Abstract

Although most cases of COVID-19 are mild cases, severe cases requiring hospitalization and mechanical ventilation were sufficient to overwhelm healthcare systems worldwide, leading to more than 6 million deaths and the increase in healthcare associated infections (HAIs). The incidence of HAIs in COVID-19 hospitalized patients has been addressed in systematic reviews, but in these there was no description of mortality related to these infections. Therefore, the aim of this review was to evaluate the impact of HAIs on mortality of hospitalized patients with COVID-19, specially by multidrug resistant bacteria as Acinetobacter baumannii. A systematic review was carried out in the PubMed database on July 2022 using the keywords “healthcare-associated infection” OR “nosocomial infection” AND “COVID-19” AND “Acinetobacter baumannii”. The incidence of HAIs in COVID-19 patients was 18.85%, with 42.17% of mortality rate and relative risk (RR) 2.08 (95%CI 1.61-2.68). Considering that the risk of death was twice greater in co-infection COVID-19/HAI, it is essential the broad vaccination against COVID-19 and the adoption of measures to reduce HAI incidence in hospitalized patients and mortality by superinfections.

Key words:
COVID-19; Healthcare associated infections; Mortality; Acinetobacter baumannii

Resumo

Apesar de a maioria dos casos de COVID-19 serem leves, os casos graves que necessitam de hospitalização e ventilação mecânica foram suficientes para sobrecarregar os sistemas de saúde no mundo, levando a mais de 6 milhões de mortes e ao aumento das infecções relacionadas à assistência à saúde (IRAS). A incidência de IRAS em pacientes hospitalizados com COVID-19 foi abordada em revisões sistemáticas, mas não houve descrição da mortalidade. Portanto, o objetivo desta revisão foi avaliar o impacto das IRAS na mortalidade de pacientes hospitalizados com COVID-19, especialmente por bactérias multirresistentes como a Acinetobacter baumannii. Uma revisão sistemática foi realizada no banco de dados PubMed em julho de 2022 usando as palavras-chave “infecção associada à saúde” OU “infecção nosocomial” E “COVID-19” E “Acinetobacter baumannii”. A incidência de IRAS em pacientes COVID-19 foi de 18,85%, a taxa de mortalidade foi de 42,17% e o risco relativo (RR) foi de 2,08 (IC 95%1,61-2,68). Considerando o risco de morte duas vezes maior na coinfecção COVID-19/IRAS, é fundamental a ampla vacinação contra COVID-19 e a adoção de medidas para reduzir a incidência de IRAS e a mortalidade por superinfecções.

Palavras-chave:
COVID-19; Infecções associadas à assistência à saúde; Mortalidade; Acinetobacter baumannii

Resumen

Aunque la mayoría de los casos de COVID-19 son leves, los casos graves que requieren hospitalización y ventilación mecánica han sido suficientes para saturar los sistemas de salud en todo el mundo, provocando más de 6 millones de muertes y un aumento de las infecciones relacionadas con la asistencia sanitaria (IRAS). La incidencia de IRAS en pacientes hospitalizados con COVID-19 fue abordada en revisiones sistemáticas, pero no hubo descripción de la mortalidad en estas. Por lo tanto, el objetivo de esta revisión fue evaluar el impacto de las IRAS en la mortalidad de pacientes hospitalizados con COVID-19, especialmente por bacterias multirresistentes como Acinetobacter baumannii. Se realizó una revisión sistemática en la base de datos PubMed en julio de 2022 utilizando las palabras clave “infección asociada a la atención médica” OR “infección nosocomial” AND “COVID-19” AND “Acinetobacter baumannii”. La incidencia de IRAS en pacientes con COVID-19 fue del 18,85%, la tasa de mortalidad fue del 42,17% y el riesgo relativo (RR) fue de 2,08 (IC95% 1,61-2,68). Teniendo en cuenta que el riesgo de muerte es dos veces mayor en la coinfección por COVID-19/IRAS, es esencial la vacunación generalizada contra la COVID-19 y la adopción de medidas para reducir la incidencia de las IRAS y la mortalidad por sobreinfecciones.

Palabras clave:
COVID-19; Infecciones relacionadas con la asistencia sanitaria; Mortalidad; Acinetobacter baumannii

Introduction

The outbreak of coronavirus disease (COVID-19) has created a global health crisis and has become the largest pandemic in human history¹1 Santoso P, Sung M, Hartantri Y, Andriyoko B, Sugianli AK, Alisjahbana B, Tjiam JSL, Debora J, Kusumawati D, Soeroto AY. MDR Pathogens Organisms as Risk Factor of Mortality in Secondary Pulmonary Bacterial Infections Among COVID-19 Patients: Observational Studies in Two Referral Hospitals in West Java, Indonesia. Int J Gen Med 2022; 15:4741-4751.. From December 31, 2019, until July 27, 2022, a total of 572,638,253 COVID-19 cases were reported, including 6,389,559 COVID-19-associated deaths²2 Johns Hopkins Coronavirus Resource Center. COVID-19 Map [Internet]. [cited 2022 set 14]. Available from: https://coronavirus.jhu.edu/map.html
https://coronavirus.jhu.edu/map.html... .

Usually, the clinical manifestations of COVID-19 are less severe, typically manifested as a mild upper respiratory tract disease or even asymptomatic “sub-clinical” infection³3 Bengoechea JA, Bamford CG. SARS-CoV-2, bacterial co-infections, and AMR: the deadly trio in COVID -19? EMBO Mol Med 2020; 12(7):e12560.. However, it can also lead to severe and critical respiratory failure requiring mechanical ventilation, resulting in septic shock or other organ dysfunction requiring intensive care treatment⁴4 Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker PGT, Fu H, Dighe A, Griffin JT, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunubá Z, FitzJohn R, Gaythorpe K, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati-Gilani G, Riley S, van Elsland S, Volz E, Wang H, Wang Y, Xi X, Donnelly CA, Ghani AC, Ferguson NM. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis 2020; 20(6):669-677.

5 Li J, Wang J, Yang Y, Cai P, Cao J, Cai X, Zhang Y. Etiology and antimicrobial resistance of secondary bacterial infections in patients hospitalized with COVID-19 in Wuhan, China: a retrospective analysis. Antimicrob Resist Infect Control 2020; 9(1):153. https://doi.org/10.1186/s13756-020-00819-1
https://doi.org/10.1186/s13756-020-00819... ^-66 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229):1054-1062.. Moreover, studies suggest that coinfections and secondary infections can play an important role in higher mortality risk among hospitalized COVID-19 patients⁵5 Li J, Wang J, Yang Y, Cai P, Cao J, Cai X, Zhang Y. Etiology and antimicrobial resistance of secondary bacterial infections in patients hospitalized with COVID-19 in Wuhan, China: a retrospective analysis. Antimicrob Resist Infect Control 2020; 9(1):153. https://doi.org/10.1186/s13756-020-00819-1
https://doi.org/10.1186/s13756-020-00819... ^,66 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229):1054-1062..

The World Health Organization (WHO) defines a healthcare-associated infection (HAI) as an infection occurring in a patient during the process of care in a hospital or other healthcare facility, which was not present or incubating at the time of admission⁷7 World Health Organization (WHO). Report on the Burden of Endemic Health Care-Associated Infection Worldwide [Internet]. 2011. [cited 2024 jun 11]. Available from: https://www.who.int/publications/i/item/report-on-the-burden-of-endemic-health-care-associated-infection-worldwide
https://www.who.int/publications/i/item/... .

COVID-19 infection increased the number of hospitalizations and the need for Intensive Care Units (ICUs) and mechanical ventilation, which are recognized risk factors associated with the development of HAIs. In addition, longer hospital stays, selective pressure exerted by the previous use of antimicrobials and, as highlighted by Shinohara et al.⁸8 Shinohara DR, Santos Saalfeld SM, Martinez HV, Altafini DD, Costa BB, Fedrigo NH, Tognim MCB. Outbreak of endemic carbapenem-resistant Acinetobacter baumannii in a coronavirus disease 2019 (COVID-19)-specific intensive care unit. Infect Control Hosp Epidemiol 2022; 43(6):815-817., inadequate training in infection prevention and control by health professionals hired on an emergency basis to respond to the COVID-19 pandemic situation, contributed to high rates of HAIs.

Zhou et al.⁶6 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229):1054-1062., analyzed 191 hospitalized adult COVID-19 patients in Wuhan and observed sepsis as a common complication in both non-survivors and survivors of the disease. They suggested that sepsis could have resulted from viral infection in these patients and hence, specific data confirming bacterial involvement in COVID-19 were still needed.

Zhang et al.⁹9 Zhang G, Hu C, Luo L, Fang F, Chen Y, Li J, Peng Z, Pan H. Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China. J Clin Virol 2020; 127:104364. analyzed 221 patients admitted in a hospital in Wuhan, China, and they observed that severely affected patients who required ICU admission and mechanical ventilation therapy showed a significant higher rate of bacterial co-infection (p < 0.001) compared with patients with non-severe COVID-19 disease (25.5% versus 1.8%).

Li et al.⁵5 Li J, Wang J, Yang Y, Cai P, Cao J, Cai X, Zhang Y. Etiology and antimicrobial resistance of secondary bacterial infections in patients hospitalized with COVID-19 in Wuhan, China: a retrospective analysis. Antimicrob Resist Infect Control 2020; 9(1):153. https://doi.org/10.1186/s13756-020-00819-1
https://doi.org/10.1186/s13756-020-00819... , in a retrospective study, observed a considerable proportion of hospitalized COVID-19 patients acquiring secondary bacterial infections, correlated with illness severity on admission and featuring gram-negative bacteria with high resistance rates like Acinetobacter baumannii and Klebsiella pneumoniae in Wuhan, China.

Acinetobacter baumannii (A. baumannii) is a ubiquitous, Gram-negative, non-flagellated coccobacillus bacterium commonly isolated from the environment. In human medicine, this opportunistic pathogen is responsible for hospital and community-acquired infections. Resistance to last-resort antibiotics, such as colistin, tigecycline, and carbapenems, underscores its significance as a nosocomial ESKAPE pathogen (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa and Enterobacter species). According to the World Health Organization (WHO) this species is classified as a bacterium for which research and development of new antibiotics is critically needed and it is also considered an urgent threat to public health by the Centers for Disease Control and Prevention (CDC)¹⁰10 Whiteway C, Breine A, Philippe C, van der Henst C. Acinetobacter baumannii. Trends Microbiol 2022; 30(2):199-200..

Shinohara et al.⁸8 Shinohara DR, Santos Saalfeld SM, Martinez HV, Altafini DD, Costa BB, Fedrigo NH, Tognim MCB. Outbreak of endemic carbapenem-resistant Acinetobacter baumannii in a coronavirus disease 2019 (COVID-19)-specific intensive care unit. Infect Control Hosp Epidemiol 2022; 43(6):815-817. reported an outbreak of Carbapenem-resistant Acinetobacter baumannii (CRAb) in a tertiary teaching hospital in southern Brazil. A total of 19 CRAb isolates were recovered from blood, endotracheal aspirates, and/or rectal swabs of 14 patients. A total of 9 deaths was observed, two (2/4) of CRAb colonized patients and seven (7/10) of infected patients. According to the authors, colonization or infection with CRAb can lead to worse outcomes by extended hospital stays, escalated medical expenses, and amplified ICU mortality rates.

Several studies have reported the incidence of HAIs in hospitalized COVID-19 patients, including the profile and risk factors of these patients as well as the profile of bacterial isolates¹¹11 Fu Y, Yang Q, Xu M, Kong H, Chen H, Fu Y, Yao Y, Zhou H, Zhou J. Secondary bacterial infections in critical ill patients with coronavirus disease 2019. Open Forum Infect Dis 2020; 7(6):ofaa220., the impact of HAIs on mortality of COVID-19 patients¹²12 Nori P, Cowman K, Chen V, Bartash R, Szymczak W, Madaline T, Punjabi Katiyar C, Jain R, Aldrich M, Weston G, Gialanella P, Corpuz M, Gendlina I, Guo Y. Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge. Infect Control Hosp Epidemiol 2021; 42(1):84-88.^,1313 Giacobbe DR, Battaglini D, Enrile EM, Dentone C, Vena A, Robba C, Ball L, Bartoletti M, Coloretti I, Di Bella S, Di Biagio A, Brunetti I, Mikulska M, Carannante N, De Maria A, Magnasco L, Maraolo AE, Mirabella M, Montrucchio G, Patroniti N, Taramasso L, Tiseo G, Fornaro G, Fraganza F, Monastra L, Roman-Pognuz E, Paluzzano G, Fiorentino G, Corcione A, Bussini L, Pascale R, Corcione S, Tonetti T, Rinaldi M, Falcone M, Biagioni E, Ranieri VM, Giannella M, De Rosa FG, Girardis M, Menichetti F, Viale P, Pelosi P, Bassetti M. Incidence and Prognosis of Ventilator-Associated Pneumonia in Critically Ill Patients with COVID-19: A Multicenter Study. J Clin Med 2021; 10(4):555. and some studies have also compared the occurrence of HAIs before and during the pandemic period¹⁴14 Pascale R, Bussini L, Gaibani P, Bovo F, Fornaro G, Lombardo D, Ambretti S, Pensalfine G, Appolloni L, Bartoletti M, Tedeschi S, Tumietto F, Lewis R, Viale P, Giannella M. Carbapenem-resistant bacteria in an intensive care unit during the coronavirus disease 2019 (COVID-19) pandemic: a multicenter before-and-after cross-sectional study. Infect Control Hosp Epidemiol 2022; 43(4):461-466.^,1515 Bahçe YG, Acer Ö, Özüdogru O. Evaluation of bacterial agents isolated from endotracheal aspirate cultures of COVID-19 general intensive care patients and their antibiotic resistance profiles compared to pre-pandemic conditions. Microb Pathog 2022; 164:105409.. In addition, various researchers have assessed the mortality rate of COVID-19 patients with and without HAIs¹⁶16 Bardi T, Pintado V, Gomez-Rojo M, Escudero-Sanchez R, Azzam Lopez A, Diez-Remesal Y, Martinez Castro N, Ruiz-Garbajosa P, Pestaña D. Nosocomial infections associated to COVID-19 in the intensive care unit: clinical characteristics and outcome. Eur J Clin Microbiol Infect Dis 2021; 40(3):495-502.

17 Cohen R, Babushkin F, Finn T, Geller K, Alexander H, Datnow C, Uda M, Shapiro M, Paikin S, Lellouche J. High Rates of Bacterial Pulmonary Co-Infections and Superinfections Identified by Multiplex PCR among Critically Ill COVID-19 Patients. Microorganisms 2021; 9(12):2483.

18 Grasselli G, Cattaneo E, Florio G. Secondary infections in critically ill patients with COVID-19. Crit Care 2021; 25(1):317.

19 Falcone M, Tiseo G, Giordano C, Leonildi A, Menichini M, Vecchione A, Pistello M, Guarracino F, Ghiadoni L, Forfori F, Barnini S, Menichetti F; Pisa COVID-19 Study Group. Predictors of hospital-acquired bacterial and fungal superinfections in COVID-19: a prospective observational study. J Antimicrob Chemother 2021; 76(4):1078-1084.

20 Kumar G, Adams A, Hererra M, Rojas ER, Singh V, Sakhuja A, Meersman M, Dalton D, Kethireddy S, Nanchal R, Guddati AK. Predictors and outcomes of healthcare-associated infections in COVID-19 patients. Int J Infect Dis 2021; 104:287-292.^-2121 Said KB, Alsolami A, Moussa S, Alfouzan F, Bashir AI, Rashidi M, Aborans R, Taha TE, Almansour H, Alazmi M, Al-Otaibi A, Aljaloud L, Al-Anazi B, Mohialdin A, Aljadani A. COVID-19 Clinical Profiles and Fatality Rates in Hospitalized Patients Reveal Case Aggravation and Selective Co-Infection by Limited Gram-Negative Bacteria. Int J Environ Res Public Health 2022; 19(9):5270..

Lansbury et al.²²22 Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect 2020; 81(2):266-275. conducted a systematic review and meta-analysis to evaluate co-infections in patients with COVID-19. The authors systematically searched Embase, Medline, Cochrane Library, LILACS and CINAHL for eligible studies published from January 1, 2020 to April 17, 2020. Thirty studies totaling 3,834 patients were included. Overall, 7% of hospitalized COVID-19 patients had a bacterial co-infection (95%CI 3-12%, n = 2183, I²2 Johns Hopkins Coronavirus Resource Center. COVID-19 Map [Internet]. [cited 2022 set 14]. Available from: https://coronavirus.jhu.edu/map.html
https://coronavirus.jhu.edu/map.html... = 92·2%), with this proportion rising to 14% in studies focusing exclusively on ICU patients. It is worth noting that these studies did not provide data on the outcomes of these co-infected patients.

Another systematic review and meta-analysis performed by Langford et al.²³23 Langford BJ, So M, Raybardhan S, Leung V, Westwood D, MacFadden DR, Soucy JR, Daneman N. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect 2020; 26(12):1622-1629., observed that of 24 studies eligible and included in the review, a population of 3,338 patients with COVID-19 was evaluated for acute bacterial infection. In the meta-analysis, secondary bacterial infection was identified in 14.3% of patients (95%CI 9.6-18.9%), although this analysis did not include an evaluation of mortality rates.

Recognizing the importance of understanding the influence of healthcare-associated infections on patient outcome and acknowledging the absence of systematic reviews specifically addressing mortality, the objective of this study was to carry out a systematic review and meta-analysis to evaluate the impact of HAIs on the mortality of hospitalized COVID-19 patients with later emphasis on infections caused specifically by A. baumannii.

Methods

Search strategy and article selection criteria

For this systematic review, a search was conducted in the PubMed database on July 4, 2022, using the following keywords in Advanced Search: “(healthcare-associated infection) OR (nosocomial infection) AND (COVID-19) AND (Acinetobacter baumannii)”. The primary aim was to identify articles presenting numerical data on co-infections among patients simultaneously affected by COVID-19 and healthcare-associated infections (HAI + COVID-19). Specifically, articles that provided information on both the mortality rate within the HAI+ COVID-19 and the COVID-19 groups were selected for inclusion in the subsequent meta-analysis. Studies published before 2020 and those with limited access to their full text were excluded from consideration.

Inclusion of additional studies occurred subsequent to the assessment of bibliographic references derived from the studies initially screened within databases. The flow of the systematic review design is presented in Figure 1.

Data extraction

The gathered data from the articles encompassed the following elements: authorship, publication year, country, study period, number of patients and number of deaths of patients with COVID-19 without co-infection (Control), number of patients and number of deaths of patients with COVID-19 and HAI (Experimental) and the prevailing bacteria associated with HAIs.

Statistical analysis

A meta-analysis of the collected data was performed using a random effect model, presented as Relative Risk (RR), with a 95% confidence interval (CI). The statistical analysis was performed using R software version 4.2.1 for Microsoft Windows, employing meta package version 5.5-0. Heterogeneity was assessed through the I²2 Johns Hopkins Coronavirus Resource Center. COVID-19 Map [Internet]. [cited 2022 set 14]. Available from: https://coronavirus.jhu.edu/map.html
https://coronavirus.jhu.edu/map.html... statistic, where an I²2 Johns Hopkins Coronavirus Resource Center. COVID-19 Map [Internet]. [cited 2022 set 14]. Available from: https://coronavirus.jhu.edu/map.html
https://coronavirus.jhu.edu/map.html... value approximating 0% indicates non-heterogeneity between studies, around 25% indicates low heterogeneity, around 50% moderate heterogeneity and close to 75% indicates high heterogeneity among studies. Concerning the analyzes presented as Relative Risk, the following methods were used: the Mantel-Haenzel method, Restricted-maximum-likelihood estimator for tau²2 Johns Hopkins Coronavirus Resource Center. COVID-19 Map [Internet]. [cited 2022 set 14]. Available from: https://coronavirus.jhu.edu/map.html
https://coronavirus.jhu.edu/map.html... and Q-profile method for interval confidence of tau²2 Johns Hopkins Coronavirus Resource Center. COVID-19 Map [Internet]. [cited 2022 set 14]. Available from: https://coronavirus.jhu.edu/map.html
https://coronavirus.jhu.edu/map.html... and tau.

A “leave-one-out” analysis was conducted to evaluate the impact of each study on the RR value. Given the presence of substantial heterogeneity among the studies, the Random effect model was employed. This analysis involved calculating RR and 95%CI (confidence interval) after excluding one study at a time.

Results

A total of 45 records were obtained through a search in the PubMed database using the keywords described in the methodology. Twenty-six studies were chosen for the systematic review and 15 of these met the criteria for meta-analysis, which presented the number of deaths in both the experimental (HAI+ COVID-19) and control group (COVID-19). Meta-analysis was used to calculate the impact of HAIs on the mortality of hospitalized patients with COVID-19. A summary of the characteristics from the 15 studies included in this meta-analysis is presented in Table 1.

A total of 8,438 hospitalized COVID-19 patients were analyzed in the 15 studies, of which 1,591 had HAI (18.85%). The present study also evaluated the number of deaths within the group called Experimental (COVID-19 + HAI) and the Control group (COVID-19), a mortality rate of 42.17% (671/1,591) and 16.6% (1,136/ 6,847) was observed, respectively (Table 1).

Considering the high heterogeneity of the studies (I²2 Johns Hopkins Coronavirus Resource Center. COVID-19 Map [Internet]. [cited 2022 set 14]. Available from: https://coronavirus.jhu.edu/map.html
https://coronavirus.jhu.edu/map.html... = 91%), a meta-analysis was performed using a random effect model (Figure 2). This analysis showed a relative risk (RR) of 2.08 (95%CI 1.61-2.68), that indicates that the risk of death in the COVID-19 + HAI group is approximately twice that observed in the COVID-19 group (Figure 2). Values below 1.0 would indicate a “protective effect” of HAIs on the risk of death, while values above 1.0 means an increase of mortality risk in the experimental group when compared to control.

The “leave-one-out” analysis yielded a range of RR values (95%CI) from 1.93 (1.52-2.46), with the exclusion of the study by Protonotariou et al.²⁴24 Protonotariou E, Mantzana P, Meletis G, Tychala A, Kassomenaki A, Vasilaki O, Kagkalou G, Gkeka I, Archonti M, Kati S, Metallidis S, Skoura L. Microbiological characteristics of bacteremias among COVID-19 hospitalized patients in a tertiary referral hospital in Northern Greece during the second epidemic wave. FEMS Microbes 2021; 2:xtab021. to 2.20 (1.72- 2.81) excluding study by Falcone et al.¹⁹19 Falcone M, Tiseo G, Giordano C, Leonildi A, Menichini M, Vecchione A, Pistello M, Guarracino F, Ghiadoni L, Forfori F, Barnini S, Menichetti F; Pisa COVID-19 Study Group. Predictors of hospital-acquired bacterial and fungal superinfections in COVID-19: a prospective observational study. J Antimicrob Chemother 2021; 76(4):1078-1084.. After this analysis on the sensitivity of the statistical test, the authors decided to maintain the 15 studies in the meta-analysis. It is also possible to observe in this complementary analysis that the removal of the studies by Kumar et al.²⁰20 Kumar G, Adams A, Hererra M, Rojas ER, Singh V, Sakhuja A, Meersman M, Dalton D, Kethireddy S, Nanchal R, Guddati AK. Predictors and outcomes of healthcare-associated infections in COVID-19 patients. Int J Infect Dis 2021; 104:287-292. and Protonotariou et al.²⁴24 Protonotariou E, Mantzana P, Meletis G, Tychala A, Kassomenaki A, Vasilaki O, Kagkalou G, Gkeka I, Archonti M, Kati S, Metallidis S, Skoura L. Microbiological characteristics of bacteremias among COVID-19 hospitalized patients in a tertiary referral hospital in Northern Greece during the second epidemic wave. FEMS Microbes 2021; 2:xtab021. led to RR values below 2.0 (RR 1.99 and 1.93, respectively). Conversely, excluding the studies by Grasseli et al.²⁵25 Grasselli G, Scaravilli V, Mangioni D, Scudeller L, Alagna L, Bartoletti M, Bellani G, Biagioni E, Bonfanti P, Bottino N, Coloretti I, Cutuli SL, De Pascale G, Ferlicca D, Fior G, Forastieri A, Franzetti M, Greco M, Guzzardella A, Linguadoca S, Meschiari M, Messina A, Monti G, Morelli P, Muscatello A, Redaelli S, Stefanini F, Tonetti T, Antonelli M, Cecconi M, Foti G, Fumagalli R, Girardis M, Ranieri M, Viale P, Raviglione M, Pesenti A, Gori A, Bandera A. Hospital-acquired infections in critically ill patients with COVID-19. Chest 2021; 160(2):454-465. and Falcone et al.¹⁹19 Falcone M, Tiseo G, Giordano C, Leonildi A, Menichini M, Vecchione A, Pistello M, Guarracino F, Ghiadoni L, Forfori F, Barnini S, Menichetti F; Pisa COVID-19 Study Group. Predictors of hospital-acquired bacterial and fungal superinfections in COVID-19: a prospective observational study. J Antimicrob Chemother 2021; 76(4):1078-1084. resulted in RR values near to 2.20 (RR 2.19 and 2.20, respectively). It is important to point that the country of study, the analysis period and the most prevalent bacteria in HAI cases could influence in the clinical outcomes of the patients (death or discharge). These aspects can be assessed in Table 1.

Despite of the importance of A. baumannii as a causative agent of HAIs in critical patients in ICUs, there are few studies that explore this aspect. The number of deaths and the respective studied population are presented in Table 2. Evidently, there is a wide range (from 30 to 70%) in the mortality rates and this variability can be explained considering the country of study and the adoption of precaution measures by the hospitals analyzed.

Discussion

As previously reported, in the present study, the incidence of HAIs observed in hospitalized COVID-19 patients was 18.85% with a mortality rate of 42.17% in patients with HAIs, 16.6% in “no-HAIs” patients with 2.08 of RR. This value of HAI incidence is close to those reported by Lansbury et al.²²22 Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect 2020; 81(2):266-275. and Langford et al.²³23 Langford BJ, So M, Raybardhan S, Leung V, Westwood D, MacFadden DR, Soucy JR, Daneman N. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect 2020; 26(12):1622-1629. in their systematic reviews, which obtained values of 14% (considering ICU patients) and 14.3%, respectively. However, HAIs incidence differs from those observed by Lansbury et al.²²22 Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect 2020; 81(2):266-275. (7% considering overall patients) and less than 4% of bacterial infections described by Westblade et al.²⁶26 Westblade LF, Simon MS, Satlin MJ. Bacterial Coinfections in Coronavirus Disease 2019. Trends Microbiol 2021; 29(10):930-941..

The HAIs incidence of our study is also similar to 16% reported by Nebreda-Mayoral et al.²⁷27 Nebreda-Mayoral T, Miguel-Gómez MA, March-Rosselló GA, Puente-Fuertes L, Cantón-Benito E, Martínez-García AM, Muñoz-Martín AB, Orduña-Domingo A. Infección bacteriana/fúngica en pacientes con COVID-19 ingresados en un hospital de tercer nivel de Castilla y León, España. Enferm Infecc Microbiol Clin 2022; 40(4):158-165. in Spain, and differs from the values obtained by Nori et al.¹²12 Nori P, Cowman K, Chen V, Bartash R, Szymczak W, Madaline T, Punjabi Katiyar C, Jain R, Aldrich M, Weston G, Gialanella P, Corpuz M, Gendlina I, Guo Y. Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge. Infect Control Hosp Epidemiol 2021; 42(1):84-88. and Kumar et al.²⁰20 Kumar G, Adams A, Hererra M, Rojas ER, Singh V, Sakhuja A, Meersman M, Dalton D, Kethireddy S, Nanchal R, Guddati AK. Predictors and outcomes of healthcare-associated infections in COVID-19 patients. Int J Infect Dis 2021; 104:287-292., both in the USA, with values of 3.6% and 3.7%, respectively. It is important to point out that the studies that analyzed patients in ICU, HAIs prevalence was significantly higher, as observed in studies by Bardi et al.¹⁶16 Bardi T, Pintado V, Gomez-Rojo M, Escudero-Sanchez R, Azzam Lopez A, Diez-Remesal Y, Martinez Castro N, Ruiz-Garbajosa P, Pestaña D. Nosocomial infections associated to COVID-19 in the intensive care unit: clinical characteristics and outcome. Eur J Clin Microbiol Infect Dis 2021; 40(3):495-502. in Spain and Copaja-Corzo et al.²⁸28 Copaja-Corzo C, Hueda-Zavaleta M, Benites-Zapata VA, Rodriguez-Morales AJ. Antibiotic use and fatal outcomes among critically ill patients with covid-19 in Tacna, Peru. Antibiotics 2021; 10(8):959. in Peru that obtained 40.7% and 40.32% of prevalence, respectively, confirming the impact of disease severity at admission on patient outcome.

Among the main causes for the occurrence of HAIs are the length of hospital stay, which tends to be higher according to the patient’s level of care, APACHE II score¹⁶16 Bardi T, Pintado V, Gomez-Rojo M, Escudero-Sanchez R, Azzam Lopez A, Diez-Remesal Y, Martinez Castro N, Ruiz-Garbajosa P, Pestaña D. Nosocomial infections associated to COVID-19 in the intensive care unit: clinical characteristics and outcome. Eur J Clin Microbiol Infect Dis 2021; 40(3):495-502.; previous empirical antibacterial therapy²⁶26 Westblade LF, Simon MS, Satlin MJ. Bacterial Coinfections in Coronavirus Disease 2019. Trends Microbiol 2021; 29(10):930-941.; CRE intestinal colonization, mechanical ventilation, use of immunomodulators and elevated CRP on admission¹⁹19 Falcone M, Tiseo G, Giordano C, Leonildi A, Menichini M, Vecchione A, Pistello M, Guarracino F, Ghiadoni L, Forfori F, Barnini S, Menichetti F; Pisa COVID-19 Study Group. Predictors of hospital-acquired bacterial and fungal superinfections in COVID-19: a prospective observational study. J Antimicrob Chemother 2021; 76(4):1078-1084..

Considering the impact of these HAIs on mortality, the rates obtained are similar to Kumar et al.²⁰20 Kumar G, Adams A, Hererra M, Rojas ER, Singh V, Sakhuja A, Meersman M, Dalton D, Kethireddy S, Nanchal R, Guddati AK. Predictors and outcomes of healthcare-associated infections in COVID-19 patients. Int J Infect Dis 2021; 104:287-292. that, despite a 3.7% of HAIs occurrence, observed 40.7% of mortality rate in patients with HAIs when compared to 11.8% in “no-HAI” patients.

The studies conducted by Nori et al.¹²12 Nori P, Cowman K, Chen V, Bartash R, Szymczak W, Madaline T, Punjabi Katiyar C, Jain R, Aldrich M, Weston G, Gialanella P, Corpuz M, Gendlina I, Guo Y. Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge. Infect Control Hosp Epidemiol 2021; 42(1):84-88., Giacobbe et al.¹³13 Giacobbe DR, Battaglini D, Enrile EM, Dentone C, Vena A, Robba C, Ball L, Bartoletti M, Coloretti I, Di Bella S, Di Biagio A, Brunetti I, Mikulska M, Carannante N, De Maria A, Magnasco L, Maraolo AE, Mirabella M, Montrucchio G, Patroniti N, Taramasso L, Tiseo G, Fornaro G, Fraganza F, Monastra L, Roman-Pognuz E, Paluzzano G, Fiorentino G, Corcione A, Bussini L, Pascale R, Corcione S, Tonetti T, Rinaldi M, Falcone M, Biagioni E, Ranieri VM, Giannella M, De Rosa FG, Girardis M, Menichetti F, Viale P, Pelosi P, Bassetti M. Incidence and Prognosis of Ventilator-Associated Pneumonia in Critically Ill Patients with COVID-19: A Multicenter Study. J Clin Med 2021; 10(4):555. and Copaja-Corzo et al.²⁸28 Copaja-Corzo C, Hueda-Zavaleta M, Benites-Zapata VA, Rodriguez-Morales AJ. Antibiotic use and fatal outcomes among critically ill patients with covid-19 in Tacna, Peru. Antibiotics 2021; 10(8):959. yielded mortality rates of 57%, 46% and 33%, respectively. Copaja-Corzo et al.²⁸28 Copaja-Corzo C, Hueda-Zavaleta M, Benites-Zapata VA, Rodriguez-Morales AJ. Antibiotic use and fatal outcomes among critically ill patients with covid-19 in Tacna, Peru. Antibiotics 2021; 10(8):959. analyzed 124 patients admitted to ICUs at a hospital in Southern Peru from March 28, 2020, to March 1, 2021 and they observed a strong association between HAIs and mortality risk, revealing an adjusted hazard ratio (aHR) of 2.7 (95%CI: 1.33-5.60).

In an investigation by Jeong et al.²⁹29 Jeong S, Lee N, Park Y, Kim J, Jeon K, Park MJ, Song W. Prevalence and Clinical Impact of Coinfection in Patients with Coronavirus Disease 2019 in Korea. Viruses 2022; 14(2):446., a total of 436 samples collected between August 2020 and October 2021 in Korea were analyzed, revealing a bacteria detection rate of 52.6%. Through multivariate analysis, several risk factors were identified, including coinfection (odds ratio [OR] = 6.095), advanced age (OR = 1.089), and elevated levels of lactate dehydrogenase (OR = 1.006). Moreover, coinfection with bacteria (OR = 11.250), resistant pathogens (OR = 11.667), and infection with multiple pathogens (OR = 10.667) were significantly related to death. Notably, the study highlighted several frequently isolated bacteria, including Staphylococcus aureus, Haemophilus influenzae, Acinetobacter species, Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, and Pseudomonas species. It is important to highlight that among the isolated A. baumannii strains, a substantial 90% demonstrated a non-susceptibility to carbapenem antibiotics.

Westblade et al.²⁶26 Westblade LF, Simon MS, Satlin MJ. Bacterial Coinfections in Coronavirus Disease 2019. Trends Microbiol 2021; 29(10):930-941. concluded that empirical antibacterial therapy and diagnostic testing for bacterial pathogens in hospitalized COVID-19 patients are indicated only for critical patients, those with severe immunosuppression, radiographic findings suggestive of bacterial pneumonia, or multiple laboratory parameters indicative of bacterial infection. The authors also showed that Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae were the most isolated bacteria, even though carbapenem-resistant Gram-negative infections are being increasingly reported in intensive care COVID-19 patients.

Nebreda-Mayoral et al.²⁷27 Nebreda-Mayoral T, Miguel-Gómez MA, March-Rosselló GA, Puente-Fuertes L, Cantón-Benito E, Martínez-García AM, Muñoz-Martín AB, Orduña-Domingo A. Infección bacteriana/fúngica en pacientes con COVID-19 ingresados en un hospital de tercer nivel de Castilla y León, España. Enferm Infecc Microbiol Clin 2022; 40(4):158-165. reported 11% superinfections (80/712) and 54% of these were gram-negative bacillus (BGN) with A. baumannii being one of the main isolated bacteria. The term superinfections is used to describe infections caused by multidrug resistant (MDR) bacteria. Additionally, all MDR isolates were only susceptible to colistin. Among the mortality predictors, coinfection with A. baumannii showed an Odds Ratio (OR) of 9.329 (95%CI 2.289-38.020), p = 0.002.

Copaja-Corzo et al.²⁸28 Copaja-Corzo C, Hueda-Zavaleta M, Benites-Zapata VA, Rodriguez-Morales AJ. Antibiotic use and fatal outcomes among critically ill patients with covid-19 in Tacna, Peru. Antibiotics 2021; 10(8):959. reported that 80% of isolated bacteria were classified as XDR (extensively resistant) to antibiotics, and the most common species were Acinetobacter baumannii (54%) and Pseudomonas aeruginosa (22%).

The worsening incidence of HAI by A. baumannii - typically important bacteria in the hospital environment - during the pandemic period was mostly due to the greater use of mechanical ventilation and inappropriate antimicrobial use. Rawson et al.³⁰30 Rawson TM, Moore LSP, Zhu N, Ranganathan N, Skolimowska K, Gilchrist M, Satta G, Cooke G, Holmes A. Bacterial and fungal coinfection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis 2020; 71(9):2459-2468. found that 72% of COVID-19 patients had received antibacterial therapy and that recorded agents tended to be broad-spectrum antibiotics prescribed empirically in both critical and non-critical settings. In the meta-analysis performed by Langford et al.²³23 Langford BJ, So M, Raybardhan S, Leung V, Westwood D, MacFadden DR, Soucy JR, Daneman N. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect 2020; 26(12):1622-1629., of 3338 hospitalized and critical COVID-19 patients across 24 studies, it was observed that most COVID-19 patients received antibiotics (71.9%, 95%CI 56.1%-87.7%). Rickman et al.³¹31 Rickman HM, Rampling T, Shaw K, Martinez-Garcia G, Hail L, Coen P, Shahmanesh M, Shin GY, Nastouli E, Houlihan CF. Nosocomial Transmission of Coronavirus Disease 2019: A Retrospective Study of 66 Hospital-acquired Cases in a London Teaching Hospital. Clin Infect Dis 2021; 72(4):690-693. also noted that patient-to-patient transmission was involved in 55% of hospital-acquired COVID-19 cases, and shared-use facilities and equipment, or staff movement potentially contributed to a further 14% of cases.

The adoption of Contact Precaution Measures is indicated to control outbreaks and prevent the dissemination of MDR pathogens. These measures include placement of patients in a private room, single and disposable gowns and cohort of patients and professionals³²32 Agência Nacional de Vigilância Sanitária (Anvisa). Prevenção de infecções por microrganismos multirresistentes em serviços de saúde. Brasília: Anvisa; 2021.. These measures, when combined with Standard Precaution Measures, like proper hand hygiene, glove usage and aprons are part of a multifaceted strategy that improves the effectiveness of these actions. It is also worth noting, the importance of cleaning and disinfecting environments, as well as antimicrobial optimization programs as strategies to reduce HAIs.

Regarding disinfection of mechanical ventilators, Cureño-Díaz et al.³³33 Cureño-Díaz MA, Durán-Manuel EM, Cruz-Cruz C, Ibáñez-Cervantes G, Rojo-Gutiérrez MI, Moncayo-Coello CV, Loyola-Cruz MÁ, Castro-Escarpulli G, Hernández DMR, Bello-López JM. Impact of the modification of a cleaning and disinfection method of mechanical ventilators of COVID-19 patients and ventilator-associated pneumonia: one year of experience. Am J Infect Control 2021; 49(12):1474-1480. conducted a study involving 338 mechanical ventilators, concluded that implementing a cleaning and disinfection protocol with enzymatic detergents/isopropyl alcohol for mechanical ventilators used by patients with SARS-CoV-2 and ESKAPE bacteria (including A. baumanii) had a positive impact on post disinfection microbial contamination rates.

Langford et al.²³23 Langford BJ, So M, Raybardhan S, Leung V, Westwood D, MacFadden DR, Soucy JR, Daneman N. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin Microbiol Infect 2020; 26(12):1622-1629. have recommended for patients with suspected bacterial infections that antibiotic selection be based on local epidemiology and patient factors, with early discontinuation when there is no evidence of bacterial infection.

These measures are strongly recommended, considering the high empirical use of broad-spectrum antibiotics observed for COVID-19 patients. There is heightening concern that antibiotic overuse during the COVID-19 pandemic will exacerbate the problem of antimicrobial resistance in clinically relevant microorganisms in the future³⁴34 Mahoney AR, Safaee MM, Wuest WM, Furst AL. The silent pandemic: Emergent antibiotic resistances following the global response to SARS-CoV-2. iScience 2021; 24(4):102304.

35 Ghosh S, Bornman C, Zafer MM. Antimicrobial Resistance Threats in the emerging COVID-19 pandemic: where do we stand? J Infect Public Health 2021; 14(5):555-560.^-3636 Lai CC, Chen SY, Ko WC, Hsueh PR. Increased antimicrobial resistance during the COVID-19 pandemic. Int J Antimicrob Agents 2021; 57(4):106324.. In order to minimize this problem, it is recommended the adoption of Antibiotic Stewardship Programs (ASPs), these programs include various interventions, ranging from Hospital Leadership Commitment to activities, such as prospective audit and feedback, which aim to monitor antibiotic prescriptions and regularly provide data on antibiotic resistance³⁷37 Centers for Disease Control and Prevention (CDC). Core Elements of Hospital Antibiotic Stewardship Programs [Internet]. 2019. [cited 2023 out 13]. Available in https://www.cdc.gov/antibiotic-use/core-elements/hospital.html
https://www.cdc.gov/antibiotic-use/core-... .

It is important to acknowledge that this study has certain limitations. The high heterogeneity (I²2 Johns Hopkins Coronavirus Resource Center. COVID-19 Map [Internet]. [cited 2022 set 14]. Available from: https://coronavirus.jhu.edu/map.html
https://coronavirus.jhu.edu/map.html... 91%); the diversity of infections included in the survey (ventilation-associated pneumonia (VAP), blood stream infections (BSI) and urinary tract infections (UTI), in contrast to some studies that included only BSI. Another limitation is the inclusion of co-infections (≤ 48 h after admission) and superinfections/secondary infections (> 48h after admission) while others included only superinfections. All these factors can interfere in the isolated bacteria and consequently in the clinical outcome.

Considering that HAIs acquired by hospitalized COVID-19 patients increased nearly twofold the risk of death, especially if caused by MDR bacteria, such as Acinetobacter baumannii. It is of paramount importance the broad vaccination against COVID-19 and the adoption of measures to reduce HAI among hospitalized patients, consequently mitigating mortality due to superinfections.

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