bacteriophage, as an intravenous therapy for pneumococcal bacteremia in a mouse model. A 2,000-g dose of Cpl-1 reduced pneumococcal titers from a median of log 10 4.70 CFU/ml to undetectable levels (

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Purpose The outcomes of patients requiring invasive mechanical ventilation for COVID-19 remain poorly defined. We sought to determine clinical characteristics and outcomes of patients with COVID-19 managed with invasive mechanical ventilation in an appropriately resourced US health care system. Methods Outcomes of COVID-19 infected patients requiring mechanical ventilation treated within the Inova Health System between March 5, 2020 and April 26, 2020 were evaluated through an electronic medical record review. Results 1023 COVID-19 positive patients were admitted to the Inova Health System during the study period. Of these, 164 (16.0%) were managed with invasive mechanical ventilation. All patients were followed to definitive disposition. 70/164 patients (42.7%) had died and 94/164 (57.3%) were still alive. Deceased patients were older (median age of 66 vs. 55, p <0.0001) and had a higher initial d-dimer (2.22 vs. 1.31, p = 0.005) and peak ferritin levels (2998 vs. 2077, p = 0.016) compared to survivors. 84.3% of patients over 70 years old died in the hospital. Conversely, 67.4% of patients age 70 or younger survived to hospital discharge. Younger age, non-Caucasian race and treatment at a tertiary care center were all associated with survivor status. Conclusion Mortality of patients with COVID-19 requiring invasive mechanical ventilation is high, with particularly daunting mortality seen in patients of advanced age, even in a well-resourced health care system. A substantial proportion of patients requiring invasive mechanical ventilation were not of advanced age, and this group had a reasonable chance for recovery.

A combination of Cpl-1, a bacteriophage lytic enzyme, and penicillin, gentamicin, levofloxacin, or azithromycin was tested against Streptococcus pneumoniae strains with various susceptibilities to penicillin. Activities of Cpl-1 and gentamicin were increasingly synergistic with a decreasing penicillin MIC, while Cpl-1 and penicillin showed synergy against an extremely penicillin-resistant strain.Streptococcus pneumoniae is a leading cause of pneumonia, otitis media, meningitis, and sepsis worldwide, and the increase in antibiotic resistance of pneumococci has limited the number of antimicrobial agents that produce reliable treatment results for these infections. Combination therapy by antimicrobials with different mechanisms of action has been used to treat infections for decades with the goal of producing a wider spectrum of action, preventing the emergence of drug-resistant subpopulations, reducing the dose of a single agent, or achieving a synergistic effect.Lytic enzymes are produced by bacteriophages at the end of their replicative cycle and can digest the bacterial cell wall within seconds. Cpl-1 is a muramidase that specifically cleaves the glycosidic bond between N-acetylmuramic acid and Nacetylglucosamine in the cell wall of S. pneumoniae (5). Purified recombinant Cpl-1 has shown extremely rapid killing of S. pneumoniae in vitro and can effectively eradicate these organisms from the nose or the bloodstream of mice (8, 9).We previously reported the synergistic effect of a combination of two phage lytic enzymes with different enzymatic activities, Cpl-1 and Pal, against S. pneumoniae in vitro, and this effect has been confirmed with mouse sepsis models (6, 10). It has not been shown, however, whether lytic phage enzymes in combination with conventional antibiotics could improve their respective efficiencies against pneumococci. In this study we report the in vitro effect of the simultaneous use of Cpl-1 and penicillin, gentamicin, levofloxacin, or azithromycin against four different strains of S. pneumoniae, with MICs of penicillin indicating a range from sensitive to extremely resistant.We produced and purified Cpl-1 from E. coli DH5␣(pJML6) as described elsewhere (8, 10). Cpl-1 was lyophilized and stored at 4°C. Penicillin and gentamicin were purchased from Sigma (St. Louis, Mo.), levofloxacin was purchased from Ortho-McNeil (Raritan, N.J.), and azithromycin was purchased from Pfizer (New York, N.Y.). Stock solutions were made by resuspending the agents in sterile water.For all the pneumococcal strains tested, we first determined MICs of each antibiotic and Cpl-1 by the macrodilution method, using 2 ml of Mueller-Hinton broth (BBL, Becton Dickinson Microbiology Systems, Cockeysville, Md.) supplemented with 5% lysed horse blood (Cleveland Scientific, Inc., Bath, Ohio). The method is described elsewhere in detail (1). The bacterial strains tested and the respective drug MICs are reported in Table 1. Antibiotic and Cpl-1 interactions were assessed by the checkerboard method with 96-well plates, in which Cp...