COVID-19: Role of superinfections in novel coronavirus deaths highlights urgent need for sustainable development of new antibiotics

To date, there are limited data on superinfections associated with COVID-19, the pandemic disease caused by the novel coronavirus SAR-CoV-2. A handful of published reports, however, largely from China, suggest that bacterial and fungal superinfections may occur in a significant percentage of patients with severe COVID-19, and that these infections are caused at least in some hospitals by antimicrobial-resistant, nosocomial pathogens. Early experience indicates that almost with all patients with severe COVID-19 receive broad spectrum antimicrobials, either for treatment of a diagnosed superinfection, or empirically due to the possibility of such an infection. An association between COVID-19 and superinfections is plausibly driven by two, non-exclusive explanations. First, SARS-CoV-2 infection leads to immune system dysregulation in severe infections, which may leave patients vulnerable to bacterial or fungal proliferation[i]. Second, critically ill patients, especially those in intensive care units or receiving mechanical ventilation, are at markedly increased risk for bacterial and fungal infections, independent of COVID-19. Superinfections were reported in 10%-20% of SARS-CoV-2-infected adults admitted to Wuhan, China hospitals through the end of January 2020, including 50%-100% of those who died[ii].

Superinfections were diagnosed in 31% of ICU patients with COVID-19 at one of these hospitals[iii]. Types of infections were bacterial or fungal pneumonia (9% of ICU patients), pneumonia with bacteremia (2%), and bacterial urinary tract infection (2%)[iv]. Organisms cultured from patients were typically highly resistant to antimicrobials, and each is found in the 2019 Centers for Disease Control’s Report on Antibiotic Resistance Threats 2019, including Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, extended spectrum beta lactamase (ESBL)-producing K. pneumoniae and Pseudomonas aeruginosa Aspergillus fumigatus, Aspergillus flavus and Candida albicans. Infections were typically diagnosed more than two weeks after the onset of COVID-19 symptoms, and they often occurred only days prior to death[v]. Bacterial and fungal infections, then, in particular those caused by antimicrobial-resistant pathogens, appear to have been significant causes of death among COVID-19 patients in Wuhan hospitals. In the first European COVID-19 case series, one of three patients with severe disease in France died after being diagnosed with secondary Acinetobacter baumannii and A. flavus co-infection[vi].

In studies from Chinese hospitals, 80%-100% and 7.5% of patients with severe COVID-19 were treated with antibiotics and antifungal agents, respectively[vii]. Broad-spectrum antibiotics including carbapenems, cephalosporins, fluoroquinolones and linezolid were prescribed most commonly[viii]. Antimicrobial agents were typically used empirically, rather than against diagnosed infections, because 25%-75% of severely ill COVID-19 patients show evidence of sepsis, and it is very difficult to exclude bacterial or fungal superinfections based on signs and symptoms, physical findings, radiographic abnormalities and laboratory results. The French patient with severe COVID-19 and apsergillosis was treated with various combinations of meropenem, tigecycline, levofloxacin, aerosolized colistimethate, voriconazole and/or isavuconazole before dying of multisystem organ failure on the 24^th day after onset of COVID-19 symptoms[ix].

Anecdotal reports of bacterial and fungal infections complicating COVID-19 similar to those from China and France are appearing on social media from physicians in New York, California, Washington, the Netherlands, the United Kingdom and other locales seeing high volumes of cases. It is likely, then, that we will need a steady supply of broad-spectrum antibiotics to treat severely ill COVID-19 patients, particularly in ICUs. In many instances, newly U.S. Food and Drug Administration-approved antibiotics of last resort against carbapenem resistant Enterobacteriaceae and other highly resistant pathogens will be needed. Tellingly, several companies responsible for bringing these new drugs through FDA approval have declared bankruptcy or left the antimicrobial field due to insufficient economic return in the marketplace. The COVID-19 crisis will vividly highlight why reimbursement models for antibiotics must be delinked from per unit use of these drugs, but rather more fairly reflect their societal and public health value. Second, the widespread use of broad-spectrum antibiotics in patients with severe COVID-19 may promote the emergence of further antibiotic resistance in U.S. hospitals. We need to assure that the economic model for antibiotics promotes the sustainable development of new drugs.

 [i] Chen, Journal of Clinical Investigation; Huang, The Lancet

[ii] Zhou F, The Lancet; Cao, Clinical Infectious Diseases; Huang

[iii] Huang

[iv] Yang, Lancet Respiratory Medicine

[v] Zhou

[vi] Lescure, Lancet Infectious Diseases

[vii] Tao Chen, BMJ; Guan, New England Journal of Medicine; Huang

[viii] Tao Chen; Cao

[ix] Lescure