Evaluation of Acinetobacter baumannii, Klebsiella pneumoniae, and Staphylococcus aureus respiratory tract superinfections among patients with COVID-19 at a tertiary-care hospital in Tehran, Iran

SARS-CoV-2, the newest and seventh member of the Coronaviridae family, is the causative agent of severe respiratory illness in humans, similar to SARS-CoV and MERS-CoV [1], which was discovered in Wuhan’s Hubei Province in China at the end of 2019 and was designated coronavirus disease 2019 (COVID-19) by the WHO on February 11, 2020 [2]. Since its first appearance, the COVID-19 virus has infected more than 753 million individuals worldwide, resulting in over 6.8 million fatalities by February 2023 [3]. This global pandemic has impacted individuals of all ages, causing various clinical symptoms ranging from the common cold to fatal pneumonia [4]. Risk factors and severe clinical COVID-19 cases are usually seen in elderly and immunocompromised individuals who suffer from various concomitant problems, such as cardiovascular diseases, diabetes, hypertension, and chronic obstructive pulmonary disease [5]. SARS-CoV-2 virus can predispose immunocompromised hosts to various bacterial infections by exaggerated production of inflammatory cytokines causing uncontrollable immune responses, multiple organ damage, and severe pneumonia [6]. The lung histopathologic findings reveal the role of healthcare-associated infections (HAIs) causing pneumonia in tissue damage, which can accompanied by increased mortality [7] (Fig. 1).

HAIs are defined as infections that manifest in hospitalized patients at least 48 h after hospital admission and are classified according to the Centers for Disease Control and Prevention/National Healthcare Safety Network (CDC/NHSN) criteria [8]. K. pneumoniae, A. baumannii, and S. aureus isolates are three prevalent microorganisms causing HAI. These organisms are the leading cause of multidrug-resistant nosocomial pathogens, the so-called Enterococcus faecium, S. aureus, K. pneumoniae, A. baumannii, Pseudomonas aeruginosa, and Enterobacter spp. (ESKAPE) group, which account for rising annual healthcare costs and mortality [9].

Carbapenem-resistant K. pneumoniae (CRKP) and A. baumannii (CRAB) isolates contributed to a significant death rate among critically ill COVID-19 patients with a prolonged hospitalization history [10, 11]. In addition, S. aureus isolates are the second leading source of up to 11.8% of HAIs in the United States. They are responsible for both community and HAIs isolated from the lower respiratory tract of COVID-19 patients receiving ventilation [12] (Fig. 1). Given the apparent complication of MRSA in causing ventilator-acquired superinfections in previous SARS-CoV and influenza outbreaks [13], the prevalence of superinfection caused by this organism should be considered in the current pandemic to account for therapeutic targets against this infection [14].

According to the superinfection rate up to 70.6% [15], there has also been a 46.8% increase trend in inappropriate antibiotic treatment among COVID-19 patients with superinfection [16].

This study aimed to assess the prevalence of healthcare-associated respiratory infections or superinfections, antibiotic resistance profiles against the three HAIs mentioned above, and compliance with clinical outcomes among COVID-19 patients admitted to the ICUs of a major hospital in Tehran, Iran.

This study detected a high HAI proportion of 83.2% among ICU-admitted COVID-19 patients. Most patients with HAI were critically ill. Additionally, we were in lacked access to microbiological data during the first admission. Thus, some might have been admitted with coinfections that were classified as superinfections. Furthermore, the length of stay in our study was relatively long (median = 18 days). In numerous other studies, the length of hospital stay was prolonged for patients with various superinfections and was accompanied by increased mortality [27‐29].

Approximately 92% of patients with HAI were intubated, and of those, 80% had at least one underlying disease, which led to a mortality rate of 90%. Similarly, in some investigations, hypertension, diabetes, and coronary heart disease were found to be most common among patients suffering from comorbidities and HAI [29, 30]. In addition, 84% of patients with HAI received immunosuppressive therapies more frequently, primarily because of multiple organ damage due to hyperinflammatory immune responses in critically ill COVID-19 patients [31]. These patients may have been infected by various bacterial, fungal, and viral superinfections that exacerbated the severity of their symptoms [32]. These factors may be justifiable for our high incidence of HAI.

In our study, antibiotic administration was more frequent among patients with HAI than those without it, which had a significant association with mortality. In addition, HAI-causing A. baumannii and K. pneumoniae isolates exhibited high resistance to many antibiotics. Similarly, in the Floridia et al. study, the most frequent pathogens causing infections were Enterobacterales, mainly K. pneumoniae, followed by A. baumannii and S. aureus isolates. In addition, a higher rate of antibiotic resistance was exhibited by these organisms during the first and second waves of COVID-19 than during a prior pandemic [33]. In one study by Kariyawasam et al., MDR isolates of K pneumoniae (n = 274), A. baumannii (n = 218), P. aeruginosa (n = 203), and MRSA (n = 132) were more frequent than the others [34]. Similar to the Mdrzycka et al. study, the highest prevalence of CRKP was up to 53%, mainly occurring in elderly and male SARS-CoV-2-infected individuals [35].

In agreement with our findings, Tadesse et al. stated the presence of carbapenemase and many antimicrobial resistance (AMR)-encoding genes, such as ESBLs, on mobile genetic elements to facilitate the accumulation and spread of AMR genes. This emphasizes why most carbapenem-resistant Gram-negative bacteria, such as CRKP and CRAB isolates, are primarily resistant to other antibiotic classes, such as aminoglycosides, fluoroquinolones, and SXT [36]. In our study, all ESBL-producing K. pneumoniae isolates were MDR. Mazzariol et al. reported a proportion of 61.5% (8/13) for CRKP and 23.5% (3/13) for ESBL-producing K. pneumoniae, which was comparable to our findings [37].

In one study by Pourajam et al., in contrast to our results, the superinfection-causing K. pneumoniae isolates showed the highest antibiotic resistance (97.9%) to CAZ, CRO, CPM, SAM, PTZ, and CP. They had increased resistance to LVX (95.8%), MER (95.8%), GM (93.6%), and AN (80.9%). While similar to our results, the resistance rate of A. baumannii isolates to COL was 10.6%, the full resistance rate to CAZ, CRO, CPM, TZP, MER, and CP, and 97.2%, 94.3%, and 60% resistance to GM, AN, and SAM were recorded, but no resistance rate to COL was found [38]. In the Bahce et al. study, similar to our study, the A. baumannii isolates showed full resistance to MEM, TPZ, CIP, LEV, and IMP. They also revealed an increased resistance to AK (63.8%), GN (95.7%), and TM (97.7%). In contrast to our results, the resistance rate of A. baumannii isolates to SXT was low (46.8%). Additionally, the resistance rate of K. pneumoniae isolates to GN (44.4%), COL (42.9%), MEM (71.4%), TZP (77.8%), CIP (100%), and FEP (77.8%) was reported to be relatively high compared to our results [39].

In a cross-sectional study by Qodrati et al., a low rate of MRSA (37.5%, 216/576) was obtained from clinical specimens one year before the pandemic. The antibiotic resistance against MRSA isolates was greater than that against MSSA isolates and was similar against GM, TE, LVX, SXT, CP, CD, and SXT. Given the full susceptibility of VAN and LZD to all S. aureus isolates, the authors considered these drugs as the first treatment priority against MRSA-causing infections [40]. Despite the frequent use of VAN in hospitalized COVID-19 patients, low numbers of MSSA (2/5) and MRSA isolates (3/5) were observed in our study. Additionally, Falcon [41] and Punjabi et al. [13] reported a low incidence of S. aureus and culture-based MRSA (5.7%) isolates from respiratory COVID-19 patient samples. In contrast to Qodrati et al., Punjabi et al. believed that continuous VAN treatment might not be more beneficial for superinfections caused by MRSA isolates [13].

Although the prescription of antimicrobial treatment in infections of the ongoing SARS-CoV-2 pandemic is unavoidable, there has been no documented sign of its efficacy in lowering mortality [42]. Some reports have shown widespread antibiotic use challenges in body metabolism and could prevent the body from generating proper antibodies against SARS-CoV-2 infections. This could be one of the main reasons for the high mortality in the ongoing COVID-19 pandemic [43]. The presence of MDR Gram-negative isolates in our investigation might justify the elevated HAI rate and consequent high incidence of superinfected patient mortality.

The current study had certain limitations. First, all analyses were conducted solely on patients with SARS-CoV-2, and the frequency of HAI in hospitalized patients without COVID-19 was not evaluated. Second, the diagnosis of HAI was based on the microbial culture results. We had some constraints in performing the molecular-based methods to detect additional atypical infectious agents. Last, we did not have access to the antibiotic administration data and preliminary microbiological culture results before hospitalization to evaluate the efficacy of antimicrobial regimens on the type and proportion of HAIs among SARS-CoV-2 patients.

The present study reveals a substantial prevalence of bacterial and fungal superinfections (83.2%) among SARS-CoV-2 ICU-admitted patients, particularly MDR CRKP and CRAB isolates. The superinfections were significantly associated with increased mechanical ventilation (92.2%) and high mortality (90%). To mitigate antimicrobial resistance, patients were treated according to their precise microbial resistance profile using antibiotic regimens based on the clinicians’ recommendations and hospital procedures. Additionally, implementing contact isolation and infection control programs is necessary if needed.