Non-viral infections and antimicrobial resistance in the time of COVID-19: what to expect?

KEYWORDS:

• Antibiotics
• antifungals
• bacterial infections
• coinfections
• COVID-19
• fungal infections
• resistance

1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting COVID-19 pandemic have already infected over 418 million people and have killed almost 6 million people. Antibiotics and antifungals are not recommended for COVID-19 pneumonia except for relatively infrequent bacterial or fungal coinfections and superinfections, usually in critically ill patients.

Early in the pandemic, especially in Asia (particularly in China), many bacterial superinfections were reported, possibly due to different hygiene levels or health standards [1]. A multicenter study showed that early coinfections (in ≤3.5% of COVID-19 patients) were usually bacterial, while secondary infections (in around 15%) were bacterial or fungal [2]. However, 50–75% (38.3–90.0%) of COVID-19 patients have been treated with antimicrobials, mostly antibiotics [2–4]. Given the scale of the pandemic, overuse and misuse of antibiotics and antifungals can increase resistance rates and emergence of multidrug resistant (MDR) bacteria and fungi.

Coinfection/superinfection rates have varied according to the countries, patients’ groups and antimicrobial agents used. Global coinfection rates in COVID-19 patients have been around 17% with the highest rate in Iran and the lowest rate in the USA [5]. Importantly, coinfections increased mortality risks and in a US study, bacterial coinfections or superinfections raised 5.8-fold mortality rates in COVID-19 inpatients [6]. We focus on bacterial and fungal infections in COVID-19 patients according to relevant articles in PubMed/MEDLINE, Scopus, and Google Scholar databases since 2020.

2. Clostridioides difficile

Concerns during the COVID-19 pandemic are prevalence and treatment of Clostridioides (formerly Clostridium) difficile-associated infections (CDIs), including those with hypervirulent ribotypes 027 and 078, as a result of broad-spectrum antibiotic therapy. CDIs mortality rates have been 3–36%, with the highest rates in patients with relapses [3]. In a multicenter study, C. difficile was detected in 10.5% of positive microbiology samples [2]. There has been a controversy about the CDI evolution during the Coronavirus pandemic, ranging from a decrease, probably linked to the strict anti-epidemic measures and patients’ isolation to an increase as reported in some studies from USA, Poland, and Italy [7].

Challenges concerning CDIs during COVID-19 pandemic are C. difficile under- or over-diagnosing and difficulties in therapy of the infections. Toxigenic C. difficile is often detected only with direct enzyme immunoassays (EIAs) for toxin detection. However, the sensitivity of C. difficile toxin A/B EIAs was <60% versus 90.0% for nucleic acid amplification test in comparison with toxigenic culture [8].

There are limited therapeutic options for CDIs. Toxigenic culture (toxin retesting of isolated C. difficile strain) is seldom performed, despite its advantage to reveal antibiotic susceptibility of C. difficile, given that resistance to metronidazole and vancomycin, the two main antibiotics for CDI therapy, has already been reported [9]. Furthermore, fidaxomicin, a macrocyclic lactone agent used to treat recurrent CDIs, is not available in many countries.

Newer agents for treatment optimization of CDI have been developed. A Phase III study evaluating a new synthetic bis-benzimidazole, ridinilazole, has been completed. It is a non-absorbable narrow-spectrum antibiotic which suppresses C. difficile cell division and, unlike vancomycin, spares the intestinal microbiota [3]. A monoclonal antibody (bezlotoxumab) targeting C. difficile toxin B is already available and can be combined with antibiotics [3]. The use of nanoantibiotics (antibiotic molecules encased with engineered nanoparticles) is a promising approach to treat various bacterial infections [3].

3. Other bacterial infections

In COVID-19 coinfections/superinfections, bacteria of numerous genera have been reported, including frequently antibiotic-resistant species such as Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Enterobacter cloacae, and Pseudomonas aeruginosa [6,10,11].

Broad-spectrum antibiotic overuse or misuse has augmented MDR in Enterobacterales (formerly Enterobacteriaceae) species. Extended-spectrum beta-lactamase (ESBL) and carbapenem resistance, often associated with MDR, strongly limit treatment options to few antibiotics, such as polymyxins, to which resistance has emerged as well. A study from Taiwan during the COVID-19 pandemic revealed a fast increase in MDR bacteria such as ESBL or carbapenemase-producing Enterobacterales, A. baumannii, and methicillin-resistant S. aureus and fungi such as Candida glabrata and Aspergillus fumigatus [12].

Although carbapenemase-producing Enterobacterales (CPE) infections are not common in COVID-19 patients, they have been about twice more frequent and fatal in these patients than in controls, especially in intensive care units (ICUs). In COVID-19 patients in Spain, CPE infection rate was 1.1% (30/2615 patients) versus 0.5% (24/4433) in non-COVID-19 controls [10]. Moreover, the 30-day mortality rate in the COVID-19 patients was 30.0% versus 16.7% in the controls [10]. The increased risk of CPE infections observed in patients with COVID-19 in Spain, Italy, and the United States, especially in ICUs, may be related to the broad-spectrum antibiotic use in the ICUs and the presence of invasive devices and mechanical ventilation [10].

Newer antibiotics or antibiotic combinations with newer beta-lactamase inhibitors such as avibactam, vaborbactam, and relebactam or with siderophores can counteract carbapenemase-associated resistance. Such newer agents are ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol (an injectable siderophore cephalosporin), and plazomicin (an aminoglycoside based on sisomicin with modifications at two positions) [3]. Cefiderocol uses a ‘Trojan Horse’ approach exploiting bacterial ferrous acquisition to increase outer membrane penetration of the drug. The agent is active against ESBL and carbapenemase producing Enterobacterales, Haemophilus,Pseudomonas, and other species [3].

Although the COVID-19 pandemic made several world organizations such as the United Nations and World Health Organization to renew programs and funding for new drug development, in March 2021, <45 new antibiotics were in development and very few (13) were in phase 3 clinical trials [13].

The good news is that the COVID-19 pandemic enlarged the use of molecular methods and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. At present, MALDI-TOF-MS is widely used to rapidly (in <1 h) identify causative agents of infections and to detect beta-lactamase/carbapenemase production [14]. The pandemic has motivated application of new antibiotics (see above) or new approaches such as phage therapy for bacterial coinfections and superinfections in patients with COVID-19 [15,16].

Unlike the antibiotics, phages and phage lysins are highly specific to the target, have low toxicity, and resistance to them is rare [11,15]. Inorganic nanosized particles such as silver nanoparticles have also shown antibacterial properties in vitro and in animal models against MDR bacteria and various fungal species [11]. Some repurposed drugs such as tamoxifen and diflunisal have demonstrated antibacterial activity [11]. Potential of phages or phage cocktails to treat carbapenem-resistant Acinetobacter baumannii pneumonia has already been evaluated in China and the USA [16].

4. Fungal infections

Both immunosuppressive drugs and antibiotic therapy increase the risk of fungal superinfections. Severe COVID-19 infections are frequently treated with systemic corticosteroids, which decrease mortality rates in hypoxemic patients; however, they also enhance risks of fungal infections such as candidiasis, pulmonary aspergillosis, mucormycosis, and Candida auris infections [17]. In a multicenter study in Europe, Aspergillus spp. were detected in 14% of positive ICU specimens from COVID-19 patients, most of whom (74.1%) had received corticosteroids [2].

C. auris can cause nosocomial outbreaks and can harbor MDR to azoles, polyenes, and sometimes echinocandins, and some strains are panresistant [18]. Invasive C. auris infections have been reported in Miami, USA, and most often (12/15 cases) in patients with COVID-19 [19].

Uncontrolled diabetes is a major risk factor for mucormycosis, an invasive and rapidly progressing fungal infection caused by Rhizopus, Mucor, Rhizomucor, and other fungal species and linked to high mortality rates. Treatment requires surgery and antifungals such as liposomal amphotericin B or isavuconazole, a broad-spectrum triazole agent. Increase in mucormycosis in time of COVID-19 can be explained by the triad of severe acute respiratory syndrome, poorly controlled diabetes, and corticosteroid use [17].

In the treatment of fungal infections, antifungal enzymes such as lysozymes and antimicrobial peptides such as cathelicidins have been studied [11,15]. Newer antifungals such as the oral formulation of amphotericin B cochleate against drug-resistant Candida and Aspergillus spp. or rezafungin or ibrexafungerp (an orally available triterpenoid agent) with increased activity against C. auris have been evaluated [18].

5. Expert opinion

COVID-19 pandemic and associated antibiotic overuse and misuse have increased both prevalence of and resistance and MDR in coinfecting bacteria and fungi, which represent a growing threat to global human health. There are important directions to counteract this evolution.

Optimization of diagnosis and treatment of COVID-19-associated infections, involving multidrug-resistant infections, C. difficile- or Candida auris infections, and mucormycosis, is highly important.

Microbiology laboratories should be appropriately equipped with or have access to molecular methods and MALDI-TOF-MS to early and reliably diagnose and treat coinfections and superinfections in COVID-19 patients. After obtaining microbiological results, narrow-spectrum antibacterial agents should be preferred for treatment.

Research and clinical studies on new antibiotics and antifungals should be enlarged. Although the pandemic made some world organizations to restart programs for new drug development, there are still few antimicrobials in phase 3 clinical trials.

Newer antibiotics such as siderophore beta-lactams against MDR Gram-negative bacteria, ridinilazole and bezlotoxumab against C. difficile infections, nanoantibiotics and antifungals such as encochleated amphotericin B, rezafungin, or ibrexafungerp should be considered and further evaluated in laboratory and clinical studies. Adjuvant treatment options could be the use of phages or phage lysins, nanoparticles, and repurposed drugs.

Last but not least, the prophylactic use of antibiotics and antifungals should be avoided in patients with mild-to-moderate COVID-19 infections and without comorbidity and laboratory proven coinfections.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.