Multidrug-Resistant Infections and Outcome of Critically Ill Patients with Coronavirus Disease 2019: A Single Center Experience

Abstract

Background:

The aim of this study was to assess the drivers of multidrug-resistant (MDR) bacterial infection development in coronavirus disease 2019 (COVID-19) and its impact on patient outcome.

Methods:

Retrospective analysis on data from 32 consecutive patients with COVID-19, admitted to our intensive care unit (ICU) from March to May 2020. Outcomes considered were MDR infection and ICU mortality.

Results:

Fifty percent of patients developed an MDR infection during ICU stay after a median time of 8 [4–11] days. Most common MDR pathogens were carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii, causing bloodstream infections and pneumonia. MDR infections were linked to a higher length of ICU stay (p = 0.002), steroid therapy (p = 0.011), and associated with a lower ICU mortality (odds ratio: 0.439, 95% confidence interval: 0.251–0.763; p < 0.001). Low-dose aspirin intake was associated with both MDR infection (p = 0.043) and survival (p = 0.015). Among MDR patients, mortality was related with piperacillin-tazobactam use (p = 0.035) and an earlier onset of MDR infection (p = 0.042).

Conclusions:

MDR infections were a common complication in critically ill COVID-19 patients at our center. MDR risk was higher among those dwelling longer in the ICU and receiving steroids. However, MDR infections were not associated with a worse outcome.

Introduction

Since December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to >200 countries, accounting for nearly 65 million cases of coronavirus disease 2019 (COVID-19) worldwide.¹ COVID-19 clinical spectrum is extremely wide, ranging from self-limited influenza-like illness to potentially lethal disease.^2–4 Up to one fourth of COVID-19 patients require intensive care unit (ICU) admission,⁵ mostly due to acute respiratory distress syndrome, with a resultant mortality rate as high as 48%.^2,6,7 Risk factors for a worse outcome in ICU COVID-19 patients include older age, male gender, history of chronic obstructive pulmonary disease, hypercholesterolemia, and type 2 diabetes,⁷ baseline alteration in creatinine, d-dimer, lactates, potassium, PaO₂/FiO₂-ratio, alveolar-arterial gradient, ischemic heart disease,⁸ lymphocytopenia, and higher cardiac troponin.^9,10

The average ICU length of stay may be as long as 12 days.^7,10,11 Thus, a significant proportion of critically ill COVID-19 patients may be exposed to ICU acquisition of multidrug-resistant (MDR) bacterial infections. In general, MDR infection rates in ICU patients range from 14% to nearly 50%.^12–14 Determinants of increased MDR infection risk in ICU include large-spectrum antibiotic administration, invasive procedure performance (mechanical ventilation, central venous access, etc.)¹⁵ and prolonged bed stay.¹⁶ In addition, ICU patients often present sepsis-related immune system downregulation.¹⁷

Hence, it is reasonable to hypothesize that ICU-related state coupled with SARS-CoV-2-induced immune dysregulation¹⁸ may significantly boost the risk of developing MDR bacterial infections in critically ill COVID-19 patients. At present, sparse data are available on MDR infection in COVID-19 ICU cases. The Italian National Health System reported a 12.2% incidence of bacterial infections (MDR and non-MDR) among overall COVID-19 cases registered.¹⁹ Focusing on ICU, the rate of hospital acquired bacterial and fungal infections was as high as 21.7%, with pulmonary infections among the most common syndromes (19.9%).²⁰ Whether MDR infections influence COVID-19 prognosis and/or are a consequence of COVID-19 immunologic treatments is at present unknown.

Therefore, we conducted this study with the aim to evaluate the drivers of MDR bacterial infection development in COVID-19 and the impact of this complication on patient outcome.

Methods

Study design

This was a retrospective analysis, in the context of a multicenter observational cohort study (International Severe Acute Respiratory and emerging Infection Consortium—ISARIC study, Oxford University) with retrospective data collection. Included were 32 consecutive patients with COVID-19, admitted to the ICU of the Monaldi Hospital, AORN Ospedali dei Colli, Naples, Italy, from March 9 to May 1, 2020. Patients were followed until death or ICU discharge and were divided into two groups: with or without any documented and clinically diagnosed infection due to an MDR organism. All patients were managed according to the standard clinical practice and the best available therapy was given to treat the new SARS-CoV-2 infection. Microbiological sampling of blood, urines, and airways was performed in all patients at least once weekly and additionally as dictated by patient conditions. Patient data collection was approved by our Institution Ethics Committee. Patient informed consent was waived by the Ethics Committee.

Definitions

Multidrug resistance was defined according to the Magiorakos et al. criteria.²¹ Patients who only showed MDR bacteria colonization (rectal/nasal carriers) were not included among “MDR infection patients.” Infections were diagnosed based on the current U.S. Centers for Disease Control and Prevention National Health care Safety Network criteria.²² COVID-19 was diagnosed based on positive results for SARS-CoV-2 RNA testing by real-time reverse transcription PCR assay on nasopharingeal swab coupled with typical clinical features of fever, pneumonia, and respiratory failure.

Variables analyzed

For each patient, we collected general clinical data, hematochemical parameters, treatments received, infectious complications observed during hospitalization, including MDR infections and disease outcome. Data were derived from patient files and our hospital electronic medical record system and entered into the dedicated ISARIC electronic case report form. In addition, detailed microbiological data were retrieved from our Microbiology and Virology central laboratory, including genus, species, and antimicrobial susceptibility testing results, which were obtained by broth microdilution (Sensititre, Thermo Fisher).

Among clinical data, there were age, gender, comorbidities, hospitalization length, length of ICU stay, and duration of invasive ventilation. Hematochemical parameters were recorded on ICU admission and on the day of microbiological sampling showing positivity for MDR pathogen or, for those without MDR infections, after 3–8 days dwelling in ICU, and included white blood cells and differential, platelet count, C-reactive protein, creatinine, bilirubin, international normalized ratio, and activated partial thromboplastin time.

Regarding treatments administered, we analyzed the antibiotics given before MDR infection diagnosis as well as regimens for MDR infection. We also analyzed treatment given for COVID-19, including antivirals, anti-inflammatory/immune modulating drugs, and antimicrobials.

Clinical outcomes considered were MDR infection and timing of its diagnosis, and ICU mortality.

Statistical analysis

Statistical analysis was performed on data obtained at the times of ICU admission and MDR isolation, assessing the clinical outcomes considered. Numerical variables were expressed as median and interquartile range (IQR), whereas categorical variables as number and percentage.

Categorical variables were compared using Fisher's exact test or Pearson's chi-square, whereas continuous variables were compared using the Mann–Whitney U test (two group differences). Variables associated to outcomes at univariate analysis (p < 0.05) were included in multivariate logistic regression models to identify covariates independently associated with the outcome of interest. Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software v. 25 (IBM Corp., Armonk, NY), with the assumption of a p-value ≤0.05 as indicative of statistical significance of the observed differences and using two-sided tests.

Results

Thirty-two patients were included, whose baseline clinical features are presented in Table 1. The majority of patients were male with a median age of 68 years (IQR 55.2–75). Chronic pulmonary disease (34.4%) and obesity (31%) were the main comorbidities. Hematochemical abnormalities mainly involved white blood cells (neutrophilia and lymphocytopenia). C-reactive protein levels were significantly increased. Most patients (78%) received an antibiotic during the first 8 days of ICU stay, with piperacillin-tazobactam being the most used drug (37.5%). More than 60% of patients received darunavir/cobicistat, others received lopinavir/ritonavir, whereas 53.1% were given corticosteroids (Table 1). As many as 40% were treated with an anti-IL-6 monoclonal antibody (28.1% with tocilizumab and 12.5% with sarilumab). Median length of ICU stay was 10.5 days (IQR 5.7–17), whereas prior hospitalization length was 2 days (IQR 1–3). Twenty-three patients (71.8%) died in the ICU.

Table 1.

Baseline Features of the 32 Coronavirus Disease 2019 Patients Included in This Study

Parameter	n (%) or median [IQR]
Age, years	68 [55.25–75]
Gender, M/F	23 (71.9)/9 (28.1)
Comorbidities
Chronic cardiac disease	8 (25)
Obesity	10 (31)
Chronic kidney disease	5 (15.6)
Diabetes mellitus	3 (9.4)
Chronic pulmonary disease	11 (34.4)
Chronic liver disease	4 (12.5)
Arterial hypertension	3 (9.4)
Malignant neoplasia	4 (12.5)
Chronic neurological disease	2 (6.3)
Hematochemical data on ICU admission
White blood cells, cells/μL	11.700 [8.700–13.600]
Neutrophils, cells/μL	9,295 [7,645–12,597]
Lymphocytes, cells/μL	675 [462–1,195]
Platelets, cells/μL	217,000 [158,500–379,250]
C-reactive protein, mg/L	142 [71–237]
Creatinin, mg/dL	0.9 [0.7–1.4]
Bilirubin, mg/dL	0.6 [0.5–1.2]
International normalized ratio	1.18 [1.11–1.25]
Activated partial thromboplastin time, sec	33 [30.1–37]
Antibiotic therapy during the 8 days before MDR infection onset	25 (78.1)
Ceftriaxone	8 (25)
Ceftaroline	4 (12.5)
Piperacillin/tazobactam	12 (37.5)
Daptomycin	3 (9.4)
Meropenem	3 (9.4)
Antibiotic therapy after MDR infection onset^a
Ceftriaxone	9 (28.1)
Ceftazidime/avibactam	6 (18.7)
Ceftaroline	5 (15.6)
Colistin	2 (6.2)
Daptomycin	6 (18.8)
Meropenem	7 (21.9)
Piperacillin/tazobactam	13 (40.6)
Teicoplanin	5 (15.6)
Trimethoprim/sulfamethoxazole	6 (18.8)
Treatments given for COVID-19
Enoxaparin	32 (100)
Aspirin	5 (15.6)
Tocilizumab	9 (28.1)
Sarilumab	4 (12.5)
Steroids	17 (53.1)
Lopinavir/ritonavir	15 (46.9)
Remdesivir	4 (12.5)
Darunavir/cobicistat	20 (62.5)
Hydroxychloroquine	28 (87.8)
Length of ICU stay (days)	10.5 [5.7–17]
Duration of invasive ventilation (days)	10 [4–13.5]
Hospitalization length before ICU admission (days)	2 [1–3]
Outcome
Survived	9 (28)
Deceased	23 (72)

Data are expressed as median and IQR or number and percentage.

For those without MDR infection, therapy received after 3–8 days dwelling in ICU.

COVID-19, coronavirus disease 2019; ICU, intensive care unit; IQR, interquartile range; MDR, multidrug-resistant; M/F, male/female.

Half of the patients studied (n = 16) developed an MDR infection during ICU admission for COVID-19. A single MDR pathogen was grown in 10 patients, 2 pathogens in 5 patients and 3 MDR pathogens in 1 patient. No mortality difference was observed between these groups (Supplementary Table S1). Most patients had more than one infectious syndrome: eight had two (both bloodstream infection [BSI] and hospital-acquired pneumonia/ventilator-associated pneumonia [HAP/VAP]), and four had BSI, HAP/VAP, and complicated urinary tract infection. No association was seen between mortality and number of infectious syndromes.

Median time to positivity of a microbiological sample for an MDR organism was 8 days. Clinical characteristics associated with MDR infection are shown in Table 2. Overall, 23 MDR isolates were grown from the 16 COVID-19 patients. The most common pathogens were carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii (Fig. 1A). Overall, >80% of MDR isolated were gram-negative bacilli. Among gram-positives, there were methicillin-resistant Staphylococcus aureus, and ampicillin-resistant or high-level aminoglycoside-resistant enterococci (Fig. 1A). The most prevalent infectious syndromes caused by MDR pathogens were BSIs and VAP (Fig. 1B). MDR infections occurred more frequently in males (94% vs. 50% in females; p = 0.015), without correlation with comorbidities, hematochemical parameters or specific antimicrobial regimen received (Table 2). MDR infections were linked to a higher length of ICU stay (16 [11–20] vs. 7 [5–10] days in no MDR; p = 0.002) and active treatment with low-dose aspirin (p = 0.043) or steroids (p = 0.011). In MDR infection patients, after the onset of an MDR infection, the specific antibiotics more commonly administered were ceftazidime/avibactam, daptomycin, and meropenem (37.5% for all of them). A correlation was observed between MDR infection and an improved outcome of ICU stay (Table 2). No variable was independently related with MDR infection on multivariate analysis.

FIG. 1.

(A) Distribution of invasive MDR pathogens isolated in the 16 of 32 critically ill coronavirus disease of 2019 patients studied. The pie chart graphically depicts the prevalence of all resistant micro-organisms isolated. The eight Klebsiella pneumoniae isolates were carbapenem-resistant, all due to KPC-type carbapenemase production. The four Acinetobacter baumannii isolates were carbapenem resistant with an extensively drug-resistant phenotype. The three Pseudomonas aeruginosa were carbapenem-resistant. The two Enterobacter clacae isolates were producers of AmpC-type beta-lactamases. The two Stenotrophomonas malthophilia isolates were co-trimoxazole-only sensitive. All Enterococcus spp. were resistant to high levels of aminoglycosides and one strain of E. faecium was also resistant to ampicillin. The Staphylococcus aureus isolate was methicillin resistant. (B) Infectious syndromes due to MDR pathogens observed in the 16 of the 32 critically ill coronavirus disease of 2019 patients studied. The bar chart graphically depicts the different types/sites of infection. cUTI, complicated urinary tract infection; HAP/VAP, hospital-acquired pneumonia/ventilator-associated pneumonia; BSI, bloodstream infection; KPC, Klebsiella pneumoniae carbapenemase; MDR, multidrug-resistant.

Table 2.

Clinical Characteristics Associated with Multidrug-Resistant Infection in Coronavirus Disease 2019 Patients

Parameter	MDR yes/no		Univariate analysis		Multivariate analysis
Parameter	MDR infection (n = 16)	No MDR infection (n = 16)	OR (95% CI)	p	OR (95% CI)	p
Age, years	65 [53–72]	68 [55–75]		0.584
Gender, M/F	15 (93.8)/1 (6.2)	8 (50)/8 (50)	15 (1.583–142.71)	0.015	1.6 (0)	0.998
Male gender	15/16 = 93.8	8/16 = 50	4.5 (0.7–26.8)	0.015
Comorbidities
Chronic cardiac disease	4 (25)	4 (25)	1.09 (0.21–5.45)	1.000
Obesity	4 (25)	6 (37.5)	1.6 (0.3–7.6)	0.704
Chronic kidney disease	1 (6.3)	4 (25)	4.6 (0.4–47.6)	0.333
Diabetes	2 (12.5)	1 (6.3)	0.4 (0.03–5.3)	0.600
Chronic pulmonary disease	7 (43.8)	4 (25)	0.3 (0.08–1.7)	0.273
Chronic liver disease	3 (18.8)	1 (6.3)	0.2 (0.02–2.9)	0.333
Arterial hypertension	1 (6.3)	2 (12.5)	2.1 (0.1–5.73)	1.000
Malignant neoplasia	1 (6.3)	3 (18.8)	3.5 (0.3–38.2)	0.598
Chronic neurological disease	1 (6.3)	1 (6.3)	1.07 (0.06–18.8)	1.000
Hematochemical data on ICU admission
White blood cells, cells/μL	12,030 [11,435–14,397]	11,770 [6,055–13,455]		0.429
Neutrophils, cells/μL	9,295 [8,650–14,225]	9,665 [5,600–12,092]		0.451
Lymphocytes, cells/μL	785 [532–1,135]	580 [365–1,450]		0.327
Platelets, cells/μL	249,000 [190,000–396,000]	183,000 [113,000–309,000]		0.105
C-reactive protein, mg/L	126 [63–234]	210 [74–251]		0.384
Creatinine, mg/dL	0.8 [0.6–1.1]	1.0 [0.8–1.5]		0.156
Bilirubin, mg/dL	0.7 [0.5–1.2]	0.6 [0.5–1.4]		0.796
International normalized ratio	1.2 [1.1–1.26]	1.17 [1.14–1.24]		0.984
Activated partial thromboplastin time, sec	31 [28–37]	33 [30–36]		0.386
Hematochemical data on MDR sampling day^a
White blood cells, cells/μL	12,465 [7,852–18,592]	12,875 [5,622–22,085]		0.955
Neutrophils, cells/μL	9,730 [5,560–16,675]	11,160 [6,082–20,427]		0.895
Lymphocytes, cells/μL	905 [445–1,145]	690 [305–1,077]		0.336
Platelets, cells/μL	346,000 [185,000–454,000]	231,000 [98,000–385,000]		0.109
C-reactive protein, mg/L	94 [50–181]	61 [13–204]		0.570
Creatinine, mg/dL	1.15 [0.8–1.7]	2.4 [0.9–5.7]		0.067
Bilirubin, mg/dL	0.9 [0.7–1.62]	1.2 [0.6–3.5]		0.905
International normalized ratio	1.65 [1.08–1.30]	1.17 [1.1–1.3]		0.479
Activated partial thromboplastin time, sec	36 [31–41]	34 [32–75]		0.493
Antibiotic therapy during the 8 days before MDR infection onset	14 (87.5)
Ceftriaxone	5 (31.2)
Ceftaroline	4 (25)
Piperacillin-tazobactam	6 (37.5)
Daptomycin	3 (18.7)
Meropenem	3 (18.7)
Antibiotic therapy after MDR infection onset
Ceftriaxone	5 (31.2)
Ceftazidime-avibactam	6 (37.5)
Ceftaroline	5 (31.2)
Colistin	2 (12.5)
Daptomycin	6 (37.5)
Meropenem	6 (37.5)
Piperacillin/tazobactam	5 (31.2)
Teicoplanin	5 (31.2)
Trimethoprim/sulfamethoxazole	4 (25)
Treatments given for COVID-19
Aspirin	5 (31.2)	0	0.4 (0.1–0.6)	0.043	24.76 (0)	1.000
Tocilizumab	5 (31.2)	4 (25)	0.7 (0.1–3.4)	1.000
Sarilumab	3 (18.8)	1 (6.2)	0.2 (0.02–3.1)	0.600	0 (0)	0.998
Tocilizumab/sarilumab	8 (50)	5 (31.2)	0.4 (0.2–0.6)	0.473
Steroids	12 (75)	5 (31.2)	0.1 (0.02–0.59)	0.011
Lopinavir/ritonavir	8 (50)	7 (43.7)	0.8 (0.2–3.5)	1.000
Remdesivir	3 (18.7)	1 (6.2)	0.2 (0.02–3.1)	0.600
Darunavir/cobicistat	12 (75)	8 (50)	0.3 (0.07–1.48)	0.273
Hydroxychloroquine	14 (87.5)	14 (87.5)	1 (0.1–8.1)	1.000
Length of ICU stay (days)	16 [11–20]	7 [5–10]		0.002	0.2 (0.02–1.6)	0.132
Duration of invasive ventilation (days)	13 [7–16]	7 [4–10]		0.020	3.3 (0.5–19.4)	0.170
Hospitalization length before ICU admission (days)	3 [1–3]	1 [1–2]		0.320
Outcome
Survived/deceased	9 (56.3)/7 (43.7)	0/16 (100)	3.2 (1.7–6.09)	0.001	0.2 (0.27–1.6)	0.132

p values indicating statistical significance are shown in bold.

Data are expressed as median and IQR or number and percentage.

For those without MDR infection, data refer to a time 3–8 days after ICU admission.

CI, confidence interval; OR, odds ratio.

As shown in Table 3, MDR infection was protective in terms of ICU mortality (odds ratio: 0.439 95% confidence interval: 0.251–0.763; p < 0.001). Factors correlated with survival were the receipt of low-dose aspirin (p = 0.015), and treatment with daptomycin either before (p = 0.021) or after (p < 0.001) MDR sampling (data not shown). Showed a relationship with survival the administration of antibiotics active on MDR gram-negatives after MDR sampling, including ceftazidime/avibactam (p = 0.005), meropenem (p = 0.014), and trimethoprim/sulfamethoxazole (p = 0.049). Use of piperacillin/tazobactam at any time correlated with mortality (not shown). In contrast, factors positively associated with a higher risk of mortality were female gender (p = 0.035) and a shorter length of hospitalization (p = < 0.001) or invasive ventilation duration (p = 0.01). No variable proved to be independently related with mortality at regression analysis.

Table 3.

Risk Factors for Mortality in Coronavirus Disease 2019 Patients Admitted to Intensive Care Unit

Parameter	Outcome		Univariate analysis		Multivariate analysis
Parameter	Survived (n = 9)	Deceased (n = 23)	OR (95% CI)	p	OR (95% CI)	p
Age, years	71 [53–74]	67 [55–75]		0.933
Gender, M/F	9 (100)/0	14 (60)/9 (40)	0.649 (0.439–0.845)	0.035	0 (0)	0.999
Comorbidities
Chronic cardiac disease	3 (33.3)	5 (21.7)	0.5 (0.1–3.4)	0.658
Obesity	1 (11.1)	9 (39.1)	4.8 (0.5–46.4)	0.210
Chronic kidney disease	0	5 (21.7)	1.5 (1.1–2)	0.281
Diabetes	1 (11.1)	2 (8.6)	0.5 (0.04–7.4)	1.000
Chronic pulmonary disease	4 (44.4)	7 (30.4)	0.63 (0.11–3.41)	0.683
Chronic liver disease	1 (11.1)	3 (13)	1.615 (0.14–18.5)	1.000
Arterial hypertension	1 (11.1)	2 (8.6)	0.76 (0.06–9.61)	1.000
Malignant neoplasia	0	4 (17.3)	1.53 (1.13–2.06)	0.285
Chronic neurological disease	1 (11.1)	1 (4.3)	0.389 (0.02–7.11)	0.513
Hematochemical data on ICU admission
White blood cells, cells/μL	10,710 [9,160–14,985]	12,100 [8,490–13,710]		0.983
Neutrophils, cells/μL	9,400 [8,020–12,645]	9,150 [7,470–12,680]		0.785
Lymphocytes, cells/μL	750 [540–1,045]	620 [380–1,500]		0.630
Platelets, cells/μL	243,000 [193,000–394,500]	208,000 [147,000–353,000]		0.346
C-reactive protein, mg/L	175 [69–251]	134 [66–238]		0.931
Creatinine, mg/dL	0.8 [0.5–1.0]	1.0 [0.7–1.6]		0.178
Bilirubin, mg/dL	0.6 [0.45–1.3]	0.65 [0.5–1.25]		0.861
International normalized ratio	1.09 [1.09–1.30]	1.19 [1.13–1.24]		0.931
Activated partial thromboplastin time, sec	30 [27–36]	33 [31–37]		0.148
Hematochemical data on MDR sampling day^a
White blood cells, cells/μL	12,030 [8,215–19,805]	12,900 [6,790–21,350]		0.737
Neutrophils, cells/μL	10,440 [5,840–18,170]	10,440 [5,770–19,940]		0.769
Lymphocytes, cells/μL	850 [405–1,100]	870 [410–1,080]		0.867
Platelets, cells/μL	369,000 [287,000–464,000]	237,000 [121,000–410,000]		0.054
C-reactive protein, mg/l	142 [34–231]	71 [24–158]		0.380
Creatinine, mg/dL	1.3 [0.5–1.75]	1.3 [0.9–4.6]		0.284
Bilirubin, mg/dL	1.1 [0.8–1.7]	0.9 [0.5–2.7]		0.571
International normalized ratio	1.16 [1.07–1.34]	1.17 [1.11–1.3]		0.602
Activated partial thromboplastin time, sec	34 [31–41.5]	35 [33–46]		0.277
MDR infection	9 (100)	7 (30.4)	0.439 (0.251–0.763)	0.001	0 (0)	0.998
Treatments given for COVID-19
Aspirin	4 (44)	1 (4.3)	0.05 (0.005–0.6)	0.015	0.177 (0)	0.632
Tocilizumab	3 (33)	6 (26)	1.4 (0.2–7.5)	0.685
Sarilumab	2 (22)	2 (8.6)	3 (0.3–25.4)	0.557
Tocilizumab/sarilumab	5 (55)	8 (34.7)	2.3 (0.4–11.2)	0.427
Steroids	7 (77)	10 (43.4)	4.5 (0.7–26.8)	0.122
Lopinavir/ritonavir	6 (66)	9 (39.1)	3.1 (0.6–15.7)	0.243
Remdesivir	3 (33)	1 (4.3)	0.09 (0.008–1.03)	0.057
Darunavir/cobicistat	7 (77)	13 (56.5)	2.6 (0.4–15.8)	0.422
Hydroxychloroquine	8 (88.8)	20 (86.9)	1.2 (0.1–13.3)	1.000
Length of ICU stay (days)	20 [17–25]	10 [5–12]		0.000	2.3 (0.7–6.8)	0.132
Duration of invasive ventilation (days)	15 [10–17]	7 [4–12]		0.010	0.6 (0.2–1.4)	0.281
Hospitalization length before ICU admission (days)	1 [0–3]	2 [1–3]		0.451

p values indicating statistical significance are shown in bold.

Data are expressed as median and IQR or number and percentage.

For those without MDR infection, data refer to a time 3–8 days after ICU admission.

Among the MDR infection subgroup, mortality was positively related with use of piperacillin-tazobactam (p = 0.035) and negatively related with ceftriaxone (p = 0.034) and daptomycin (p = 0.007) administration (Supplementary Table S1). A shorter time to onset of MDR infection was related to a higher mortality (p = 0.042).

Discussion

Our study shows that MDR infections are a common complication in COVID-19 ICU patients, and are not associated with a higher risk of death. In our experience, MDR infection occurred in half of COVID-19 patients, a rate higher than that observed in recent case series from different settings,^23,24 and was mostly a late complication in those surviving longer.

Indeed, a shorter length of hospital stay was associated with a higher mortality (in all COVID-19 and in MDR-COVID-19 patients), suggesting that most deaths occurred early after ICU admission (Table 3). This might differentiate severe COVID-19 from other critical illness states, where a prolonged ICU stay typically translates into a worse outcome.^24,25 Median time of hospitalization in ICU was 10 days in our 32 patients, but was 16 days for those who developed an MDR infection. Thus, we confirm previous data¹⁶ that prolonged ICU hospitalization translates into a higher risk of developing MDR infection in COVID-19.

Since COVID-19 is an acute disease, often leading to death, once patients survive the initial critical phase, remaining in ICU, they attain a higher chance of survival and, in contrast, of developing an MDR infection. Thus, we hypothesize that the protective effect of MDR infection is in reality an indirect effect originating from the association of this late complication to survival. Also, our data corroborate those from Zhou et al. showing the duration of hospital and ICU stay does not correlate to a higher risk of a negative outcome in COVID-19 patients.¹⁰

Similar to other settings,²⁶ the use of steroids correlated to a higher risk of developing MDR infection (Table 2). In contrast, we did not observe a link between anti-interleukin-6 (IL-6) antibody administration and MDR infections. The association between steroid treatment and MDR infections deserves further comment. We hypothesize that patients who received steroids survived longer (Table 3, difference not significant) and were, therefore, more likely to develop an MDR infection during ICU stay.

The use of antibiotics per se did not correlate with a higher probability of MDR infection (Table 2), at variance with what was suggested by prior studies in different groups of patients.²⁷ However, this result could be due to the small sample size of our study. The use of piperacillin-tazobactam before MDR infection onset emerged as a risk factor for mortality (Supplementary Table S1), and may deserve further investigation in a larger study.

Although our study population was mostly made of males (72%), MDR infections were observed almost only in male patients. This is in line with previous studies showing male predisposition to develop MDR bacterial infections.^16,28,29

Even if largely novel, our findings are limited by the low number of patients studied, likely accounting for the absence of independent risk factors for mortality on multivariate analyses. In addition, we could not compare the incidence of MDR infections in ICU COVID-19 patients with that of a control group, as our hospital ICU was converted to COVID-19-only during the study accrual time. Finally, the high ICU mortality observed in this subset of patients could have partly biased results, making them not entirely applicable to the current scenario.

We believe our results may support clinicians in early suspecting MDR infections in critically ill COVID-19 patients who dwell longer in the ICU and in prompting a judicious use of MDR-selecting antibiotics.

Conclusions

MDR infections were a common complication in critically ill COVID-19 patients in our patient cohort. MDR risk was higher among those dwelling longer in the ICU and receiving steroids. However, MDR infections were not associated with a worse outcome. In a subset of patients, death occurs early. When this does not happen, additional ICU-related complications may ensue, including MDR infections. Further studies on a larger number of patients are needed to confirm our results or bring new insights regarding factors associated with increased risk for developing an MDR infection in COVID-19 patients and the impact of these infections on patient outcomes.

Ethics Approval

The study and its observational procedures were approved by our institutional ethics committee.

Footnotes

Authors' Contributions

All authors have contributed to and agreed on the content of the article, and the respective roles of each author are as follows: A.K., F.B., R.Z., and E.D.-M. worked on concept of the study; M.G., F.P., M.P.U., and P.S. worked on data collection and data interpretation; A.K., R.Z., and E.D.-M. drafted the article. All authors read, critically revised, and approved the final version of the article.

Disclosure Statement

Authors have no conflict of interest to disclose relevant to the content of this study. E.D.-M. received grant support and personal fees, outside of this study, from Roche, Pfizer, MSD, Angelini, Bio-Merieux, Abbvie, Nordic Pharma, Sanofi-Aventis, Medtronic, and DiaSorin. R.Z. and R.A. received personal fees, outside of this study, from Nordic Pharma.

Funding Information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Supplementary Material

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Supplementary Material

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