Discussion

We describe bacterial infections and antibiotic utilization in hospitalized cancer patients diagnosed with COVID-19 between March 1, 2020, and May 31, 2020, in New York City, an early epicenter of the COVID-19 pandemic in the United States. More than half of the study patients were diagnosed with a bacterial infection during the hospitalization, and pneumonia accounted for the bulk of infections. Most patients received antibiotics, but the median durations were within recommended lengths for the types of infection observed. Rates of bacterial infection and antibiotic prescribing, as well as antibiotic durations increased with increasing COVID-19 severity.

Rates of microbiologically confirmed bacterial respiratory and bloodstream infections in hospitalized patients during the initial COVID-19 surge range from 2.3% to 8.2%, but data specific to cancer patients are limited. ^{Reference Nori, Cowman and Chen6,Reference Russell, Fairfield and Drake8,Reference Arentz, Yim and Klaff21–Reference Vaughn, Gandhi and Petty24} Our investigation of SARS-CoV-2–infected cancer patients revealed an overall higher rate of microbiologically confirmed bacterial infections (27%), although other infection types were included. Pneumonia was commonly diagnosed, but only 19 (12%) of 159 cases had positive respiratory cultures. In the only other study examining hospitalized patients with cancer and COVID-19, the rate of microbiologically documented bacterial infections was 17%. ^{Reference Gudiol, Dura-Miralles and Aguilar-Company25} Gudiol et al ^{Reference Gudiol, Dura-Miralles and Aguilar-Company25} also reported that lower respiratory tract infections (67 of 167, 40%) were common in their patient cohort, but there was a higher diagnostic yield, with only 17 (25%) of 67 cases having no organisms identified. ^{Reference Gudiol, Dura-Miralles and Aguilar-Company25} Notably, bacterial infection rates, particularly for pneumonias, may be underestimated if only microbiologically confirmed infections are counted.

Among the 140 lower respiratory tract infections without a bacterial microbiologic diagnosis in our study, 103 were CAP and 37 were HAP or VAP. Among the 37 HAP and VAP cases, 2 were diagnosed with a probable invasive fungal infection (1 pulmonary aspergillosis, 1 pulmonary coccidiomycosis). Of the 35 remaining HAP and VAP cases, these patients had clinical worsening in the setting of a new radiographic infiltrate, suggesting nosocomial superinfection. We acknowledge that the 103 cases designated as CAP could have solely been from SARS-CoV-2 infection. Clinical symptoms such as fever, cough, and shortness of breath combined with abnormal chest imaging (eg, lobar consolidation, ground glass opacities, reticular infiltrates) have been well described in patients with lower respiratory tract involvement with COVID-19. ^{Reference Metlay and Waterer26} This clinical picture, however, is nonspecific because bacterial pneumonia can also present similarly. ^{Reference Kalil, Metersky and Klompas15,Reference Mandell, Wunderink and Anzueto16}

Several studies have noted reduced respiratory sampling (7.7%–17.7%) during the pandemic because patients may not have been able to produce phlegm and/or fewer diagnostic procedures (eg, bronchoscopy) may have been performed due to concerns about healthcare worker safety. ^{Reference Russell, Fairfield and Drake8,Reference Vaughn, Gandhi and Petty24} The poor sensitivity of cultures and incomplete use of diagnostic tests are other well-recognized limitations. ^{Reference Kalil, Metersky and Klompas15,Reference Jain, Self and Wunderink27} Even under circumstances in which all available tests are submitted, diagnostic yield remains low. In a large population-based surveillance study for CAP, blood, urine, and respiratory specimens were systematically collected for culture, serologic testing, antigen detection, and molecular diagnostic testing, but a bacterial pathogen was detected in only 247 (11%) of 2,259 individuals. ^{Reference Jain, Self and Wunderink27} According to the 2019 American Thoracic Society and Infectious Diseases Society of America guidelines in the pre–COVID-19 era, routine testing is recommended only for patients with severe CAP or if there are concerns for multidrug-resistant pathogens. ^{Reference Metlay, Waterer and Long28} Thus, CAP diagnosis does not rely on microbiologic confirmation. One area that warrants further investigation is whether SARS-CoV-2 can predispose a patient to bacterial pneumonia, similar to what has been demonstrated with influenza virus. ^{Reference Rowe, Meliopoulos, Iverson, Bomme, Schultz-Cherry and Rosch29} Because bacterial coinfection in critically ill patients has ranged from 23% to 30% in past influenza epidemics, antibacterial treatment is recommended in adults with clinical and radiographic evidence of CAP who test positive for influenza. ^{Reference Metlay, Waterer and Long28,Reference Shah, Greenberg and McNulty30} A recent case series showed that coinfection with bacterial pathogens (including Mycoplasma and Chlamydophila) did occur in patients who died from COVID-19 pneumonia. ^{Reference Du, Tu and Zhu31} The true picture of bacterial coinfection is thus not clear because it has been challenging to definitively include or exclude other concomitant bacterial etiologies in SARS-CoV-2–infected patients with lower respiratory tract findings.

Compared with the general patient population, cancer patients have a higher infectious morbidity and mortality due to the underlying malignancy and/or its treatment. This disparity is borne out in our study by an additional 77 infections (31%) not involving the respiratory tract or bloodstream and included fever and neutropenia, gastrointestinal infections, skin and soft-tissue infections, and urinary tract infections. In contrast, only 1,002 (2%) of 48,092 hospitalized patients infected with SARS-CoV-2 from the United Kingdom were diagnosed with other bacterial infections in addition to pneumonia or bacteremia. ^{Reference Russell, Fairfield and Drake8}

It is not surprising that 274 (77%) of 358 patients in this study were exposed to antibiotics during their COVID-19 admission. Many other studies have noted high rates (ie, >70%) of antibiotic administration in hospitalized SARS-CoV-2-infected patients. ^{Reference Nori, Cowman and Chen6,Reference Rawson, Moore and Zhu7,Reference Cong, Poudel, Alhusein, Wang, Yao and Lambert32} However, the proportion of patients diagnosed with a bacterial infection and given antibiotics differed by severity of illness. Although this finding seems intuitive, no prior study has systematically assessed both parameters (bacterial infection and antibiotic utilization) along with COVID-19 severity. In patients with mild COVID-19, 47 (35%) of 133 were diagnosed with a bacterial infection and 78 (59%) received empiric antibiotics for a median of 1 day. Thus, the data suggest that hospitalized cancer patients with mild COVID-19 can avoid or have early discontinuation of empiric antibiotics with active antimicrobial stewardship oversight. Other hospital ASPs have shown that they could discontinue or narrow antibiotics for CAP in patients with COVID-19 within 72 hours of admission. ^{Reference Pettit, Nguyen and Lew33,Reference Evans, Davidson, Low, Basarab and Arnold34} This finding contrasts with a report by Cong et al, ^{Reference Cong, Poudel, Alhusein, Wang, Yao and Lambert32} who reviewed 118 publications and stratified patients with COVID-19 into mild-to-moderate or severe-to-critical illness categories. Antibiotic prescribing during the first 6 months of the COVID-19 pandemic was high (>75%) in both groups. This highlights the potential role that ASPs can play to better optimize anti-infectives during pandemics.

In more severely ill patients, the risk and rate of bacterial infection are higher. Because COVID-19 in patients with cancer is marked by substantial rates of hospitalization, severe outcomes, and additional difficulty in discriminating bacterial infection from severe COVID-19 inflammation, the administration of empiric antibiotic therapy under these circumstances is understandable. ^{Reference Robilotti, Babady and Mead4,Reference Lucien, Canarie and Kilgore35} In out study, nearly all patients who required high-flow oxygen or mechanical ventilation (severe COVID-19) were prescribed antibiotics, and 104 (81%) of 128 patients were diagnosed with a bacterial infection. Even so, the median antibiotic LOT for study patients with severe COVID-19 was 8 days. Martin et al ^{Reference Martin, Shulder, Dobrzynski, Quartuccio and Pillinger36} similarly noted that ICU stay and the necessity for mechanical ventilation were predictors for antibiotic prescribing in hospitalized patients with COVID-19.

In examining antibiotic duration by infection type, the median antibiotic LOT for bacterial infections was not overly long and was consistent with standard duration of therapy. Both ASP members and ID consultation teams strived to maintain standard duration of therapy for suspected or documented bacterial infections and actively discontinued empiric antibiotic therapy in cases where bacterial etiology was unlikely. For example, the median antibiotic LOT for respiratory infections was 7 days, which was in line with national guidelines for CAP, HAP, and VAP. ^{Reference Kalil, Metersky and Klompas15,Reference Metlay, Waterer and Long28} Of the 5 patients who had a bloodstream infection, the median antibiotic LOT was short because 3 patients died. Similar to other studies, broad-spectrum antibiotics (eg, piperacillin/tazobactam, cefepime, meropenem) as well as agents used for respiratory infections were the most commonly prescribed agents between March 2020 and May 2020. ^{Reference Andrews, Budd and Hendrick37–Reference Dieringer, Furukawa and Graber39}

This study had several limitations. In this is single-center retrospective study, we also included clinically diagnosed bacterial infections without microbiologic confirmation. This method may have led to an overestimation of infection rates, specifically lower-respiratory-tract infections of which CAP was predominant. Although fever, respiratory symptoms, and lung infiltrates could all be due to COVID-19, there is conversely insufficient high-quality evidence to safely withhold antibacterial therapy in hospitalized cancer patients, most of whom required supplemental oxygen in our study. Patients with multiple bacterial infections can have overlapping antibiotic therapy, so we looked at patients with a single infection so that we could clearly identify antibiotic duration by infection type. Although the exclusion of patients with multiple bacterial infections could lead to the underestimation of antibiotic LOT, the number of patients with multiple infections was small. Antibiotic LOT could also have been underestimated because we did not include outpatient prescriptions given upon hospital discharge. The results of this study may not be generalizable to noncancer settings or institutions that lack a robust ASP. Also, these findings may not be generalizable to later surges from SARS-CoV-2 viral variants of concern [eg, δ (delta) and (omicron) varaints]. The development of COVID-19 therapeutics (eg, antivirals, monoclonal antibodies) and a higher proportion of vaccinated individuals should reduce the proportion of cancer patients who require hospitalization and/or who develop severe COVID-19.

In conclusion, hospitalized cancer patients with COVID-19 had a high rate of bacterial infections. Although antibiotic prescribing was common, the proportion of patients diagnosed with a bacterial infection and given antibiotics increased as patients developed more severe COVID-19. Median durations of antibiotic therapy were within recommended lengths for the types of infections seen. In mild COVID-19 cases, antibiotic therapy was short, suggesting that empiric antibiotics can be safely avoided or stopped in this group.