Pre-optimized phage therapy on secondary <i>Acinetobacter baumannii</i> infection in four critical COVID-19 patients

Wu, Nannan; Dai, Jia; Guo, Mingquan; Li, Jianhui; Zhou, Xin; Li, Feng; Gao, Yuan; Qu, Hongping; Lu, Hongzhou; Jin, Jing; Li, Tao; Shi, Lei; Wu, Qifan; Tan, Ruoming; Zhu, Mingli; Yang, Lan; Ling, Yun; Xing, Shunpeng; Zhang, Jianzhong; Yao, Bangxin; Le, Shuai; Gu, Jingmin; Qin, Jinhong; Li, Jie; Cheng, Mengjun; Tan, Demeng; Li, Linlin; Zhang, Yiyuan; Zhu, Zhaoqin; Cai, Jinfeng; Song, Zhigang; Guo, Xin; Chen, Li‐Kuang; Zhu, Tongyu

doi:10.1080/22221751.2021.1902754

Cited by 89 publications

(74 citation statements)

References 21 publications

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“…In the latter cohort, four patients have been coinfected with MDR A. baumannii (12.5%) [201]. CRAB outbreaks in COVID-19 patients seem to be effectively treated with a pre-optimized two-phage cocktail [202]. This finding is important, because OXA-23 CRAB infections have become a serious threat against SARS-CoV-2 infected patients in ICUs [203].…”

Section: Sars-cov-2 and Resistant A Baumannii Coinfectionsmentioning

confidence: 99%

Acinetobacter baumannii Antibiotic Resistance Mechanisms

et al. 2021

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Acinetobacter baumannii is a Gram-negative ESKAPE microorganism that poses a threat to public health by causing severe and invasive (mostly nosocomial) infections linked with high mortality rates. During the last years, this pathogen displayed multidrug resistance (MDR), mainly due to extensive antibiotic abuse and poor stewardship. MDR isolates are associated with medical history of long hospitalization stays, presence of catheters, and mechanical ventilation, while immunocompromised and severely ill hosts predispose to invasive infections. Next-generation sequencing techniques have revolutionized diagnosis of severe A. baumannii infections, contributing to timely diagnosis and personalized therapeutic regimens according to the identification of the respective resistance genes. The aim of this review is to describe in detail all current knowledge on the genetic background of A. baumannii resistance mechanisms in humans as regards beta-lactams (penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors), aminoglycosides, tetracyclines, fluoroquinolones, macrolides, lincosamides, streptogramin antibiotics, polymyxins, and others (amphenicols, oxazolidinones, rifamycins, fosfomycin, diaminopyrimidines, sulfonamides, glycopeptide, and lipopeptide antibiotics). Mechanisms of antimicrobial resistance refer mainly to regulation of antibiotic transportation through bacterial membranes, alteration of the antibiotic target site, and enzymatic modifications resulting in antibiotic neutralization. Virulence factors that may affect antibiotic susceptibility profiles and confer drug resistance are also being discussed. Reports from cases of A. baumannii coinfection with SARS-CoV-2 during the COVID-19 pandemic in terms of resistance profiles and MDR genes have been investigated.

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Section: Sars-cov-2 and Resistant A Baumannii Coinfectionsmentioning

confidence: 99%

Acinetobacter baumannii Antibiotic Resistance Mechanisms

et al. 2021

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“…Shinohara et al also report a monoclonal outbreak of an endemic strain of CRAb (14 cases) in a new COVID-19 ICU of a tertiary teaching hospital in southern Brazil [ 18 ]. Interestingly, CRAb outbreaks in COVID-19 patients seem to be effectively treated with a pre-optimized two-phage cocktail [ 110 ].…”

Section: Sars-cov-2 and A Baumanniimentioning

confidence: 99%

Acinetobacter baumannii Infections in Times of COVID-19 Pandemic

2021

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The COVID-19 pandemic has generated an overuse of antimicrobials in critically ill patients. Acinetobacter baumannii frequently causes nosocomial infections, particularly in intensive care units (ICUs), where the incidence has increased over time. Since the WHO declared the COVID-19 pandemic on 12 March 2020, the disease has spread rapidly, and many of the patients infected with SARS-CoV-2 needed to be admitted to the ICU. Bacterial co-pathogens are commonly identified in viral respiratory infections and are important causes of morbidity and mortality. However, we cannot neglect the increased incidence of antimicrobial resistance, which may be attributed to the excess use of antimicrobial agents during the COVID-19 pandemic. Patients with COVID-19 could be vulnerable to other infections owing to multiple comorbidities with severe COVID-19, prolonged hospitalization, and SARS-CoV-2-associated immune dysfunction. These patients have acquired secondary bacterial infections or superinfections, mainly bacteremia and urinary tract infections. This review will summarize the prevalence of A. baumannii coinfection and secondary infection in patients with COVID-19.

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“…Single intratracheal phage administration has successfully improved mortality in murine PsA mediated pneumonia models [ 13 , 15 , 16 ]. Additionally, our one-time IMIT administration conforms to recent literature seeking efficacy via similar dosing frequency in other pathogens including Acinetobacter baumanii (AB) [ 26 , 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Successful Intratracheal Treatment of Phage and Antibiotic Combination Therapy of a Multi-Drug Resistant Pseudomonas aeruginosa Murine Model

et al. 2021

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Background: Pseudomonas aeruginosa (PsA) is a common etiology of bacteria-mediated lower respiratory tract infections, including pneumonia, hospital acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Given the paucity of novel antibiotics in our foreseeable pipeline, developing novel non-antibiotic antimicrobial therapies saliently targeting drug resistant PsA isolates remains a priority. Lytic bacteriophages (or phages) have come under scrutiny as a potential antimicrobial for refractory bacterial infections. We evaluated intratracheally and intraperitoneally (IP) administered phage therapy (with/without meropenem) in an acute immunocompromised mouse model of multi-drug resistant (MDR) PsA pulmonary infection. The MDR P. aeruginosa respiratory disease model used in these studies was developed to investigate novel therapies that might have efficacy as either monotherapies or as combination therapy with meropenem. Methods: We utilized eight-week-old, 18 g BALB/cJ female mice and an MDR strain of PsA (UNC-D). Mice were immunosuppressed with cyclophosphamide. We employed a three-phage cocktail targeting PsA (PaAH2ΦP (103), PaBAP5Φ2 (130), and PaΦ (134)), confirmed to exhibit in vitro suppression of the infecting isolate out to 45 h. Suppression was confirmed with phages acting in isolation and in combination with meropenem. Results: IP administration of phage did not protect mice from death. A one-time delivery of phage directly to the lungs via a single intubation-mediated, intratracheal (IMIT) instillation protected mice from lethal infection. Protection was observed despite delaying therapy out to 6 h. Finally, we observed that, by slowing the progression of infection by treatment with a sub-efficacious dose of meropenem, we could protect the mice from lethal infection via IP phage administration coupled to meropenem, observing partial additive effects of phage–antibiotic combination therapy. Conclusions: A personalized phage cocktail administered via IMIT exhibits high therapeutic efficacy, despite delayed treatment of 6 h in a lethal MDR PsA pneumonia model. IP phage alone did not forestall mortality, but exhibited efficacy when combined with meropenem and IMIT-administered phage. These additive effects of combined IP phage and meropenem confirm that phage may indeed reach the lung bed via the systemic circulation and protect mice if the infection is not too acute. Therefore, adjunctive phage therapy with concerted attention to identifying optimal phage targeting of the infecting isolate in vitro may exhibit transformative potential for combating the specter of MDR bacterial infections. Phage should serve as an integral component of a four-pronged approach coupled with antibiotics, source control, and immune optimization.

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Pre-optimized phage therapy on secondary Acinetobacter baumannii infection in four critical COVID-19 patients

Cited by 89 publications

References 21 publications

Acinetobacter baumannii Antibiotic Resistance Mechanisms

Acinetobacter baumannii Antibiotic Resistance Mechanisms

Acinetobacter baumannii Infections in Times of COVID-19 Pandemic

Successful Intratracheal Treatment of Phage and Antibiotic Combination Therapy of a Multi-Drug Resistant Pseudomonas aeruginosa Murine Model

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