ORIGINAL ARTICLE

Observational Study on Secondary Bacterial Infection

and the Use of Antibiotics in COVID-19 Patients Treated
in a Tertiary Referral Hospital

Khie Chen Lie1,2*, Sharifah Shakinah1, Adeline Pasaribu1, Robert Sinto1,2,

Leonard Nainggolan1,2
1
Division of Tropical and Infectious Disease, Department of Internal Medicine, Faculty of Medicine Universitas
Indonesia – Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
2
Member of Antimicrobial Stewardship Committee, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.

*Corresponding Author:
Khie Chen Lie, MD, PhD. Division of Tropical and Infectious Disease, Department of Internal Medicine, Faculty of
Medicine Universitas Indonesia – Cipto Mangunkusumo Hospital. Jl. Diponegoro no. 71, Jakarta 10430, Indonesia.
Email: drkhiechen@gmail.com.

Abstract
Background: Data on secondary bacterial infection in patients with COVID-19 in Indonesia are still
limited, while the use of empirical antibiotics continues to increase. This study aims to determine the secondary
bacterial infection rate in hospitalized COVID-19 patients and factors related to secondary bacterial infection.
Methods: This is a retrospective cohort study on hospitalized COVID-19 patients undergoing treatment at
Cipto Mangunkusumo Hospital from March 2020 to September 2020. Secondary bacterial infection is defined
as the identification of a bacterial pathogen from a microbiological examination. Results: From a total of 255
subjects, secondary infection was identified in 14.5%. Predictors of secondary infection were early symptoms
of shortness of breath (OR 5.31, 95% CI 1.3 – 21.5), decreased consciousness (OR 4.81, 95% CI 1.77 – 13.0),
length of stay > 12 days (OR 8.2, 95% CI 2.9 – 23.3), and central venous catheter placement (OR 3.0, 95%
CI 1.1 – 8.0) The most common pathogen of secondary bacterial infection is Acinetobacter sp. (n=9; 28%).
Empirical antibiotics were administered to 82.4% of subjects with predominant use of macrolides (n=141; 32.4%).
Conclusion: The secondary bacterial infection rate in COVID-19 was 14.5% and is associated with dyspnea,
decreased consciousness, length of stay >12 days, and central venous catheter placement. The use of antibiotics
in COVID-19 reaches 82.4% and requires special attention to prevent the occurrence of antibiotic resistance.

Keywords: COVID-19, secondary bacterial infection, antibiotics, antibiotic stewardship.

INTRODUCTION Several studies have reported bacterial co-

Coronavirus disease 2019 (COVID-19) infection and secondary bacterial infection in
is a respiratory infection with high morbidity patients with COVID-19. Langford et al4 reported
and mortality worldwide. This disease is that 3.5% of COVID-19 patients had bacterial
caused by Severe Acute Respiratory Syndrome co-infection, and 14.3% had secondary bacterial
Coronavirus 2 (SARS-CoV-2) and has a wide infection. Another study on severe and critical
spectrum of diseases from asymptomatic to COVID-19 also reported a high incidence of
severe pneumonia resulting in acute respiratory bacterial co-infection prevalence of up to 20% of
failure and death.1,2 By 2022, there have been total cases.5 With the low prevalence of bacterial
more than 300 million cases and 5 million co-infection and secondary bacterial infection,
cumulative deaths due to COVID-19 globally.3 however, studies showed that more than 70%

Acta Med Indones - Indones J Intern Med • Vol 54 • Number 2 • April 2022 161
Khie Chen Lie Acta Med Indones-Indones J Intern Med

of COVID-19 patients who were hospitalized according to the World Health Organization
received antibiotics. This excessive use of (WHO) criteria. Corticosteroids and
antibiotics must be monitored closely because immunosuppressants, including anti-cytokine
excessive and irrational use of antibiotics will agents, calcineurin inhibitors, antimetabolites,
affect the normal flora in the body and increase and similar therapies were found in the medical
bacterial resistance.4,6 records to be used for treating the comorbid prior
This study aims to provide an overview of to COVID-19 infection, as well as for treating
the incidence of co-infection and secondary the COVID-19 itself once a patient was infected.
infection as well as the causative pathogen in Procalcitonin (PCT) and c-reactive protein
COVID-19 patients. In addition, this study also (CRP) values ​​were obtained from laboratory
assessed the predicting factors for the presence tests performed at the admission. Sepsis and
of secondary infection in COVID-19 patients Sequential Organ Failure Assessment (SOFA)
undergoing treatment. score were determined based on the diagnosis
in the medical record or the worst SOFA score
METHODS >2 was obtained during the hospitalization of
the patients.
Study Design and Participant
This retrospective cohort study collected Sample Size and Data Collection
data from medical records of COVID-19 patients The sample estimate was calculated by
who were hospitalized at Cipto Mangunkusumo considering the prevalence of COVID-19
Hospital. COVID-19 was confirmed by the infection when the study was designed, which
reverse transcriptase-polymerase chain reaction was 21%, with a 95% confidence level, and
(RT-PCR) method. Data on confirmed COVID-19 5% prediction error. Therefore, a sample size
adult patients were collected consecutively from of 255 subjects was determined. Data were
March to September 2020. collected consecutively from the medical records
of patients who were hospitalized in Cipto
Ethics
Mangunkusumo Hospital in the period from
This study was approved by the Ethical March 2020 until the required number of samples
Committe of Faculty of Medicine Universitas was achieved.
Indonesia (Ref. Number: 1454/UN2.F1/ETIK/
PPM.00.02/2020). Outcome Measurement
The outcome measured in this study was
Study Definition
the incidence of secondary bacterial infection in
COVID-19 infection is defined as an RT- COVID-19 and its associated factors.
PCR confirmed positive COVID-19 from
nasopharyngeal swab accompanied by signs and Statistical Analysis
symptoms of COVID-19 and other laboratory Demographic and clinical characteristics of
examinations that support the diagnosis of patients are presented in percentage, as shown
COVID-19. Bacterial co-infection is defined as in the table. Variables that are hypothesized to
the presence of a pathogen other than SARS- be related to the outcome (secondary bacterial
CoV-2 in a COVID-19 patient within the first infection) were analyzed univariately. The
48 hours of hospital admission. Secondary variables that meet the requirements for
bacterial infection was defined as the presence multivariate analysis using logistic regression
of a pathogen other than SARS-CoV-2 in a were further analyzed to obtain the odds ratio
COVID-19 patient after the first 48 hours (OR) value. The value of p<0.05 was considered
of hospital admission. The microbiological as statistically significant. Data analysis was
examination was carried out in patients with performed with SPSS version 25.0.
suspected secondary bacterial co-infection
according to the standard of care based on the RESULTS
instruction from the attending physicians. A total of 255 records of hospitalized
The degree of COVID-19 is classified COVID-19 patients were reviewed. It was found

162
Vol 54 • Number 2 • April 2022 Observational Study on Secondary Bacterial Infection

that 98 subjects (36.5%) were diagnosed with infection. Compared to all subjects with
sepsis, 27 subjects (10.6%) had bacterial co- COVID-19, the group with secondary bacterial
infection, 37 subjects (14.5%) had secondary infection had more comorbidities. The average
bacterial infection, and 45 subjects (17.6%) length of stay for COVID-19 subjects was 11.9
died during hospitalization. Table 1 shows the days and the group with secondary bacterial
demographic data and clinical characteristics. infection has longer length of stay, i.e., 22 days
Of all subjects, the average age was 46 on average.
years. The most frequently reported COVID-19 The group with secondary bacterial infection
complaints are fatigue, cough, and fever. In had a higher proportion of ventilator use, ICU
the group with secondary bacterial infection, care, corticosteroid and immunosuppressant
complaints of tachypnea, dyspnea, fatigue, therapy, sepsis, and in-hospital mortality than
anorexia, myalgia, nausea, vomiting, and the group without secondary bacterial infection.
decreased consciousness were more common The use of antibiotics in COVID-19 was 100% in
than in the group without secondary bacterial the group with secondary bacterial infection and

Table 1. Characteristics of Study Subjects

Secondary Bacterial Infection
Total Subject With Secondary Without Secondary
Characteristics
(n=255) Bacterial Infection Bacterial Infection
(n=37) (n=218)
Gender
Female, n (%) 122 (47.8) 25 (67.6) 101 (50.5)
Male, n (%) 133 (52.2) 12 (32.4) 108 (49.5)
Mean Age, (SD) 46 (16.2) 50 (15.9) 45 (16.2)
Clinical Manifestation
Fever, n (%) 159 (62.4) 25 (67.6) 134 (61.5)
-- Cough, n(%) 183 (71.8) 30 (81.1) 153 (70.2)
-- Tachypnea, n (%) 122 (47.8) 30 (81.1) 92 (42.2)
-- Dyspnea, n (%) 144 (56.5) 34 (91.9) 110 (50.5)
-- Fatigue, n (%) 195 (76.5) 34 (91.9) 161 (73.9)
-- Anorexia, n (%) 154 (60.4) 31 (83.8) 123 (56.4)
-- Myalgia, n (%) 67 (26.3) 6 (16.2) 61 (28)
-- Headache, n (% 34 (13.3) 1 (2.7) 33 (15.8)
-- Diarrhea, n (%) 23 (9) 4 (10.8) 19 (8.7)
-- Nausea, n (%) 71 (27.8) 17 (45.9) 52 (24.8)
-- Vomiting, n (% 28 (11) 8 (21.6) 20 (9.2)
-- Anosmia, n (%) 22 (8.6) 1 (2.7) 21 (9,6)
-- Ageusia, n (%) 19 (7.5) 1 (2.7) 18 (8,3)
-- Loss of consciousness, n (%) 45 (17.6) 21 (56.8) 24 (11)
Comorbidity (based on Charlson
Comorbidity Index)
-- Without comorbid 106 (41.5) 7 (18.9) 99 (45.5)
-- Mild 74 (29) 10 (27.1) 64 (29.4)
-- Moderate 48 (18.8) 11 (29.7) 37 (17.0)
-- Severe 27 (10.7) 9 (24.3) 18 (8.1)
COVID-19 Severity
-- Mild 138 (54.1) 6 (16.2) 132 (60.5)
-- Moderate 22 (8.7) 1 (2.8) 21 (9.6)
-- Severe/Critically ill 95 (37.2) 30 (81) 65 (29.9)
Length of stay, mean (SD) 11.9 (9) 22 (13.5) 10 (10)
ICU admission; n(%) 83 (32.5) 27 (73.0) 55 (25.2)
History of hospital admission within the 101 (39.6) 18 (48.6) 83 (38.1)
previous 2 weeks; n (%)
History of long-term care, n (%) 59 (23.1) 15 (40.5) 44 (20.2)
CVC placement 43 (16.9) 21 (56.8) 22 (10.1)
History of mechanical ventilation, n (%) 35 (13.7) 18 (48.6) 17 (7.8)
History of corticosteroid consumption, n (%) 90 (35.3) 24 (64.9) 66 (30.3)

163
Khie Chen Lie Acta Med Indones-Indones J Intern Med

History of immunosuppressant 86 (33.7) 23 (62.2) 63 (28.9)

consumption, n (%)
Antibiotics treatment, n (%) 210 (82.4) 37 (100) 173 (79.4)
Early antibiotics treatment*, n (%) 170 (81) 31 (83.8) 139 (63.8)
Combination of antibiotics treatment*, n (%) 124 (59) 30 (81.1) 94 (43.1)
Use of Broad-Spectrum Antibiotics*, n (%) 254 (99.5) 37 (100) 217 (99.5)
Organ dysfunction, n (%) 55 (21.6) 21 (56.8) 34 (15.6)
SOFA score, median (IQR) 2 (0-14) 6 (0-13) 0 (0-14)
Bacterial co-infection 27 (11.0) 11 (29.7) 16 (7.3)
Sepsis, n (%) 98 (36.5) 30 (81.1) 63 (28.9)
Mortality during hospitalization, n (%) 45 (17.6) 21 (56.8) 24 (11)

SD: standard deviation, COVID-19: coronavirus disease 2019, ICU: intensive care unit, CVC: central venous catheter
*from subjects receiving antibiotics

79.4% in the group without secondary bacterial in the previous two weeks, history of long-term
infection. 59% of subjects with COVID-19 care, bacterial co-infection, organ dysfunction,
received combination of antibiotics, including sepsis, comorbidities, CRP level, procalcitonin
81% of subjects in the group with a secondary values, and SOFA scores. COVID-19 is classified
bacterial infection. into mild and moderate to critical groups. CRP
Table 2 describes the univariate and level cut-off used in this study was 80 mg/
multivariate analysis of factors associated L7, procalcitonin levels cut-off point was 0.25
with secondary bacterial infection in ng/ml8, and SOFA score cut-off point was 2.
COVID-19, including age, gender, clinical Prolonged length of stay was determined with the
manifestations, length of stay, ICU care, cut-off of 12 days for the group with the length
use of mechanical ventilators, use of central of stay associated with the risk of secondary
venous catheters, corticosteroid therapy and/or infection.9,10
immunosuppression, history of hospitalization

Table 2. Factors Associated with Secondary Bacterial Infection in COVID-19 Patients.

Univariate Multivariate
Variables
OR (95% CI) p-value OR (95% CI) p-value
Age group (<60 y.o.) 1.1 (0.5 – 2.5) 0.68
Gender 2.12 (1.0 – 4.4) 0.05 1.5 (0.58 – 4.9) 0.38
Fever 1.30 (0.62 – 2.7) 0.58
Cough 1.82 (0.76 – 4.35) 0.236 1.0 (0.28 – 3.9) 0.92
Tachypnea 5.8 (2.4 – 13.9) <0.001 1.4 (0.3 – 6.0) 0.61
Dyspnea 11.1 (3.3 – 37.3) <0.001 5.31 (1.3 – 21.5) 0.02
Fatigue 4.0 (1.1 – 13.5) 0.02 1.21 (0.1 – 7.46) 0.834
Anorexia 3.99 (1.5 – 9.9) 0.002 1.3 (0.36 – 4.9) 0.657
Myalgia 0.49 (0.19 – 1.25) 0.16 1.82 (0.45 – 7.32) 0.39
Headache 0.1 (0.02 – 1.1) 0.037 0.12 (0.01 – 1.43) 0.095
Diarrhea 1.2 (0.40 – 3.9) 0.755
Nausea 2.58 (1.2 – 5.2) 0.01 2.2 (0.8 – 5.7) 0.086
Vomiting 2.73 (1.1 – 6.7) 0.04 1.2 (0.24 – 5.7) 0.82
Anosmia 0.26 (0.03 – 1.99) 0.27
Ageusia 0.309 (0.04 – 2.38) 0.32
Loss of consciousness 10.6 (4.8 – 23.0) <0.001 4.81 (1.77 – 13.0) 0.002
COVID-19 severity 7.93 (3.1 – 10.8) <0.001 0.495 (0.045 – 5.38) 0.564
Length of stay 10.7 (4.5 – 25.8) <0.001 8.2 (2.9 – 23.3) <0.001
ICU admission 8.0 (3.6 -17.5) <0.001 0.95 (0.24 – 3.7) 0.956
History of mechanical 11.2 (4.9 – 25.0) <0.001 1.3 (0.28 – 6.1) 0.713
ventilation
CVC placement 11.6 (5.3 -25.6) <0.001 3.0 (1.1 – 8.0) 0.023

164
Vol 54 • Number 2 • April 2022 Observational Study on Secondary Bacterial Infection

History of corticosteroid 4.2 (2.0 – 8.8) <0.001 1.33 (0.08 – 21.8) 0.84
consumption
History of immunosuppressant 4.0 (1.9 – 8.3) <0.001 0.75 (0.2 – 2.2) 0.61
consumption
History of hospital admission 1.54 (0.76 – 3.10) 0.27
within the previous 2 weeks
Long-term care 2.6 (1.2 – 5.6) 0.011 1.3 (0.43 – 3.9) 0.622
Organ dysfunction 7.1 (3.3 – 14.9) <0.001 0.9 (0.1 – 5.5) 0.968
Sepsis 10.5 (4.4 – 25.2) <0.001 2.3 (0.52 – 10.8) 0.258
Comorbidity 3.48 (1.7 – 7.12) 0.01 1.0 (0.3 – 3.4) 0.917
CRP level 2.7 (1.3 – 5.7) 0.006 1.3 (0.49 – 3.8) 0.537
Procalcitonin level 1.5 (0.74 – 3.0) 0.275
SOFA score 8.37 (3.8 – 18.1) <0.001 0.47 (0.11 – 2.0) 0.31
Bacterial co-infection 5.34 (2.2 – 12.7) <0.001 1.8 (0.52 – 6.44) 0.34

OR: odds ratio, 95% CI: 95% confidence interval, COVID-19: coronavirus disease 2019, ICU: intensive care unit, CVC:
central venous catheter, CRP: c-reactive protein, SOFA: sequential organ failure assessment

Based on multivariate analysis, several grew from the culture sample after 48 hours of
factors associated with secondary bacterial hospitalization. The prevalence of secondary
infection in COVID-19 were complaints of bacterial infection in all study subjects was
dyspnea (OR 5.31, 95% CI 1.3 – 21.5), decreased 14.5%. Of the 255 subjects, 46 subjects (18%)
consciousness (OR 4.81, 95% CI 1.77 – 13.0), underwent microorganism culture examination.
prolonged length of stay (OR 8.2, 95% CI 2.9 There was a total of 66 samples used for
– 23.3), and central venous catheter placement microorganism culture examination, consisting
(OR 3.0, 95% CI 1.1 – 8.0). of 22 blood samples, 32 sputum samples, two
Etiologic Pathogens Cause Secondary bronchoalveolar lavages (BAL) fluid samples,
Bacterial Infections in COVID-19 four urine samples, one pleural fluid sample, four
Secondary bacterial infection in wound tissue samples, and one cerebrospinal
COVID-19 was determined by the presence of fluid sample. Of the total 66 samples, 49
microorganisms other than SARS-CoV-2 that samples were positive, and 17 were sterile

Figure 1. Etiologic Pathogen of Secondary Bacterial Infections in COVID-19

165
Khie Chen Lie Acta Med Indones-Indones J Intern Med

(14 blood culture samples, two urine culture DISCUSSION

samples, and one BAL fluid culture sample). In this study, 14.5% of subjects with
The secondary bacterial infections found were COVID-19 developed secondary bacterial
hospital-acquired pneumonia (27 cases, 73%), infection during their hospitalization. Most of
catheter-related bloodstream infections (8 cases, the subjects with secondary bacterial infection
21.6%), and catheter-associated urinary tract had severe/critical COVID-19. Approximately
infections (2 cases, 5.4%). Pathogenic etiology 50% of the subjects were admitted to the ICU,
of secondary bacterial infection is dominated by on ventilator, treated with corticosteroids and/or
gram-negative bacteria, i.e., Acinetobacter sp. immunosuppressants, and diagnosed with sepsis.
(28%), Klebsiella sp. (27%), and Pseudomonas Mortality was observed in more than half of the
sp. (18%). Fungal cultures were found positive subjects in the COVID-19 group with secondary
in 5 sputum samples that showed the growth of bacterial infection (56.8%). This was much
Candida sp., and one blood sample showed the higher than the mortality in the group without
growth of Candida albicans. secondary bacterial infection (11%).
Antibiotics Consumption in COVID-19 The prevalence of secondary bacterial
Antibiotics were used in 82.4% of subjects, infection in COVID-19 in this study is in
including those without bacterial co-infection accordance with data in a systematic review
and secondary bacterial infection. 99.5% of the conducted by Langford et al.4 on 24 COVID-19
antibiotics administered in our subjects were studies, where the prevalence of secondary
broad-spectrum antibiotics, such as macrolides bacterial in patients was 14.3%. A study in
(33%), cephalosporins (25%), and quinolones Surabaya, Indonesia, showed a prevalence of
(17%). The most frequently used antibiotics in 19.7%.11 These two studies also showed an
this study was azithromycin from the macrolides, increase in the duration of infection, use of
ceftriaxone, cefotaxime, and cefoperazone ventilator, and ICU admission in the group with
from the third generation of cephalosporins, secondary bacterial infections.
and levofloxacin and moxifloxacin from the COVID-19 infection leads to histological and
quinolones (Figure 2). functional respiratory damage. Histologically,

Quinolones Cephalosporins 3rd gen Carbapenems Macrolides

Cephalosporines 4th gen Penicillin Anti-tuberculosis drugs Metronidazole
Aminoglycosides Tygecyclins Co-Trimoxazole Polymyxins

0%
0%
1%2%
1%2%
6% 17%

4%

25%

33%

9%

Figure 2. Antibiotic Consumption in COVID-19

166
Vol 54 • Number 2 • April 2022 Observational Study on Secondary Bacterial Infection

cellular damage, goblet cell hyperplasia, severity of COVID-19, even before the respiratory
increased mucus secretion, mucociliary disturbance appears.17 Therefore, according to this
disturbances, and discoordination may occur. study, impaired consciousness is associated with
In addition, the alveolar macrophage cells secondary bacterial infection in COVID-19.
deplete and phagocytes’ function is impaired, Based on the analysis of this study, the
which cause a decrease in the ability of bacterial prolonged length of stay for more than 12
clearance by phagocytes and an increase in the days and central venous catheter placement
rate of bacterial replication. In viral and bacterial in COVID-19 patients were associated with
co-infection, pathogen-associated molecular the risk of secondary bacterial infection.
patterns (PAMPs) and damage-associated Prolonged treatment is associated with the risk
molecular patterns (DAMPs) are formed. These of nosocomial infection, which is mainly related
molecules bind to pattern recognition receptors to medical devices and surgical procedures.10,18–21
(PRRs) and activate the formation of interferons The results obtained from this study are in
(IFNs), cytokines, and chemokines that act as accordance with the results of other studies in
pro-inflammatory molecules, causing more COVID-19 patients with secondary bacterial
extensive tissue damage.12–14 The presence of infections. The most common infections reported
immune dysregulation in both co-infection and in this study were pneumonia and catheter-
secondary bacterial infection in COVID-19 associated bloodstream infections.22,23 Central
leads to worse clinical manifestations in the venous catheter placement is also associated with
COVID-19 group with secondary bacterial an increased risk of nosocomial infection.24,25 In
infection in this study. severe and critically ill COVID-19 patients, the
Factors associated with secondary bacterial risk of prolonged length of stay was increased,
infection in COVID-19 are dyspnea on admission, followed by an increase in the duration of use
decreased consciousness, prolonged hospital of a central venous catheter, the risk of entry of
stay, and central venous catheter placement bacteria through the catheter (catheter as port
during treatment. In this study, dyspnea was d’entrée), and a decrease in the immune system
experienced by almost all subjects with secondary of the patient, and hence, increased the risk of
bacterial infection. The association between the secondary catheter-related bacterial infection.24
two could be due to complaints of dyspnea All study subjects with secondary bacterial
which were more common in severe/critical infection received broad-spectrum antibiotics
COVID-19 – the predominant grade in the therapy, and so did 80% of subjects without
secondary bacterial infection group. However, secondary bacterial infection. The same thing
in multivariate analysis, it was found that the was found in another study, with the rate of
severity of COVID-19 was not associated with antibiotics use in COVID-19 patients reached
secondary bacterial infection, and therefore, 90%.4,26 This high number of antibiotics usage
the association between dyspnea and secondary can be caused by the difficulties experienced
bacterial infection appeared to be independent by medical personnel in distinguishing clinical
from the degree of COVID-19. Dyspnea was symptoms of bacterial and viral infections, since
also found in other studies observing secondary both have similar manifestations. In addition, at
bacterial infection in COVID-19, accompanied the beginning of the pandemic, administration of
by fever and gastrointestinal symptoms.15 macrolide antibiotics, i.e., azithromycin, was still
Impaired consciousness is a factor associated recommended for COVID-19 with or without
with secondary bacterial infection in COVID-19. suspicion of co-infection or secondary bacterial
COVID-19 patients with impaired consciousness infection, which led to extremely frequent use
have a higher risk of admission to ICU, of it.27 Cephalosporins and quinolones were also
intubation, need for mechanical ventilation, widely used in this study. These two groups were
prolonged length of stay, prolonged need for widely used because they are the recommended
ventilator, and mortality.16 In addition, impaired regimens in the management of community and
consciousness also acts as an indicator of the nosocomial pneumonia in bacterial infections.28,29

167
Khie Chen Lie Acta Med Indones-Indones J Intern Med

The frequent use of antibiotics without References

bacterial infection increases the risk of antibiotic 1. Coronavirus disease (COVID-19) – World Health
resistance and multi-drug resistant (MDR) Organization [Internet]. [cited 2022 Feb 14]. Available
bacteria.30 This is also portrayed by identifying from: https://www.who.int/emergencies/diseases/
novel-coronavirus-2019
the pathogens causing secondary bacterial
2. Chen N, Zhou M, Dong X, et al. Epidemiological
infections in this study, which were mostly and clinical characteristics of 99 cases of 2019 novel
gram-negative bacteria, i.e., Acinetobacter sp., coronavirus pneumonia in Wuhan, China: a descriptive
Klebsiella sp., and Pseudomonas sp. These study. Lancet. 2020;395(10223):507–13.
data are consistent with the annual pattern of 3. WHO Coronavirus (COVID-19) Dashboard [Internet].
nosocomial bacteria and in line with other [cited 2022 Feb 3]. Available from: https://covid19.
who.int/table
studies on secondary bacterial infection in
4. Langford BJ, So M, Raybardhan S, et al. Bacterial
COVID-19.11,22,31,32 co-infection and secondary infection in patients with
Based on our result, we found that the COVID-19: a living rapid review and meta-analysis.
intensification of proper implementation of Clin Microbiol Infect. 2020;26(12):1622–9.
antimicrobial stewardship is needed, mainly 5. Elabbadi A, Turpin M, Gerotziafas GT, et al. Bacterial
to prevent the irrational use of antibiotics coinfection in critically ill COVID-19 patients with
severe pneumonia. Infection. 2021;49(3):559–62.
in COVID-19. Guidelines for secondary
6. Rawson TM, Moore LSP, Zhu N, et al. Bacterial and
bacterial infection in COVID-19, accurate and fungal coinfection in individuals with Coronavirus:
rapid laboratory investigations, and access to A rapid review to support COVID-19 antimicrobial
microbiological examinations are the keys in prescribing. Clin Infect Dis. 2020;71(9):2459–68.
preventing antimicrobial resistance.32,33 7. Elemraid MA, Rushton SP, Thomas MF, et al. Utility
The limitation of this study is that we used of inflammatory markers in predicting the aetiology
of pneumonia in children. Diag Microbiol Infect Dis.
retrospective design with secondary data from
2014;79(4):458–62.
medical records. Some of the required data, 8. Cleland DA, Eranki AP. Procalcitonin. In: StatPearls
such as CRP and procalcitonin, were not always [Internet]. Treasure Island (FL): StatPearls Publishing;
available, and only some subjects had the 2022 [cited 2022 Feb 4]. Available from: http://www.
respective tests. In addition, the identification of ncbi.nlm.nih.gov/books/NBK539794/
patients with secondary bacterial infection was 9. Lambden S, Laterre PF, Levy MM, et al. The SOFA
score—development, utility and challenges of
determined based on the results of microorganism
accurate assessment in clinical trials. Critical Care.
cultures of patients who were suspected to 2019;23(1):374.
have secondary bacterial infection. Secondary 10. Wolkewitz M, Schumacher M, Rücker G, et al.
bacterial infection could not be appropriately Estimands to quantify prolonged hospital stay
identified in subjects without typical clinical associated with nosocomial infections. BMC Med Res
characteristics. Methodol. 2019;19(1):111.
11. Asmarawati TP, Rosyid AN, Suryantoro SD, et al.
The clinical impact of bacterial co-infection among
CONCLUSION moderate, severe and critically ill COVID-19 patients
Secondary bacterial infection was found in the second referral hospital in Surabaya. F1000Res.
in 14.5% of hospitalized COVID-19 patients. 2021;10:113.
12. Manna S, Baindara P, Mandal SM. Molecular
Factors associated with secondary bacterial
pathogenesis of secondary bacterial infection
infection were complaints of dyspnea on initial associated to viral infections including SARS-CoV-2.
admission, decreased consciousness, length of J Infect Publ Health. 2020;13(10):1397–404.
stay of more than 12 days, and central venous 13. Mirzaei R, Goodarzi P, Asadi M, et al. Bacterial
catheter placement during treatment. The use of co-infections with SARS-CoV-2. IUBMB Life.
antibiotics in COVID-19 infection was found in 2020;72(10):2097–111.
14. SARS-CoV-2, bacterial co-infections, and AMR:
82.4% of subjects and was widely administered
the deadly trio in COVID-19? EMBO Mol Med.
to subjects with and without secondary bacterial 2020;12(7):e12560.
infection. The use of antibiotics in COVID-19 15. He S, Liu W, Jiang M, et al. Clinical characteristics
infection requires special attention to prevent the of COVID-19 patients with clinically diagnosed
occurrence of antibiotic resistance. bacterial co-infection: A multi-center study. PLOS

168
Vol 54 • Number 2 • April 2022 Observational Study on Secondary Bacterial Infection

ONE. 2021;16(4):e0249668. 25. Ong CCH, Farhanah S, Linn KZ, et al. Nosocomial
16. Attia AS, Hussein M, Aboueisha MA, et al. Altered infections among COVID-19 patients: an analysis of
mental status is a predictor of poor outcomes in intensive care unit surveillance data. Antimicrobial
COVID-19 patients: A cohort study. PLOS ONE. Resistance & Infection Control. 2021;10(1):119.
2021;16(10):e0258095. 26. Gaynes R, Edwards JR, National Nosocomial Infections
17. Mao L, Jin H, Wang M, et al. Neurologic manifestations Surveillance System. Overview of nosocomial
of hospitalized patients with Coronavirus disease 2019 infections caused by gram-negative bacilli. Clin Infect
in Wuhan, China. JAMA Neurology. 2020;77(6):683– Dis. 2005;41(6):848–54.
90. 27. Burhan E, Susanto AD, Isbaniah F, et al. Pedoman
18. Rees EM, Nightingale ES, Jafari Y, et al. COVID-19 Tatalaksana COVID-19. 3rd ed. Jakarta: PDPI, PERKI,
length of hospital stay: a systematic review and data PAPDI, PERDATIN, IDAI; 2020.
synthesis. BMC Medicine. 2020;18(1):270. 28. Metlay JP, Waterer GW, Long AC, et al. Diagnosis
19. Vekaria B, Overton C, Wiśniowski A, et al. Hospital and treatment of adults with community-acquired
length of stay for COVID-19 patients: Data-driven pneumonia. An official clinical practice guideline of
methods for forward planning. BMC Infect Dis. the American Thoracic Society and Infectious Diseases
2021;21(1):700. Society of America. Am J Respir Crit Care Med.
20. Zhou Q, Fan L, Lai X, et al. Estimating extra length 2019;200(7):e45–67.
of stay and risk factors of mortality attributable to 29. Kalil AC, Metersky ML, Klompas M, et al.
healthcare-associated infection at a Chinese university Management of adults with hospital-acquired and
hospital: a multi-state model. BMC Infect Dis. ventilator-associated pneumonia: 2016 clinical practice
2019;19(1):975. guidelines by the Infectious Diseases Society of
21. Peleg AY, Hooper DC. Hospital-acquired infections America and the American Thoracic Society. Clinical
due to gram-negative bacteria. N Engl J Med. Infectious Diseases. 2016;63(5):e61–111.
2010;362(19):1804–13. 30. Feldman C, Anderson R. The role of co-infections
22. Sharifipour E, Shams S, Esmkhani M, et al. Evaluation and secondary infections in patients with COVID-19.
of bacterial co-infections of the respiratory tract in Pneumonia. 2021;13(1):5.
COVID-19 patients admitted to ICU. BMC Infect Dis. 31. O’Toole RF. The interface between COVID-19
2020;20(1):646. and bacterial healthcare-associated infections. Clin
23. Rothe K, Feihl S, Schneider J, et al. Rates of bacterial Microbiol Infect. 2021;27(12):1772–6.
co-infections and antimicrobial use in COVID-19 32. Abdela SG, Liesenborghs L, Tadese F, et al. Antibiotic
patients: a retrospective cohort study in light of Overuse for COVID-19: Are we adding insult to
antibiotic stewardship. Eur J Clin Microbiol Infect injury? The American Journal of Tropical Medicine
Dis. 2021;40(4):859–69. and Hygiene. 2021;105(6):1519–20.
24. Fakih MG, Bufalino A, Sturm L, et al. Coronavirus 33. Founou RC, Blocker AJ, Noubom M, et al. The
disease 2019 (COVID-19) pandemic, central-line– COVID-19 pandemic: a threat to antimicrobial
associated bloodstream infection (CLABSI), and resistance containment. Future Sci OA. 7(8):FSO736.
catheter-associated urinary tract infection (CAUTI):
The urgent need to refocus on hardwiring prevention
efforts. Infect Control Hosp Epidemiol;1–6.

169