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 Journal of Microbiology, Immunology and Infection 55 (2022) 985e992

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.e-jmii.com

Review Article

Coronavirus disease 2019 (COVID-19)

associated bacterial coinfection: Incidence,
diagnosis and treatment
Huan-Yi Wu a, Peng-Hao Chang b, Kuan-Yu Chen c, I-Fan Lin d,
Wen-Hsin Hsih e, Wan-Lin Tsai f, Jiun-An Chen g,
Susan Shin-Jung Lee a,h,i,*, the GREAT working group

a
Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Veterans General
Hospital, Kaohsiung, Taiwan
b
Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital,
Linkou, Taiwan
c
Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service
General Hospital, National Defense Medical Center, Taipei, Taiwan
d
Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
e
Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital,
Taichung, Taiwan
f
Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
g
Division of Pediatric Infectious Diseases, China Medical University Children’s Hospital, China Medical
University, Taichung, Taiwan
h
Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
i
School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan

Received 5 June 2022; received in revised form 25 August 2022; accepted 23 September 2022
Available online 7 October 2022

KEYWORDS Abstracts Coronavirus disease 2019 (COVID-19) emerged as a pandemic that spread rapidly
Bacterial coinfection; around the world, causing nearly 500 billion infections and more than 6 million deaths to date.
Coronavirus disease During the first wave of the pandemic, empirical antibiotics was prescribed in over 70% of hos-
2019 (COVID-19); pitalized COVID-19 patients. However, research now shows a low incidence rate of bacterial
Diagnosis; coinfection in hospitalized COVID-19 patients, between 2.5% and 5.1%. The rate of secondary
Incidence; infections was 3.7% in overall, but can be as high as 41.9% in the intensive care units. Over-
Pathogen prescription of antibiotics to treat COVID-19 patients fueled the ongoing antimicrobial resis-
tance globally. Diagnosis of bacterial coinfection is challenging due to indistinguishable clinical
presentations with overlapping lower respiratory tract symptoms such as fever, cough and dys-
pnea. Other diagnostic methods include conventional culture, diagnostic syndromic testing,
serology test and biomarkers. COVID-19 patients with bacterial coinfection or secondary

* Corresponding author. 386, Ta-Chung 1st Rd., Kaohsiung 813, Taiwan. Fax: þ886 -7 -3468292.
E-mail address: ssjlee@gmail.com (S.S.-J. Lee).

https://doi.org/10.1016/j.jmii.2022.09.006
1684-1182/Copyright ª 2022, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 H.-Y. Wu, P.-H. Chang, K.-Y. Chen et al.

infection have a higher in-hospital mortality and longer length of stay, timely and appropriate
antibiotic use aided by accurate diagnosis is crucial to improve patient outcome and prevent
antimicrobial resistance.
Copyright ª 2022, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction symptoms, diagnostic measures, treatment and outcome of

COVID-19 associated bacterial infections.
In December 2019, a novel coronavirus, SARS-CoV-2,
emerged to cause a pandemic that rapidly spread to Incidence of bacterial coinfections
cause nearly 500 billion infections and more than 6 million
deaths, by the end of March, 2022. The World Health Or-
COVID-19 patients with coinfections or secondary infections
ganization (WHO) declared Coronavirus disease 2019
have poor outcomes, and are associated with a higher in-
(COVID-19) outbreak as a Public Health Emergency of In-
hospital mortality rate, higher rate of ventilation use and
ternational Concern (PHEIC) on Jan 30, 2020. In severe
longer hospital stay.7e10 The definition of COVID-19 asso-
cases of COVID-19, viral pneumonia occurs and a hyper-
ciated bacterial coinfections and secondary infections
inflammatory syndrome or “cytokine storm” resembling
varied across different studies. Most studies defined a
bacterial sepsis, with multiorgan failure and elevated in-
bacterial coinfection to occur within 48 h of admission and
flammatory biomarkers may develop.1,2 Bacterial coin-
infections after 48 h of admission as secondary
fections and superinfections may further increase
infections,10e12 while other studies used a cut-off of 72 h
mortality, leading to empiric and frequently inappropriate
after admission.13,14 The incidence rate is influenced by the
antimicrobial use and increased antimicrobial resistance.
different diagnostic procedures and specimen types used in
Coinfections with bacteria occurs during other viral in-
the studies, as well as a seasonal factor. Common sites of
fections, such as influenza, respiratory syncytial virus
infection and pathogens were listed in Table 1. The studies
(RSV), severe acute respiratory syndrome (SARS) and Middle
included were mostly from the COVID-19 pandemics of
East respiratory syndrome (MERS). The incidence rate of
alpha- and delta-variants. As the omicron-variant was only
bacterial coinfections in patients with influenza ranged
first identified in November, 2021, currently, none of the
from 2% to 65%, with Streptococcus pneumoniae and
studies specifically focused on the epidemiology of COVID-
Staphylococcus aureus accounting for 35% and 28% respec-
19 associated bacterial coinfection in omicron-variants.
tively.3 Bacterial/fungal coinfection rates in SARS ranged
from 1% to 43%, with S. pneumoniae and Staphylococcus
spp. being most commonly reported at admission.4 How- Community-acquired bacterial infection
ever, rates of bacterial coinfection in critically ill patients
with MERS varied from 1% (5/349) to 19%.4e6 During the first Incidence rate of community-acquired bacterial coin-
wave of COVID-19 pandemic, empiric antibacterial agents fections among hospitalized COVID-19 patients, defined as
were prescribed in 56e90% of patients due to previous occurring within 48 h of admission with positive microbi-
experience of bacterial coinfections occurring in other ology results, is very low; ranging from 2.5% to
respiratory viral pneumonia, uncertainty concerning the 5.1%.10,11,14e17 Bacterial coinfection rates reported in
novel coronavirus, severity in critically ill patients and outpatient populations are as low as 1%. However, the
difficulty in establishing or excluding a diagnosis of bacte- incidence rate can be underestimated when the diagnosis is
rial coinfection clinically. The objective of this study was to based on positive microbiology results. Most of the studies
review current literature on the incidence, pathogenesis, were retrospective and not all patients within the study had

Table 1 Common sites of infection and associated pathogens in COVID-19 associated bacterial infections (CABI).
Site of infection Common pathogens
Community-acquired bacterial infections
Urinary tract infection15,19 E. coli, K. pneumoniae
Respiratory tract infection15 S. pneumoniae, H. influenzae, S. aureus
Skin and soft tissue infection13,15
Secondary bacterial infections
Bloodstream infection25,28 Coagulase-negative Staphylococcus spp., Enterococcus spp.
Ventilator associated pneumonia28,30,31 Pseudomonas aeruginosa, MRSA, Enterobacter spp.
and Klebsiella spp.

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 Journal of Microbiology, Immunology and Infection 55 (2022) 985e992

specimens collected for conventional cultures. In addition, p Z 0.02),28 diabetes mellitus, and use of corticosteroid or
empirical antibiotics were often used before specimen tocilizumab.8,9,18,28,29 According to a retrospective study in
collection which may further lower the yield rates of the United States including 64,691 patients, early steroid
microbiological cultures. One retrospective cohort study and tocilizumab use were associated with an increased risk
including 64,691 patients reported a bacterial coinfection of bacterial secondary infection with incidence rates of
rate of 18.5% when the diagnosis was made by clinical 5.7% and 9.9% respectively.18
judgement.18 Bacteremia, ventilator-associated pneumonia (VAP),
The most common clinical syndromes of bacterial coin- hospital-acquired pneumonia/tracheobronchitis were the
fections were genitourinary tract infections, which most common clinical syndromes of superinfection and
accounted for 57%e70% of all infection sites,15,19 followed pathogens were similar to those found in patients without
by 19% respiratory tract infections15; skin and soft tissue COVID-19. Median time to the first secondary infection from
infection and bacteremia in 1%.13,15 Klebsiella spp., hospital admission was 12 days (IQR 8.5e16.5 days) and
Escherichia coli, Haemophilus influenzae, S. pneumoniae median time to the first secondary lower respiratory tract
and S. aureus were the most commonly isolated pathogens infection after hospital admission was 16 days (IQR 10e29
in patients with community-acquired bacterial days).25
coinfections.7,10 The most common pathogens found in bloodstream in-
Risk factors for bacterial coinfections in COVID-19 pa- fections were Coagulase-negative Staphylococcus spp.,
tients included older age of greater than 72 years old, Enterococcus faecium and Enterococcus faecalis.25,28
chronic kidney disease and admission from a skilled nursing Coagulase-negative staphylococci are common skin colo-
facility. Older age with a median of 72.6 years old in nizers, and was defined as true infections only if two or
confirmed CABI group versus 64.5 years old in those without more positive cultures along with clinical signs suggesting
CABI was found in one study (rate ratio 1.3, 95% CI bloodstream infection. Pseudomonas aeruginosa (38%),
1.08e1.57, P Z 0.06).14 A skilled nursing facility was methicillin-resistance S. aureus (MRSA) (24%), Enterobacter
defined as one which provided high level of medical care by spp. (18.8%) and Klebsiella spp. were the most frequently
or under the direct supervision of licensed health pro- isolated pathogens from respiratory tract specimens in
fessionals.14,20 Severe and critically ill patients had a patients with VAP.28,30,31
4.42-fold (95% CI: 1.63e11.9) higher risk for bacterial co- One review article including 621 patients from 75 studies
infection at admission.21 A higher proportion of patients focusing on postmortem autopsy found that 32% had po-
with bacterial infections received treatment with systemic tential lung superinfections. Pneumonia accounted for 95%
steroids (AOR 4.60; 95% CI: 1.24e17.05) compared to those of the cases while 3.5% were lung abscesses or empyema
without bacterial infections. and 1.5% had septic emboli. The most frequent pathogens
The diagnosis of atypical pneumonia in patients with were Acinetobacter baumannii, S. aureus, P. aeruginosa
COVID-19 is difficult due to similar clinical manifestations, and Klebsiella pneumoniae.32
and diagnosis require serology testing for Mycoplasma
pneumoniae, Chlamydia pneumoniae and/or Legionella
pneumoniae. One retrospective study in Europe including Pathogenesis
443 COVID-19 patients found that at admission, 26% of the
patients tested positive for Mycoplasma IgM, 18% of the SARS-CoV-2 infect humans through binding to the ACE2 re-
patients positive for Chlamydia IgM, but none had positive ceptors. The exact mechanism of how SARS-CoV-2 virus
results for Legionella urinary antigen test.20 Patients who contribute to the pathogenesis of bacterial secondary
had positive antibody tests were associated with more se- infection is unknown. SARS-CoV-2 has demonstrated rapid
vere clinical features, higher white blood cell counts, lower evolution with emergence of variants of concern that differ
lymphocyte counts and a higher oxygen demand. A wide in pathogenesis, transmissibility and severity. The current
variation in positivity rate of Mycoplasma IgM, ranging from dominant variant worldwide, the omicron-variant, has
0% to 56.4%, were reported in COVID-19 patients.10,20,22e24 shown to have high transmissibility but low severity, and
However, the results should be interpreted carefully, as to milder pathological changes in the upper and lower respi-
whether the high incidence rate of positive Mycoplasma IgM ratory tract of omicron infected hamsters compared to
serology is the consequence of true coinfection or due to those caused by previous variants.33 These features may
cross-reactivity of antibodies during SARS-CoV-2 infection. potentially affect the pathogenesis of bacterial coinfec-
tion. The area of pathogenesis of bacterial coinfection in
COVID-19 in different variants of concern requires further
Secondary bacterial infection research. However, how other respiratory viruses such as
influenza, parainfluenza and RSV may cause secondary
Secondary infections appear to be more common than bacterial infections is well studied and may provide a clue
community acquired infections in COVID-19 patients with to the possible co-pathogenesis in SARS-CoV-2 infections.
an incidence rate of 3.7% in all hospitalized patients, and During acute infection, respiratory viruses damage the
up to 41.9% in patients admitted to the intensive care units human’s respiratory tract, and not only breakdown its
(ICU).7,9,17,25e30 Risk factors included age greater than 60 integrity but also affect its physiological function. Virus can
years old, receiving mechanical ventilation, urinary cathe- facilitate bacterial adhesion to respiratory epithelial cells
terization, arteriovenous catheterization, having a higher which may increase bacterial colonization and contribute
APACHE II score (15 points vs 13 points in those with and to secondary infections. The disease severity varies be-
without nosocomial infections in the ICU, respectively, tween different viruses and bacteria.34,35 Studies using an

987
 H.-Y. Wu, P.-H. Chang, K.-Y. Chen et al.

influenza murine model showed that both viral and bacte- admission. A thorough history taking to include extrap-
rial titers were increased in the lungs during coinfections ulmonary symptoms, and focused physical examination
compared with single infections, through a synergistic type along with laboratory tests, can be a guide for physician to
I interferon response. This response also results in suggest a diagnosis of bacterial coinfection and use anti-
increased susceptibility to invasive infections causing high biotic appropriately.
mortality.35
Viral infections impair both the innate and adaptive
immune response. An animal study on the pathogenesis of Diagnosis
how influenza infection facilitates bacterial superinfection
revealed significant impairment of the early alveolar COVID-19 associated bacterial infections can be difficult to
macrophage mediated bacterial clearance in influenza- diagnose owing to similar clinical presentations to patients
infected mice.35 Cytokines and chemokines released by without coinfection and lack of microbiologic testing in
alveolar macrophages, which is required for recruitment COVID-19 patients. Reduced microbiologic testing may be
and activation of neutrophils, were also decreased during due to concerns with transmission of SARS-CoV-2 during
influenza infection.36 It has been demonstrated that SARS- procedures to obtain respiratory tract specimens and the
CoV, which causes SARS, regulate immune function- acute service pressure during the pandemic.21 As a conse-
related gene expression in human monocytes and also quence, syndromic diagnostic testing and biomarkers were
suppress type I interferon (IFN) production by impeding the widely used, in addition to conventional cultures, for the
formation of functional TRAF3-containing complex resulting diagnosis of bacterial coinfections during the COVID-19
in secondary bacterial infection.37 Further research on the pandemic. Comparison of different diagnostic methods
molecular pathogenesis of COVID-19 associated secondary are listed in Table 2.
bacterial coinfection is essential for the development of
future diagnostic and therapeutic strategies.
Conventional cultures

Clinical manifestations Conventional cultures remain the diagnostic gold standard

not only for identifying the causative pathogen but also for
The symptoms of COVID-19 associated bacterial coin- antibiotic susceptibility testing. However, bacterial coin-
fections and secondary infections are very similar to those fections can be underestimated if conventional culture is
in patients without COVID-19 infection. For example, be- the only measure for diagnosis. Only 40.8%e73% of hospi-
sides fever, patients with urinary tract infection often talized COVID-19 patients had blood cultures
present with urgency, frequency, dysuria and flank pain. collected10,25,38 and about 15e20% had respiratory tract
Patients with lower respiratory tract coinfections and sec- specimens obtained. Sputum and tracheal aspirates were
ondary infections had symptoms including fever, cough with the most common respiratory specimens sent for culture in
or without sputum production and dyspnea.32 Differenti- non-ventilated and ventilated patient, respectively, fol-
ating between respiratory symptoms caused by COVID-19 lowed by bronchoalveolar lavage.10
with and without bacterial coinfection is a challenge. This Another concern is the difficulty in differentiating a true
resulted in over-prescription of empirical antibiotics in infection from colonization, which may lead to over-
patients presented with only respiratory manifestations. diagnosis of bacterial infections. An increased prevalence
However, bacterial coinfections in sites other than the of fungal and P. aeruginosa colonization in severe COVID-19
lungs accounts for the majority of the patients upon patients compared to non-COVID-19 cases were reported.39

Table 2 Comparison of different diagnostic methods used in COVID-19 associated bacterial infections (CABI).
Methods Advantage Disadvantage
Conventional cultures - Able to identify causative pathogen - Need to differentiate colonization
and determine antibiotic from infection
susceptibility
Syndromic - Short turnaround time - Need to differentiate colonization
diagnostic testing - Can identify some fastidious micro- from infection
organisms and common resistance - High cost
target genes
Procalcitonin - Can be used to guide discontinua- - Low specificity in COVID-19 patients
tion of antibiotics under adequate
infection source control
Serology testing - Can be used to aid diagnosis of - Cross-reactivity of antibodies during
atypical bacterial pneumonia with SARS-CoV-2 infection should be
compatible clinical presentation considered
- Pneumococcal and Legionella uri-
nary Ag for rapid diagnosis

988
 Journal of Microbiology, Immunology and Infection 55 (2022) 985e992

Thus, when making a diagnosis, clinical symptoms, under- In hospitalized patients, PCT had a sensitivity of 91% and
lying diseases, risk factors and disease severity should also a specificity of 81% for the detection of secondary bacterial
be taken into consideration. infections with a cut-off value of 0.55 ng/mL. Meanwhile,
CRP has a lower sensitivity and specificity of 81% and 76%
Syndromic diagnostic testing respectively.49 In patients admitted to ICU, a PCT level
above 1 ng/mL ruled in secondary bacterial infection with a
PPV of 93%, whereas PCT level below 0.25 ng/mL ruled out
Syndromic diagnostic testing is an alternative method for
secondary bacterial infection with a NPV of 81%.45 As CRP
detection of coinfection and can reduce approximately 1
often rises in the initial stage of COVID-19, it does not have
day in turnaround time compared with conventional cul-
a predictive value for the diagnosis of bacterial coinfection
tures. The panel can also detect some fastidious microor-
at admission and during ICU stay, serial PCT may have a role
ganisms and common resistance target genes within one
to rule out nosocomial bacterial infections and to guide
day. There are several studies40e42 on the accuracy of
antimicrobial stewardship.45
multiplex PCR compared with conventional cultures in
critically ill COVID-19 patients using lower respiratory tract
specimens. The results showed a sensitivity rate ranging Serology testing
from 89.3% to 100% and the specificity rate from 88.4% to
100% depending on the pathogen40; and a positive predic- Serology testing has been widely used to diagnose atypical
tive value (PPV) of about 60% and negative predictive value bacterial pneumonia, including Mycoplasma IgG, IgM,
exceeding 99%.41,42 Chlamydia IgG, IgM and Legionella urinary antigen. The
Another prospective cohort study including 200 COVID- sensitivity of serologic tests depends on the time point of
19 patients conducted in Germany and Switzerland found the serum sample and on the availability of paired serum
that 43% of the patients with a positive result of collected 2-4 weeks later. Pneumonia caused by S. pneu-
community-acquired bacterial pathogens (CABP) were moniae can also diagnosed with urine pneumococcal anti-
detected at admission.43 The specimens were collected via gen, sensitivity and specificity were 60% and 99.7%
the nasopharyngeal swab and the most frequently isolated respectively.50 Mycoplasma IgM positive rates in hospital-
pathogens were S. aureus (27%) and H. influenzae (13.5%). ized COVID-19 patients ranged from 0% up to 56.4% and
A positive CABP was not correlated with ICU admission, most studies report M. pneumoniae coinfection rate in the
mortality and inflammatory markers. range of 1.5%e3.5%.10,24 The incidence of Mycoplasma
In conclusion, based on the excellent sensitivity, syn- pneumonia may be overestimated when based on serology
dromic diagnostic testing may be useful to rule out testing only, since these studies were retrospectively
bacterial coinfections and to avoid antibiotic over- reviewed and Mycoplasma IgM was tested only one time.
prescription, but routine screening with nasopharyngeal
specimen at admission may result in a high detection rate Treatment
of bacteria that represent colonization only and is not
recommended.
During the first wave of COVID-19, most of the hospitalized
patients were prescribed at least one antibiotic, despite a
Role on biomarkers low incidence rate of community-acquired bacterial coin-
fections. One systemic review including 24 studies and 3506
Procalcitonin (PCT) and C-reactive protein (CRP) are two patients demonstrated that 71.8% (95%CI: 56.1%e87.7%) of
biomarkers frequently tested in patients with infectious the patients received an antibiotic at some time during
diseases. PCT is a peptide precursor of calcitonin which is admission while only 3.5% of the patient were diagnosed
released in response to pro-inflammatory stimuli, espe- with community-acquired bacterial infection and 14.3% had
cially bacterial infections, and has been useful as a diag- hospital-acquired bacterial infection.16 Quinolones and the
nostic indicator to discriminate between bacterial and viral 3rd generation cephalosporins were the most commonly
infections. According to the recommendation of 2021 Sur- prescribed, comprising of up to 74% of antibiotics used.16
viving Sepsis Campaign, PCT has limited role in initiation of The pooled prevalence of co-infection with resistant bac-
antimicrobials but can be used to guide antibiotic discon- teria was 24% (95% CI 8e40%; n Z 25 studies: I2 Z 99%).
tinuation under adequate infection source control.44 CRP is Among multi-drug resistant organisms, methicillin-resistant
an acute phase reactant produced during an inflammation S. aureus, carbapenem-resistant A. baumannii, K. pneu-
process but according to previous research, it is nonspecific moniae, and P. aeruginosa were most commonly re-
in diagnosing bacterial infection. ported.51 The COVID-19 pandemic has fueled the
COVID-19 patients without bacterial coinfections can antimicrobial resistance (AMR) global crisis due to the in-
present with high CRP levels and a low to moderate PCT crease in the empiric use of antibiotics, disruptions to
levels initially.45,46 In a study including 5700 COVID-19 infection prevention and control practices in overwhelmed
hospitalized patients in New York, the average PCT level health systems, and diversion of human and financial re-
was 0.2 ng/mL at admission.47 However, a rise in PCT level sources away from antibiotic stewardship and AMR pro-
is associated with disease severity in COVID-19 patients, grams. Studies evaluating the impact of COVID-19 pandemic
and may also indicate bacterial coinfection. One meta- on antimicrobial resistance showed that the rate of A.
analysis showed that increased PCT values with a cutoff > baumannii and K. pneumoniae resistance to carbapenems
0.5 ng/mL was associated with a nearly 5-fold higher risk of significantly increased in 2020 compared with isolates in the
severe SARS-CoV-2 infection.48 pre-COVID-19 era; in addition, a significant increase in

989
 H.-Y. Wu, P.-H. Chang, K.-Y. Chen et al.

resistance to polymyxin B, particularly for K. pneumoniae secondary infection and timely initiation of appropriate
isolates, with a rate increase from 5% to 50%, was antibiotics is crucial to improve survival.
observed.52,53 Antimicrobial resistance kills an estimated
700,000 people every year, in view of this, both the WHO Conclusions
guidelines and 2021 NICE guideline recommend not to give
antibiotic therapy or prophylaxis for patients with mild or COVID-19 associated bacterial coinfections are rare during
moderate COVID-19, unless signs and symptoms of a bac- the pandemic, and most of the published guidelines
terial infection exist. recommend against routine antibiotic use. The most com-
Genitourinary tract infection accounts for 57%e70% of mon sites of bacterial coinfections at admission include the
community-acquired bacterial infections in hospitalized genitourinary tract, followed by the lower respiratory
COVID-19 patients15,19 and the most common pathogen is E. tract. Bloodstream infection and ventilator-associated
coli and Klebsiella spp. Empiric antibiotics should target E. pneumonia comprise the majority of secondary infections.
coli and Klebsiella spp. and tailored to the local resistance Studies included were mostly from during the COVID-19
patterns when bacterial coinfections of genitourinary tract pandemics with the alpha- and delta-variants. The
is highly suspected. Bacterial pneumonia is the second most omicron-variant was first identified in November, 2021. To
common community-acquired coinfection in COVID-19 date, none of the studies specifically addressed the
patients, most frequently caused by H. influenzae, S. epidemiology of COVID-19 associated bacterial coinfection
pneumoniae or S. aureus, and often treated with either a in omicron-variants, and further research is required.
third-generation cephalosporin, such as ceftriaxone, or Conventional culture remains the most important diag-
fluoroquinolones. Rationale for the choice of antibiotics nostic measure but syndromic testing and biomarkers can
includes: first, ceftriaxone and fluoroquinolones are active be a useful tool for antibiotic stewardship to guide de-
against most community-acquired pathogens, and fluo- escalation and discontinuation of unnecessary antibiotics.
roquinolones against pathogens of atypical pneumonia. Syndromic diagnostic testing has a high sensitivity for
Second, once daily dosing is more convenient and can diagnosing bacterial coinfections, and can be used to
reduce the frequency of patient contact with healthcare exclude bacterial coinfection; nevertheless, routine
personnel. Fluoroquinolones are associated with QTc pro- screening for “nasopharyngeal” specimens is not recom-
longation and should be used with caution. mended as it may only lead to detection of colonized
Empirical antibiotic for secondary bacterial infections pathogens. Serology testing is important for identifying the
should target common pathogens caused by the most presence of atypical pneumonia; however, results vary
frequent clinical syndromes associated with COVID-19, widely across studies, and the true incidence of atypical
including bacteremia, ventilator-associated pneumonia pneumonia among COVID-19 patients requires further study.
(VAP), and hospital-acquired pneumonia/tracheo- Higher in-hospital mortality rates are seen in COVID-19
bronchitis. Choice of antibiotic should be tailored to the patients with bacterial coinfection and secondary infec-
local resistance patterns. Coagulase-negative Staphylo- tion. However, due to the low incidence of coinfection,
coccus spp. and E. faecium were the most frequently iso- empiric antibiotic with a 3rd generation cephalosporin or
lated organism from bloodstream infections while P. fluoroquinolones to cover commonly encountered
aeruginosa and MRSA were major pathogens of VAP. community-acquired pathogens is recommended only if a
Obtaining cultures of the blood, urine, sputum and a uri- bacterial coinfection is highly suspected. Antibiotics
nary antigen serological test prior to initiating antibiotics is treatment for secondary infections should be tailored to
important if bacterial coinfection or secondary infection is local epidemiology and resistance patterns. Continuing
suspected to allow de-escalation and specific antimicrobial antimicrobial stewardship during the COVID-19 pandemic is
treatment, to reduce AMR. The necessity of antibiotic use crucial to prevent antimicrobial resistance.
should be assessed daily.
Declaration of competing interest
Outcome
All authors report no conflicts of interest.
Bacterial coinfections or secondary infections in COVID-19
patients are associated with a poor prognosis. Overall Acknowledgement
mortality in patients hospitalized for more than 48 h was
9.8% in a cohort of 989 patients with either coinfection or We thank the Guidelines Recommendations for Evidence-
secondary infection.11 A study including 1,565 patients, based Antimicrobial use in Taiwan (GREAT) working group
with 3.7% having at least one episode of hospital-acquired for performing part of the literature search for review.
infection, demonstrated a significantly higher in-hospital This study received grants from the Medical Foundation
mortality rate in patients with secondary infections in memory of Dr Deh-Lin Cheng, Kaohsiung, Taiwan and
compared with those without (40.7% and 11.8%, Veterans Affairs Council, Republic of China (VAC111-005).
p < 0.001).9 Another retrospective, observational study of
254 critically ill patients also demonstrated that those with References
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