Antibiotic Resistance in Respiratory Bacterial Isolates From Critical Care Patients Infected With Sars-CoV2

doi:10.21203/rs.3.rs-1941894/v1

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Antibiotic Resistance in Respiratory Bacterial Isolates From Critical Care Patients Infected With Sars-CoV2

https://doi.org/10.21203/rs.3.rs-1941894/v1

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Purpose. Although secondary bacterial infections are uncommon in COVID-19, ventilator pneumonia is a hazard. We undertook a retrospective, observational study at an ICU in Vicenza, Italy, comparing pulmonary bacterial isolates between COVID-19 and non-COVID-19 patients.

Methods. Respiratory bacteria were recovered from: (i) ICU patients admitted in Feb-May 2019, pre-pandemic; (ii) ICU patients admitted with COVID-19 during the first (Feb-May 2020) wave and (iii) non-COVID-19 ICU patients from Feb-May 2020.

Results. We reviewed 120 patients, 61 in the control (2019) group and 59 (28 COVID-19 and 31 non-COVID-19) from 2020. Two hundred isolates were grown: 101 from the 2019 control patients, 42 from the 2020 COVID-19 patients and 57 from the 2020 non-COVID patients. Enterobacterales dominated throughout but Pseudomonas aeruginosa was significantly (p <0.01) more prevalent in COVID-19 than non-COVID patients and MDR P. aeruginosa (3/12; 25%) were exclusively found in COVID-19 patients. Other critical resistance types (MRSA, ESBL- and carbapenemase-producing Enterobacterales) were rare, without significant differences in prevalence between groups. ICU and hospital mortality were greater among COVID-19 than non-COVID patients. Deaths occurred in 6/9 COVID patients (66.7%) who did not receive targeted antibiotic therapy despite microbiological diagnosis.

Conclusion. These data underscore the importance of secondary bacterial pathogens in ICU COVID patients and the threat of antibiotic inadequacy favouring poor outcomes in VAP. The organisms found in COVID patients were typical of VAP, though P. aeruginosa was more prominent.

ICU

COVID-19

antibiotic resistance

ventilator-associated pneumonia (VAP)

Secondary bacterial infections are common in patients with viral pneumonia and can worsen the clinical prognosis [1, 2], including for those with viral pneumonia due to SARS-CoV2. Whilst most mild to moderate COVID-19 is not associated with secondary bacterial infection, patients admitted to ICU are vulnerable to ventilator-associated pneumonias, with the hazard increasing if ventilation is prolonged [3, 4]. What remains less clear is whether the pathogens of secondary ventilator-associated pneumonias (VAP) in COVID-19 patients differ from those of ‘typical’ pre-COVID ICU patients in terms of species distribution or antimicrobial resistance, and the extent to which this varies from country to country [5].

Accordingly, we performed a retrospective, observational study, reviewing patients admitted into a regional ICU centre in the Veneto region of North-east Italy. Specifically, we compared the agents of bacterial pneumonia in three groups of ICU patients: (i) those admitted prior to the pandemic, (ii) those with COVID-19 admitted during the first wave of the pandemic, and (iii) non-COVID-19 patients treated during the first pandemic period.

Study location and patients

The ICU is a 14-bed medical-surgical unit at the 1050-bed General Hospital of Vicenza, situated between Venice and Verona in the Veneto region of Italy. During the first epidemic wave of SARS-CoV2 the intensive care capacity was increased to a maximum of 28 beds, split across the ICU itself and Critical Coronary Care, with the latter dedicated to COVID-free patients.

COVID-19 and non-COVID patients admitted from 22 February 2020 to 31 May 2020 who developed bacterial low respiratory tract infections (LRTIs) were assessed, thus encompassing the peak of the first wave of the SARS-CoV2 epidemic in Vicenza. The control group comprised ICU patients who developed LRTI during the corresponding (pre-COVID) period in the preceding year (22 February-31 May 2019).

Microbiological and clinical diagnostics

During the COVID epidemic, all patients referring to the hospital Emergency Unit due to respiratory failure underwent a standard screening protocol including: rapid molecular testing for SARS-CoV2, (Cobas® SARS-CoV-2 Test, Roche Molecular Systems, Pleasanton, CA, USA); chest X-ray imaging, and arterial blood gas assay (ABG) by radial artery puncture in order to determine pH, bicarbonate, partial pressure of oxygen, partial pressure of carbon dioxide, and oxygen saturation. Patients negative for SARS-CoV2 by nasopharyngeal screening but exhibiting a clinical and radiological picture typical of COVID-19-related pneumonia had an additional PCR for SARS-CoV2, performed on a tracheal aspirate.

Bronchoscopy, X-ray imaging or pulmonary CT scanning and ABG also were performed for any non-COVID or pre-COVID ICU patients suspected of developing secondary pneumonia, based upon at least one of the following symptoms: worsening of respiratory function, relapse and/or increase of fever, onset of sepsis (leucocytosis, increase of CRP and/or procalcitonin) [6].

Pharmaceutical management of COVID-19 patients

The majority of COVID-19 patients were given empirical antibiotics (generally a b-lactam, frequently together with azithromycin) as soon as SARS-CoV2 infection was diagnosed. Subsequently-abandoned “non-conventional” therapies for COVID-19 during the first wave included hydroxychloroquine (200 mg b.i.d.) and lopinavir/ritonavir (400/100 mg b.i.d.); these were frequently administered in addition to standard care, which included high-dose methylprednisolone (20 or 40 mg b.i.d. intravenously, depending on patient weight) and thromboembolic prophylaxis with enoxaparin.

COVID-19–associated acute respiratory distress syndrome (ARDS) was defined according to the Berlin definition [7], and managed as recommended [8].

Data collection

Data input was performed manually in Microsoft Office Excel, with the following information recorded: hospital record number; gender; date of birth; date of hospital admission; date of ICU admission (if different); age at ICU admission, and main diagnosis at admission. Any other diagnoses indicated in the clinical records and constituting: (1) a co-morbidity, (2) a chronic disease directly related to ICU admission, or (3) a secondary pathological event that occurred during the ICU stay was also recorded. The date of the primary outcome (death, or transfer to another unit) and - for patients transferred from the ICU to other units in the same hospital - the date of transfer, were also recorded until the final outcome (death or discharge to home). Cases where only questionable pathogens (principally coagulase-negative staphylococci) were isolated were reviewed individually and discounted unless therapy was escalated based upon the microbiological result, implying that the organism was thought to be clinically significant.

Statistical analyses

Normally-distributed variables were reported as means with standard deviations and were compared by Student's t-test or by chi-squared test with Yates’ correction. Non-normally-distributed continuous data were reported as medians with interquartile ranges (IQRs) and were compared using the Mann-Whitney U-test or the Kruskal-Wallis test. All statistical analyses were performed using R v. 4.0.3 (www.r-project.com), and a two-sided p < 0.05 was routinely considered to be significant.

The study reviewed a total of 120 patients (Table 1), 61 in the control (2019) group and 59 in the COVID (2020) period: the latter group comprised 28 (47.5%) with SARS-CoV2 infection and 31 (52.5%) without COVID-19. Men dominated in the 2019 series and in both the COVID and non-COVID 2020 series (67.2–77.4%); mean ages were in the 60–65 years range in all groups. The great majority of patients in all groups were ventilated. The distributions between medical, surgical and trauma patients in the 2019 series and the 2020 non-COVID series were similar. The general pattern in 2019 was for most ICU patients to be transferred in from other hospital wards or units; this was true also for COVID ICU patients in 2020, whereas a large majority of the 2020 non-COVID patients were direct admissions from the community. The median duration of ICU stay was longest for the 2020 ICU COVID patients (22.3 days, IQR 11.0-32.25) and shorter for both the 2019 control patients (14.9 days, IQR 3–21.0) and for the 2020 non-COVID group (12.5 days, IQR 3.5–19.5). Of note, 19 of 28 COVID patients analysed were admitted into the ICU after a 1.9-day median stay in the Infectious Diseases Unit, where they were started with standard care for COVID-19 plus the “non-conventional” therapies then used (see methods).

Table 1

Characteristics of the study patients
Pt. specifics	2019	2020-all	2020-COVID	2020 non-COVID	p-value § 2020 non-COVID vs. 2019	p-value ^§ 2020 COVID vs. 2020 non-COVID
N° of pts.	61	59	28	31
N° (%) of male patients	41 (67.2)	46 (78.0)	22 (72.7)	24 (77.4)	0.4389	1
N° (%) of female patients	20 (32.8)	13 (22.0)	6 (27.3)	7 (22.6)	0.4389	1
Mean age (years) ± SD	63.5 ± 16.3	63.4 ± 14.2	64.3 ± 10.7	61.9 ± 16.9	0.954	0.6214
Age range (years)	19–93	21–84	42–84	21–81	-	-
Median length of ICU stay (days) (IQR)	14.9 (3–21.0)	17.1 (5.5–24.5)	22.3 (11.0-32.25)	12.5 (3.5–19.5)	0.4026	0.008689***
Median length of hospital stay (days) (IQR)	27.7 (10.0–30.0)	26.2 (11–38)	32.2 (13.75–51.25)	20.7 (6.5–29.0)	0.7243	0.0002222***
N° (%) of ICU deaths	16 (26.2)	17 (28.8)	12 (42.8)	5 (16.1)	0.4075	0.04818**
N° (%) of hospital deaths	17 (27.8)	25 (42.4)	16 (57.1)	9 (29.0)	1	0.05509*
N° (%) of ventilated patients	48 (78.7)	56 (94.9)	28 (100.0)	28 (90.3)	0.271	0.273
Diagnosis on admission:
Medical (%)	30 (49.2)	47 (79.7)	26 (92.9)	18 (58.2)	0.5582	0.005685***
Surgical (%)	24 (39.3)	7 (11.9)	2 (7.1)	7 (22.5)	0.1693	0.199
Trauma (%)	7 (11.5)	5 (8.4)	0	6 (19.3)	0.4784	0.04288**
Patients admitted from:
The community (%)	19 (31.1)	28 (44.1)	9 (32.2)	26 (83.9)	5.088e-06***	0.0001609***
Another hospital (%)	7 (11.5)	9 (15.2)	0	1 (3.2)	0.3493	1
Other wards (%)	35 (57.4)	24 (40.7)	19 (67.8)	4 (12.9)	0.0001148***	5.023e-05***
Patients discharged home (%)	0	1 (1.7)	0	1	0.72	1
Patients transferred to other wards (%)	30 (49.3)	24 (40.7)	12 (42.8)	11 (35.5)	0.3042	0.7546
Patients transferred to other hospital (%)	15 (24.5)	17 (28.8)	3 (10.7)	14 (45.2)	0.07673*	0.008551***
Diabetes (%)	7 (11.5)	8 (13.5)	4 (14.3)	4 (12.9)	1	1
Chronic renal failure (%)	2 (3.8)	2 (3.4)	2 (7.1)	0	0.79	0.4274
Cirrhosis (%)	2 (3.8)	1 (1.7)	0	2 (6.4)	0.86	0.5176
Sepsis/septic shock (%)	6 (9.8)	2 (3.4)	1 (3.6)	1 (3.2)	0.475	1
§ * p < 0.01; ** p < 0.05; * p < 0.1**

In total, 200 lower respiratory tract isolates were grown: 101 from the 2019 control patients, 42 from the 2020 COVID-19 patients and 57 from the 2020 non-COVID patients (Table 2). Enterobacterales comprised the largest groups in the 2019 series (50/101 isolates) and in the 2020 non-COVID patients (24/57) but were less dominant in the 2020 COVID patients, where their proportion (13/42) was nearly matched by that of Pseudomonas aeruginosa (12/42).

Table 2

Respiratory isolates from the study patients
Isolate	2019 (%)2	2020-all (%)	2020-COVID (%)	2020 non-COVID (%)	p-value § 2020 non-COVID vs. 2019	p-value § 2020 COVID vs. 2020 non-COVID
P. aeruginosa	15 (14.8)	16 (16.1)	12 (28.6)	4 (7.0)	0.23	0.009***
MDR P. aeruginosa	2 [13.3]	3 [18.7]	3 [25.0]	0	0.74	0.14
E. coli	13 (12.8)	6 (6.1)	0 (0.0)	6 (10.5)	0.85	0.08*
Klebsiella spp.	13 (12.8)	25 (25.3)	12 (28.6)	13 (22.8)	0.16	0.67
S. marcescens	10 (9.9)	1 (1.0)	1 (2.4)	0 (0.0)	0.03**	0.87
Enterobacter spp.	9 (8.9)	3 (3.0)	0 (0.0)	3 (5.3)	0.60	0.36
Citrobacter spp.	5 (4.9)	1 (1.0)	0 (0.0)	1 (1.7)	0.56	1
ESBL Enterobacterales	2 [3.7]^a	6 [15.4] ^a	4 [30.8] ^a	2 [8.0] ^a	0.95	0.41
CRE Enterobacterales	4 [7.5] ^a	0	0	0	0.32	-
S. aureus	13 (12.9)	17 (17.2)	4 (9.5)	13 (22.8)	0.16	0.14
MSSA	10 [76.9] ^b	11 [64.7] ^b	2 [50.0] ^b	9 [69.2] ^b	0.40	0.16
MRSA	3 [23.1] ^b	6 [35.3] ^b	2 [50.0] ^b	4 [30.8] ^b	0.43	0.97
Haemophilus spp.	6 (6.0)	3 (3.0)	0 (0.0)	3 (5.3)	1.00	0.36
E. faecium	4 (4.0)	1 (1.0)	0 (0.0)	1 (1.7)	0.77	1
E. faecalis	3 (3.0)	10 (10.1)	6 (14.2)	4 (7.0)	0.43	0.40
S. maltophilia	3 (3.0)	0 (0.0)	0 (0.0)	0 (0.0)	0.47	-
S. pneumoniae	2 (2.0)	6 (6.1)	3 (7.1)	3 (5.3)	0.51	1
Other	5 (4.9) ^{^}	10 (10.1) ^ç	4 (9.5) ^&	6 (10.6) ^#	0.31	1
GRAND TOTAL	101 (100.0)	99 (100.0)	42 (100.0)	57 (100.0)
^ other Enterobacterales (3), S. agalactiae (1), S. oralis (1) ç other Enterobacterales (3), Corynebacterium spp, (3), Streptococcus spp (3), S. epidermidis (1) & Corynebacterium spp, (2), S. mitis (1) S. epidermidis (1) # other Enterobacterales (2), Streptococcus spp (2), A. baumannii (1), Corynebacterium spp. (1)
Italic rows (rows 2,8,9,11, and 12), giving information about key resistances, are subsets of isolates in the preceding row(s). In these cases, the percentages, shown in square brackets, indicate the proportion of isolates with the indicated resistance, not the proportion of total isolates. To avoid double counting, these numbers are not included in the Grand Total row. ^a As proportion of Enterobacterales; ^b as proportion of Enterobacterales
§ * p < 0.01; ** p < 0.05; * p < 0.1**

Comparing 2019 with the whole 2020 cohort, there was a notably decline of Serratia spp., probably reflecting a clonal outbreak in the earlier year; in 2020 there was a significantly (p < 0.01) larger proportion of P. aeruginosa in the COVID compared with the non-COVID patients, with MDR P. aeruginosa (3/12; 25%) exclusively found in two COVID patients. One of these two died in the ICU and the other was transferred to another hospital for respiratory weaning after a long ICU stay; both were free of significant comorbidities. Numbers of MRSA, carbapenemase-producing Enterobacterales and ESBL-producing Enterobacterales were small in all groups, with differences between groups not achieving statistical significance. Four COVID patients had ESBL producers and, among these, two died. Carbapenem-resistant Enterobacterales (n = 4) were detected only in the 2019 series, as part of a nosocomial cluster, including one patient who died of septic shock due to K. pneumoniae with a KPC enzyme.

Among the 2019 control group, 16 patients (26.2%) died during their ICU stay and 17 (27.8%) during their entire hospitalization. In 2020, seventeen (28.8%) died in the ICU and 25 (42.4%) during hospitalization. The mortality rate was higher among COVID than in non-COVID patients, both in ICU (42.8% vs. 16,1%, p = 0.048) and in the hospital as a whole (57.1 vs. 29.0; p = 0.055). Among the 2019 patients, ‘respiratory failure due to pneumonia’ was recorded for 11 of the 16 ICU deaths whilst, among the 16 hospital deaths with COVID-19, 13 were classified as resulting from sepsis after a worsening of the chest X-ray consistent with bacterial superinfection.

Fifty-six (91.8%) of the 61 patients analysed in 2019 received an antibiotic during their ICU stay. In the vast majority of cases (54/56, 96.5%) treatment was empirical, being started as soon as the onset of HAP/VAP was suspected. Among the 28 COVID patients, 16 (57.2%) received empirical antibiotics from the diagnosis of SARS-CoV2 infection, 3 (10.7%) only once bacteria had been isolated from lower respiratory samples, whilst 9 (32.1%) did not receive targeted antibiotic treatment. Six of these latter 9 untreated patients (66.7%) died.

All 28 COVID patients had been treated, prior to bacteriological diagnosis, with then-standard care for COVID-19; all but 2 had received “non-conventional” therapies (see methods). Non-COVID patients admitted in 2020 were given antibiotic therapy once the onset of HAP/VAP was suspected; all of 5 ICU deaths occurred in stroke patients who had not been treated, despite isolation of clinically relevant organisms, including Staphylococcus aureus, Enterococcus faecium, or Klebsiella pneumoniae.

The prevalence of bacterial co-infection and secondary infection in critically-ill patients affected by COVID-19 is still debated, as is the role of resistant bacteria.

A recent metanalysis of 12 studies [9] concluded that the overall incidence of bacterial co-infections is low, with only 3.5% of hospitalized COVID patients affected. However, this proportion rises markedly in severely-ill patients, with the majority of their infections being hospital-acquired and arising 10–15 days after ICU admission. Invasive mechanical ventilation, steroid therapy, prolonged ICU stay and extensive use of broad-spectrum antimicrobial drugs may facilitate infection, with bacterial pathogens recovered from between 32% and 50% of critical-care COVID patients. A growing body of studies report a high incidence of secondary infection involving resistant strains [10–12], particularly in the ICU [13, 14] and perhaps reflecting antibiotic overuse and poor stewardship earlier in the patients’ hospital journey [15, 16].

In our experience, COVID patients were older (mean 64.3 + 10.7 years vs. 61.9 + 16.9 years) compared with non-COVID patients admitted in the same period (2020); however, their age range was also narrower, and all of the COVID patients who needed intensive care were aged over 40, according with the well-established correlation between age and severity of disease [17]. Twelve COVID patients died in the ICU (42.8%) - an almost 3-fold higher ICU mortality rate compared with critical non-COVID patients (16.1%) admitted in the same period (2020), despite the prevalence of severe comorbidities and median ages being similar between the two groups. This finding accords with other reports [4, 18]. In nine of 28 COVID patients (32.1%), targeted antibiotic treatment for VAP was not given, despite current recommendations [19], and despite isolation of clinically relevant pathogens such as S. aureus, Streptococcus pneumoniae or K. pneumoniae). Six of these nine patients (none, upon ICU admission, with a Charlson Comorbidity Index [20] > 5) died in the ICU. A clinical underestimation of the impact of bacterial superinfection, as well as difficulty in radiological differentiation of bacterial pneumonia from a typical COVID picture, may have contributed to the inadequacy of microbiological handling, which evidently affected the final outcome.

The median interval between ICU admission and the first respiratory isolate among COVID patients was 14.2 ± 16.8 SD days. Gram-positive pathogens were isolated earlier than Gram-negative organisms (median: 13.3 vs. 17.2 days). The median interval for P. aeruginosa was 19 days and its isolation was significantly (p = 0.009) more frequent amongst COVID than in non-COVID patients. The prominent role of P. aeruginosa in late-onset VAP among COVID patients has been noted by others too [21]. In our experience, P. aeruginosa VAPs were associated with poor outcomes among COVID patients, with the organism recovered from 6 of the 12 cases that died (50.0%), despite the microbiological adequacy of antibiotic therapy. It is unclear whether the organism causes poor outcomes, or if it tends to colonise and infect patients with an inherently poor prognosis. Women infected with P. aeruginosa displayed a particularly high fatality (83.3% vs. 32.8% for men) with septic shock as well as pneumonia in one case).

With the caveat that the figures are small, the distribution of MDR bacterial isolates was not significantly different between the 2019 control group and the 2020 COVID-19 and non-COVID-19 patients [Table 2]. A higher prevalence of ESBL Enterobacterales was observed in 2020, particularly amongst COVID patients, although differences between groups did not achieve statistical significance. Carbapenem-resistant Enterobacterales, all with KPC enzymes, were detected only in 2019 and were part of a cluster affecting three hospital Units; no carbapenemase producers were found among the 2020 isolates, perhaps reflecting a wider decline of this mode of resistance in Italian ICUs patients over the past two years [22].

All but two patients diagnosed with COVID pneumonia were treated with “non-conventional” therapies, comprising hydroxychloroquine alone in 20 cases (71.5%), lopinavir/ritonavir alone in two (7.1%), and with both drugs together in 16 cases (57.1%); in two cases, a triple association of hydroxychloroquine, lopinavir ritonavir and a leukotriene receptor antagonist (Montelukast) was administered. Such a massive use of drugs, now recognised as ineffective against SARS-CoV2 but carrying a well-known cardiovascular risk [23], may have worsened outcomes. Notably, death was universal among those COVID patients with a cardiac comorbidity at ICU admission who were given non-conventional treatment and high-dose corticosteroids.

In conclusion, these data underscore the importance of secondary bacterial pathogens in ICU COVID patients and the threat of antibiotic treatment inadequacy related to clinical underestimation of VAP. The organisms found were those typical of VAP and VAP, though P. aeruginosa was unusually prominent compared both non-COVID patients in both 2019 and 2020.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Conflict of interest/Competing interests

DML: Advisory Boards or ad hoc consultancy Accelerate, Antabio, Centauri, Entasis, GSK, Integra-Holdings, Meiji, Menarini, Mutabilis, Nordic, Paion, ParaPharm, Pfizer, QPEX, Shionogi, Summit/Discuva, Sumitovant, T.A.Z., VenatoRx, Wockhardt, Zambon, Paid lectures – bioMérieux, Beckman Coulter, Cardiome, GSK, Hikma, Merck/MSD, Menarini, Nordic, Pfizer and Shionogi. Relevant shareholdings – Dechra, GSK, Merck, Pfizer and Perkin Elmer amounting to less than 10% of portfolio value; Share options: T.A.Z. He also has nominated holdings in Avacta, Diaceutics, Evgen, Faron, Genedrive, Poolbeg, Renalytics, Saietta, Synairgen and Verici through Enterprise Investment Schemes but has no authority to trade these shares directly. All other authors have no relevant financial or non-financial interests to disclose

Availability of data and material

All data generated or analysed during this study are included in this published article (and its supplementary information files).

Code availability

Not applicable.

Ethics approval

Since this study was performed retrospectively on specimens that were collected as part of the routine sampling required for the microbiological assessment of patients admitted into ICUs, there was no possible risk to any of the patients reviewed, nor any study-contingent modification of their treatment. Consequently, individual consent was not needed. The Institutional Sanitary Board approved the protocol and confirmed that submission to their Ethics Committee was not required, provided that the principal investigator (Paolo Benedetti) was personally responsible for the security of patient-identifiable data.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Paolo Benedetti and David Martin Livermore. The first draft of the manuscript was written by Paolo Benedetti and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

ACKNOWLEDGEMENTS

We are indebted to the Institutional Sanitary Board of the Vicenza Hospital for the assistance in performing the study. We are also grateful to Dr V. Danzi for giving the permission to examine patients’ clinical records in the ICU.

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Antibiotic Resistance in Respiratory Bacterial Isolates From Critical Care Patients Infected With Sars-CoV2

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Abstract

Introduction

Patients And Methods

Study location and patients

Microbiological and clinical diagnostics

Pharmaceutical management of COVID-19 patients

Data collection

Statistical analyses

Results

Discussion

Declarations

References

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