Systemic use of the endolysin Cpl-1 rescues mice with fatal pneumococcal pneumonia.
OBJECTIVE
Community-acquired pneumonia is a very common infectious disease associated with significant morbidity and mortality. Streptococcus pneumoniae is the predominant pathogen in this disease, and pneumococcal resistance to multiple antibiotics is increasing. The recently purified bacteriophage endolysin Cpl-1 rapidly and specifically kills pneumococci on contact. The aim of this study was to determine the therapeutic potential of Cpl-1 in a mouse model of severe pneumococcal pneumonia.


METHODS
Controlled, in vivo laboratory study.


METHODS
Female C57/Bl6 mice, 8-12 weeks old.


METHODS
Mice were transnasally infected with pneumococci and therapeutically treated with Cpl-1 or amoxicillin by intraperitoneal injections starting 24 or 48 hours after infection.


RESULTS
Judged from clinical appearance, decreased body weight, reduced dynamic lung compliance and Pao2/Fio2 ratio, and morphologic changes in the lungs, mice suffered from severe pneumonia at the onset of therapy. When treatment was commenced 24 hours after infection, 100% Cpl-1-treated and 86% amoxicillin-treated mice survived otherwise fatal pneumonia and showed rapid recovery. When treatment was started 48 hours after infection, mice had developed bacteremia, and three of seven (42%) Cpl-1-treated and five of seven (71%) amoxicillin-treated animals survived. Cpl-1 dramatically reduced pulmonary bacterial counts, and prevented bacteremia, systemic hypotension, and lactate increase when treatment commenced at 24 hours. In vivo, treatment with Cpl-1 or amoxicillin effectively reduced counts of penicillin-susceptible pneumococci. The inflammatory response in Cpl-1-and amoxicillin-treated mice was lower than in untreated mice, as determined by multiplex cytokine assay of lung and blood samples. In human epithelial cell cultures, lysed bacteria evoked less proinflammatory cytokine release and cell death, as compared with viable bacteria.


CONCLUSIONS
Cpl-1 may provide a new therapeutic option in the treatment of pneumococcal pneumonia.
Witzenrath
Martin
M
Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. martin.witzenrath@charite.de
Schmeck
Bernd
B
Doehn
Jan M
JM
Tschernig
Thomas
T
Zahlten
Janine
J
Loeffler
Jutta M
JM
Zemlin
Maren
M
Müller
Holger
H
Gutbier
Birgitt
B
Schütte
Hartwig
H
Hippenstiel
Stefan
S
Fischetti
Vincent A
VA
Suttorp
Norbert
N
Rosseau
Simone
S
D000658:Amoxicillin / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000008:administration & dosage / Q000627:therapeutic use*; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy*
D000658:Amoxicillin; D009113:Muramidase