Date Published: March 5, 2018
Publisher: Public Library of Science
Author(s): Norman Zinne, Marcus Krueger, Doris Hoeltig, Burkhard Tuemmler, Erin C. Boyle, Christian Biancosino, Klaus Hoeffler, Peter Braubach, Taufiek K. Rajab, Anatol Ciubotaru, Judith Rohde, Karl-Heinz Waldmann, Axel Haverich, Abdelwahab Omri.
The emergence of multi-drug resistant bacteria threatens to end the era of antibiotics. Drug resistant bacteria have evolved mechanisms to overcome antibiotics at therapeutic doses and further dose increases are not possible due to systemic toxicity. Here we present a pilot study of ex vivo lung perfusion (EVLP) with high dose antibiotic therapy followed by autotransplantation as a new therapy of last resort for otherwise incurable multidrug resistant lung infections. Severe Pseudomonas aeruginosa pneumonia was induced in the lower left lungs (LLL) of 18 Mini-Lewe pigs. Animals in the control group (n = 6) did not receive colistin. Animals in the conventional treatment group (n = 6) received intravenous application of 2 mg/kg body weight colistin daily. Animals in the EVLP group (n = 6) had their LLL explanted and perfused ex vivo with a perfusion solution containing 200 μg/ml colistin. After two hours of ex vivo treatment, autotransplantation of the LLL was performed. All animals were followed for 4 days following the initiation of treatment. In the control and conventional treatment groups, the infection-related mortality rate after five days was 66.7%. In the EVLP group, there was one infection-related mortality and one procedure-related mortality, for an overall mortality rate of 33.3%. Moreover, the clinical symptoms of infection were less severe in the EVLP group than the other groups. Ex vivo lung perfusion with very high dose antibiotics presents a new therapeutic option of last resort for otherwise incurable multidrug resistant pneumonia without toxic side effects on other organs.
Ventilator-associated pneumonia (VAP) is currently the most commonly-acquired infection in intensive care units and represents a major cause of morbidity and mortality. The mortality rate for VAP ranges from 24% to 50% and can exceed 70% if the pneumonia is caused by high-risk pathogens[1–3]. Pseudomonas aeruginosa is one of the most frequent pathogens responsible for VAP and is associated with a high mortality rate. The development of resistance of P. aeruginosa to antibiotics is increasing globally and occurs as a result of various mechanisms, e.g. blocking drug penetration, efflux pumps, or modification of drug targets[6–8]. Since multidrug resistance, especially in Gram-negative bacteria, is one of the major concerns in current treatment strategies for pneumonia, new therapeutic alternatives are urgently needed[2,5,9].
This experimental study was designed to explore the potential of ex vivo treatment for lung infections involving multidrug resistant bacteria. Using a large animal model of pneumonia, we have demonstrated that ex vivo high dose antimicrobial therapy followed by autotransplantation can be used to treat bacterial lung infections. EVLP allows us to specifically treat lungs with high doses of antibiotics without collateral drug toxicity to other organs. A recent study by Nakajima et al. , also performed EVLP with high dose antibiotics and found that this effectively reduced bacterial numbers. Our pilot study significantly extends these findings, showing that ex vivo treated lungs could be re-transplanted and resulted a higher rate of survival and a reduction in clinical symptoms as compared to conventional i.v. antibiotic therapy.