Biotechnology and Genetic Engineering Reviews

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Bacterial co-infections and antimicrobial

resistance associated with the Coronavirus
Disease 2019 infection

Addisu D. Teklemariam, Anwar M. Hashem, Saber H. Saber, Mohammed S.

Almuhayawi, Shafiul Haque, Turki S. Abujamel & Steve Harakeh

To cite this article: Addisu D. Teklemariam, Anwar M. Hashem, Saber H. Saber, Mohammed
S. Almuhayawi, Shafiul Haque, Turki S. Abujamel & Steve Harakeh (2022): Bacterial co-
infections and antimicrobial resistance associated with the Coronavirus Disease 2019 infection,
Biotechnology and Genetic Engineering Reviews, DOI: 10.1080/02648725.2022.2122297

To link to this article: https://doi.org/10.1080/02648725.2022.2122297

Published online: 19 Sep 2022.

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BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS
https://doi.org/10.1080/02648725.2022.2122297

REVIEW ARTICLE

Bacterial co-infections and antimicrobial resistance

associated with the Coronavirus Disease 2019 infection
Addisu D. Teklemariama, Anwar M. Hashemb,c, Saber H. Saberd,
Mohammed S. Almuhayawib, Shafiul Haquee, Turki S. Abujamelc,f
and Steve Harakeh g,h
a
Department of Biology, Faculty of sciences, King Abdulaziz University, Jeddah, Saudi Arabia;
b
Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz
University, Jeddah, Saudi Arabia; cVaccines and immunotherapy Unit, King Fahd Medical Research
Center, King Abdulaziz University, Jeddah, Saudi Arabia; dMolecular Cell Biology Laboratory,
Department of Zoology, Faculty of Science, Assiut University, Asyut, Egypt; eResearch and Scientific
Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia;
f
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz
University, Jeddah, Saudi Arabia; gKing Fahd Medical Research Center, King Abdulaziz University,
Jeddah, Saudi Arabia; hFaculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

ABSTRACT ARTICLE HISTORY

Bacterial co-infections are typically associated with viral Received 18 June 2022
respiratory tract infections and pose a significant public Accepted 3 August 2022
health problem around the world. COVID-19 infection KEYWORDS
damages tissues lining the respiratory track and regulates Bacteria; co-infection;
immune cells/cytokines leading to microbiome dysbiosis COVID-19; patients; SARS-
and facilitating the area to be colonized by pathogenic bac­ CoV-2
terial agents. There have been reports of different types of
bacterial co-infection in COVID-19 patients. Some of these
reports showed despite geographical differences and differ­
ences in hospital settings, bacterial co-infections are a major
cause of morbidity and mortality in COVID-19 patients. The
inappropriate use of antibiotics for bacterial infections, parti­
cularly broad-spectrum antibiotics, can also further compli­
cate the infection process, often leading to multi drug
resistance, clinical deterioration, poor prognosis, and even­
tually death. To this end, researchers must establish a new
therapeutic approach to control SARS-CoV-2 and the asso­
ciated microbial coinfections. Hence, the aim of this review is
to highlight the bacterial co-infection that has been recorded
in COVID-19 patients and the status of antimicrobial resis­
tance associated with the dual infections.

1. Introduction
The novel Coronavirus 2019 (COVID-19) is an acute respiratory disease
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
a novel virus that belongs to the Coronaviridae family (Kumar et al., 2021).

CONTACT Steve Harakeh sharakeh@gmail.com King Fahd Medical Research Center, King Abdulaziz
University, Jeddah, Saudi Arabia
© 2022 Informa UK Limited, trading as Taylor & Francis Group
2 A. D. TEKLEMARIAM ET AL.

In December 2019, the first case of this disease was reported in Wuhan,
China, and it spread around the world (Kumar et al., 2021). On
22 March 2020, the World Health Organization (WHO) declared the disease
a pandemic (Kumar et al., 2021). Inhaled or splashed droplets from infected
patients transmit SARS-CoV-2. The incubation period for this disease
ranges from 2 to 14 days. A higher spread rate has been observed for SARS-
CoV-2 than that of the Middle East coronavirus and the severe acute
respiratory syndrome coronavirus (Sharma et al., 2020).
As of 3rd June 2022, there have been 528, 816, 317 Covid-19 cases with 6,
294, 969 confirmed deaths reported all over the globe (WHO, 2022). Several
variants of SARS-CoV-2 have been reported in different countries at differ­
ent periods (Aleem et al., 2022). These variants are designated with Greek
alphabet as Alpha (first reported in UK, late 2020), Beta (first reported in
South Africa, late 2020), Gamma (first reported in Japan, December 2020),
Delta (first reported in India, December 2020), Omicron (first reported in
Botswana, and then southern Africa, November 2021) (Aleem et al., 2022).
All of these variants showed different level of transmissibility and respon­
sible for varied degree of infections (Aleem et al., 2022).
In response to the pandemic, researchers raced to develop a vaccine to
create herd immunity and reduce the damages caused by the virus. In this
regard, WHO has launched the Pfizer COVID-19 vaccine (BNT162b2) for
emergency use as of 31st December 2020. Afterwards, Oxford’s/AstraZeneca
vaccine was produced by the SKBio and Serum Institute India on 15th
February 2021, followed by Janssen (Johnson & Johnson) (Ad26COV2S),
on 12 March 2021, and on 30 April 2021 Moderna’s vaccine have been
released (WHO, 2021). These vaccines were produced using two main
platforms (mRNA and adenoviruses) and showed varied levels of efficacy
(protection) across the globe (WHO, 2021). Currently, a total of 11, 947,
644, 522 vaccine doses have been administered (WHO, 2022).
During early COVID-19 pandemic, researchers propose three potential
circumstances of bacterial/SARS-CoV-2 co-infection; namely, secondary
SARS-CoV-2 infection following bacterial infection or colonization, sec­
ondary bacterial superinfection following SARS-CoV-2 or combined viral/
bacterial pneumonia (Feldman & Anderson, 2021). Bacterial co-infections
are the main agent which complicate the respiratory infection, often result­
ing in clinical deterioration (Feldman & Anderson, 2021). This scenario is
studied in the previous seasonal flu pandemics as well as other respiratory
infections that were caused huge public health burden in the globe
(Vaillancourt & Jorth, 2020). The replication of viral particles in the respira­
tory tract may lead to the distraction of the respiratory tract (RT) epithelium
and its innate barrier function, are recognized to promote the colonization
of foreign bacteria and cause the disease (Nirwati et al., 2019; Vaillancourt &
Jorth, 2020).
 BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 3

Bacterial co-infection has been reported to occur in COVID-19 patients

(Chen et al., 2020a; Fattorini et al., 2020; Rawson et al., 2020). The presence
of bacteria in COVID-19 patients is a distressing problem as it complicates
the treatment process and may lead to poor prognosis and rise the like­
lihood of fatality (Chen et al., 2020a). In addition, wrong prescription of
antibiotics particularly broad-spectrum antibiotics to bacterial infection
may lead to development of antimicrobial resistance in the clinics
(Rawson et al., 2020).
The prevalence rate of bacterial co-infection in patients with COVID-19
varied with depending on the geographic location and the hospital settings
where the disease occurred (Westblade et al., 2021). According to the retro­
spective observational studies in Barcelona and New York, relatively low pre­
valence of (7.2% (72/989)) (Garcia-Vidal et al., 2021), and 3.6% (152/4267)
(Nori et al., 2021) of bacterial co-infection was reported in COVID19 patients,
respectively. Similar study was conducted in French indicated that 28% (26/92)
of severely ill COVID-19 patients were co-infected with clinically relevant
bacteria in the intensive care units (ICUs) (Contou et al., 2020). Similarly, in
a study by Bazaid et al. (2022) the prevalence of bacterial coinfection in the non-
ICU patient was lower (53%) than ICU (74%) (Bazaid et al., 2022). This could
be due to the frequent use of catheters in ICU patients, including arteriovenous,
endotracheal, and urinary tubes.
When we consider bacterial co-infection, a variety of bacterial strains
including extended spectrum β-lactamase-positive (ESBL) Klebsiella pneumo­
niae (K. pneumoniae), ESBL-positive Pseudomonas aeruginosa
(P. aeruginosa), and ESBL-negative Serratia marcescens, and others have
been commonly detected in patients with COVID-19 that are aggravating
the severity of the disease (Yang et al., 2020). In COVID-19 patients, intra­
cellular bacterial infections like mycoplasma are rarely investigated (Li et al.,
2020; Pisu et al., 2020). Mycoplasma pneumoniae (M. pneumoniae) has
recently been reported as a potential co-infection in COVID-19 disease as
published in 2020, in examined 138 patients with COVID-19 and found that
26.5% had Mycoplasma infections (Geng et al., 2020).
Numerous reports indicate that bacterial co-infection in COVID-19
patient has increased the use of antibiotics, which increases the risk of
developing multidrug-resistant (MDR) infections (Kariyawasam et al.,
2021; Patel et al., 2021; Polly et al., 2022). Despite efforts to reduce anti­
microbial resistance (AMR), the pathogens that cause resistant infections
continue to thrive in medical and hospital facilities, exposing patients at risk
regardless of how severe their medical conditions are (Weiner-Lastinger
et al., 2020). In contrast to COVID-19, AMR has not received the same level
of global attention. Hence, understanding the prevalence bacterial infection
in association with COVID-19 patients, and the causative agents including
their level of antimicrobial resistance, is essential for researchers to establish
4 A. D. TEKLEMARIAM ET AL.

a new therapeutic approach to control SARS-CoV-2 infection. Hence, the

aim of this review is to highlight the bacterial co-infection that has been
recorded in the era of COVID-19 pandemics and the status of AMR
associated with the co-infections.

2. Synergy between bacteria and respiratory viruses

While some preliminary data have been published, it’s still unclear whether
there’s a similar synergy between bacteria and SARS-CoV-2 infections as
there is in the case of the influenza virus (Zhou et al., 2021). It has been
recognized that the innate immune system may be affected by the viral
infection of the respiratory tract (RT) where the macrophages found in the
infected pulmonary tissue become stunned by apoptotic tissue and conse­
quently become inefficient in clearing bacterial cells from the system
(Ahmed-Hassan et al., 2020). Moreover, macrophages and dendritic cells
have lessened antigen-presenting capacity subsequent to viral and bacterial
infections, which is associated with the cytokine transforming growth factor
beta (TGF-β) and immunosuppressive microenvironment involving
T (Treg) cells (Roquilly et al., 2017). It has also been recognized that the
RT microbiome modified by the initial immune system resulted due to the
viral lung infection, which lead to weaken immune response towards bac­
terial and associated viral infections (Hanada et al., 2018). Additional
mechanisms such as mucus thickening and injured epithelial cells could
be occur following viral infection which distract the mucocilliary clearance
and weakening the movement of immune cells, respectively (Manohar et al.,
2020). In the case of SARS-CoV-2 infection, pus and/or fluid filled pulmon­
ary alveoli can serve as a conducive habitat for clinically relevant bacteria,
such as S. aureus and P. aeruginosa (Manohar et al., 2020). In such kind of
synergy, physicians administered antibiotics which would be useful or may
not be beneficial as it was reported (Magagnoli et al., 2020).
The outcome of viral infections can be significantly influenced by bacterial
co-infections, particularly in cases of severe illness, which result in death
(Kiedrowski & Bomberger, 2018; Lansbury et al., 2020). In a study by
Brockmeier et al. SARS-CoV and Bordetella pertussis co-infections caused
severe lung lesions as it was recorded in the histopathological and gross
examination of the tissues taken from of the co-infected group and
a significant upregulation of the expressions of proinflammatory cytokines,
particularly MCP-1 and IL-6 (Brockmeier et al., 2008) were recorded which
implies there is a synergistic effect between these two pathogens. The level of
systemic inflammation can increase in response to co-infection, thereby
increasing the severity of the illness increased which delaying the recovery
period. In the COVID-19 patients, the level of proinflammatory cytokines
linked to severe injury of lung, particularly IL-6, has increased significantly
 BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 5

(Tang et al., 2020). In a study by Martins-Filho et al., (2020) the risk of death
from SARS-CoV-2 increased 2.5 fold when fungi and bacteria were co-infected
showing that there is a certain relationship between SARS-CoV-2 and bacterial
or fungal pathogens.
The interaction and the consequence of the bacterial co-infection asso­
ciated with Covid-19 infection is presented in Figure 1.

3. Factors predispose for bacterial co-infection

There are many factors which predispose the COVID-19 patient to bacterial
infections including intrinsic factor which are associated with the patients,
such as age of the patient, severity of illness, comorbid, such as metabolic and
chronic diseases (Nasir et al., 2021). There are also several other external
factors that can exert a significant influence on the overall outcomes of the
treatment, including the type of ward, the safety of the clinic, the number and
condition of patients as shown in Figure 2. The infection with SARS-CoV-2
can lead to the impairment of the body’s immune function due to damage to
lymphocytes, specifically, the T, B, and NK cells (Wang et al., 2020b). The co-
infection may be associated with the reduction of lymphocytes and the

Figure 1. Diagrammatic illustration showing the interaction and the consequence of the
bacterial co-infection associated with Covid-19 infection.
6 A. D. TEKLEMARIAM ET AL.

Figure 2. Major predisposing factors of bacterial co-infection in COVID-19 patients.

function of host immune system (Luo et al., 2019). In severe cases the
mortality rate is higher than the non-severe cases (Qin et al., 2020) and this
is partly associated with the higher co-infection rate in severely infected
patients. (Netea et al., 2020) reported that in most cases, SARS-CoV-2
infection is mild, however, co-infection can rise the vulnerability of patients
to severe illness by affecting the body’s immune system. Patients admitted to
hospital for different infections can acquired both COVID-19 and bacterial
infections from hospital environment simultaneously. Similarly, in case of the
severely ill cases, they are usually obtain therapeutic agents with catheters,
resulting in increased sensitivity to co-infections especially MDR pathogens,
such as Escherichia coli (E. coli), Acinetobacter baumannii (A. baumannii),
Enterococcus spp. and P. aeruginosa (Rawson et al., 2020).

4. Reports on COVID-19 patients with bacterial co-infections

Recent research findings indicated that bacterium such as P. aeruginosa,
M. pneumonia and Haemophilus influenza (H. influenza) are the most fre­
quently isolated strains from Broncho alveolar lavage and/or sputum of the
COVID-19 patients (Lansbury et al., 2020). On the contrary, bacterial
 BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 7

pathogens, such as S. aureus, Streptococcus pneumoniae (S. pneumoniae) and

Streptococcus pyogenes were isolated from the co-infected patients with influ­
enza (Lansbury et al., 2020). Currently, (Gu et al., 2020) reported the diversity
of bacteria in the intestinal system is significantly reduced in COVID-19
patients, while the abundance of bacterium such as Rothia, Veillonella,
Actinomyces and Streptococcus are considerably higher (Table 1). On the
contrary, relative abundance of other intestinal flora such as Romboutsia,
Blautia, Bifidobacterium, and Collinsella, is lower. A comparative study con­
ducted by Shafran et al. indicated that in comparison to the influenza patients,
the COVID-19 patients had higher rates of bacterial infections with the rate of
8.7% vs 12.6%, respectively. Remarkably, the time elapse between the admis­
sion of the patient to the first clinical symptom was shorter in influenza (1–3
days) patient than in COVID-19 (1–8 days) (Shafran et al., 2021). In this study,
the late bacterial infection that has been caused by Gram positive bacteria (>48
h after admission) were less common in influenza patients than the COVID-19
patients (9.5% vs 28%). According to their report, bacterial co-infection was
linked to a higher risk of death in both cases, where it was 3.09-fold and
2.7-fold for Influenza and COVID 19 patients, respectively.
Researchers conducted a cross-sectional study at Nahavand Hospitals in
Iran to determine how many COVID-19 patients had experienced bacterial
infection (Mahmoudi, 2020). The study found that nearly 43 (12.46%)
patients had been infected (Mahmoudi, 2020). Among the bacterial isolates,
Methicillin-sensitive Staphylococcus aureus (MSSA) 9 (20.93%) and E. coli 7
(16.28%) are the most prevalent bacterial isolates. The team also isolated
other bacterial pathogens including Enterobacter species, S. pneumonia and
P. aeruginosa. The antimicrobial sensitivity results of this study revealed that
Enterobacteriaceae isolates from COVID-19 patients had the highest resis­
tance to cefepime (42.5%), ceftazidime (47.5%), piperacillin (67.5%) and
cotrimoxazole (74%). A 100% susceptibility was recorded for all isolates
using amikacin. Similarly, 100% susceptibility of S. aureus isolates for
vancomycin were recorded, while 90% of P. aeruginosa isolates was suscep­
tible to imipenem (Mahmoudi, 2020). In France, Contou et al. (2020)
reported that 28% of bacterial co-infection occurred at ICU admitted
patients with severe SARSCoV-2 pneumonia, and the most common iso­
lates include: H. influenza, S. aureus, Enterobacteriaceae and S. pneumoniae
(Contou et al., 2020).

5. Co-infection associated MDR in COVID-19 era

AMR is a global health concern. By 2050, the number of people dying from
AMR will surpass 10 million, and its cost will reach 100 trillion dollars
(O’Neill, 2016). Microorganisms’ resistance towards clinically relevant anti­
biotics and associated losses varies from country to country. In the United
8 A. D. TEKLEMARIAM ET AL.

States, more than 35,000 people die from AMR infections each year
(Control & Prevention, 2019).
Even though antibiotics are unsuccessful in treating COVID-19, doctors
still prescribe them for a variety of reasons (Alhazzani et al., 2020). The
wrong administration of broad-spectrum antibiotics during the COVID-19
pandemics resulted in serious AMR development in the clinic, which
ultimately impacted management of AMR and antibiotic stewardship
(Alhazzani et al., 2020).
In past SARS-CoV outbreaks, Wi et al. found that patients with bacterial
co-infections were the chief spreaders of resistant bacteria in clinics, with
each individual possibly infecting 10 or more other individuals (Wilder-
Smith et al., 2004). Due to the overlapping nature of bacterial and viral
pneumonia, unnecessary antibiotics may be prescribed (Huttner et al.,
2020). Besides, the continuous use of clinically significant antibiotics in
combination with prolonged hospital stays in an overcrowded area has
also been reported to be a risk factor for hospital-acquired infections with
MDR organisms (Phua et al., 2020; Zhou et al., 2020). The rise in the
prevalence of AMR during the COVID-19 era were not limited to some of
the factors which are mentioned above, rather it is associated with several
factors which directly or indirectly contribute to the occurrence of MDR
infections (See Figure 3).
In a recent study conducted by Bazaid et al. (2022) A. baumannii and
K. pneumoniae were the most prevalent bacterial co-infection (56% each)
reported in one ICU center in Saudi Arabia with multiple resistance to all
tested antibiotics except colistin. Conversely, P. aeruginosa (15%) and E. coli
(31%) were the predominant infections reported in non-ICU patients with
higher resistance of E. coli to trimethoprim/sulfamethoxazole and pipera­
cillin/tazobactam. In a different study, Rifampicin resistant pulmonary
tuberculosis with COVID-19 was reported in a 26-year-old Indian female.
However, the clinical output of the disease was not clearly presented (Yadav
and Rawal, 2021). On top of these reports, the prevalence of MDR co-
infections in COVID-19 patients reported from different health-care centers
at different geographical locations. Some of these reports are fragmented
and reported from individual (local/regional) health sectors, which might
not be reflective of the prevalence of the country (Table 2).
Despite the rare occurrence of bacterial co-infections among COVID-19
patients at the time of hospital admission, many patients receive antibacter­
ial therapies, have prolonged hospital stays, and get infection while in the
hospital (ref). These situations have been led to resistance to several con­
ventional antibiotics including carbapenem, fluoroquinolones, macrolide,
and other antibiotics. A New York hospital reported 13 cases of carbapene­
mase-producing enterobacteria, including carbapenemase producing
K. pneumoniae (CPKP) and New Delhi metallo-β-lactamase (NDM)-
 BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 9

Figure 3. Bacterial co-infection as one factors linked with the rise of MDR in COVID-19 era.

producing Enterobacter cloacae, when the pandemic hit the city (Gomez-
Simmonds et al., 2021). Among the 13 patients, one was receiving ventila­
tion during the infection period, and five died. Multiple lineages were
identified by genomic sequencing, suggesting that there was no single strain
responsible for the outbreak. Five patients in another New York hospital
had recently acquired E. cloacae infections with NDM (Nori et al., 2020)),
but they did not have a history of recent international travel. Of the five, four
died of septic shock.
There has been an increase in patients with carbapenem-resistant
Acinetobacter baumannii (CRAB) in New Jersey during the COVID-19
surge (Perez et al., 2020). CRAB bacteria were identified in 34 patients,
none of whom had prior infections or colonizations, and most of these
patients were hospitalized from home and were mechanically ventilated
when the bacteria were detected (Perez et al., 2020). Twenty out of the
twenty CRAB-infected patients died (Perez et al., 2020). There were 26
isolates that harbored an OXA-23 carbapenemase, and three that were
NDM-positive (Perez et al., 2020). The outbreak was attributed to deviations
from typical infection control and prevention practices. Some of them
include reducing the frequency of changing catheters, face shields, and
ventilator circuits, ceasing contact precautions for certain MDR pathogens,
increasing staff-to-patient ratios, and involving inappropriate staff in ICUs
(Perez et al., 2020).
During the COVID-19 surges, a rise in Gram-negative carbapenem-
resistant bacterial infections has also been observed in European hospitals.
10 A. D. TEKLEMARIAM ET AL.

Table 1. Most common bacterial co-infections reported associated with COVID-19

Prevalence of
bacterial
Isolated bacterial strains co-infection Locations References
K. pneumoniae was the prevalent bacteria, followed 29% and 21% India Vijay et al.
by A. baumannii respectively (2021)
Acinetobacter baumannii and S. aureus 90 and 10% UK Sharifipour
respectively et al.
(2020)
NR 15% China Zhou et al.
(2020)
NR 7.7% Wuhan, China Zhang et al.
(2020b)
NR 11% Italy Huttner et al.
(2020)
A. baumannii and K. pneumoniae NR Wuhan China Chen et al.
(2020a)
M. pneumoniae and Chlamydia pneumoniae 8.8% India Chaudhry
et al.
(2021)
NR 44.7% France D’Humières
et al.
(2021)
S. aureus NR USA, Denton, Texas Singh et al.
(2021)
NR 0.8% Netherlands Karami et al.
(2021)
NR 2.7% Hong Kong (1 hospital) Cheng et al.
(2020)
NR 19.8% Paris, France Elabbadi et al.
(1 hospital) (2021)
NR 2.5% Barcelona, Spain Garcia-Vidal
(1 hospital) et al.
(2021)
S. aureus, S. parasanguinis, E. faecalis and NR North Middlesex Gil et al.
K. pneumoniae, E. coli, P. mirabilis, S. epidermidis University Hospital, (2021)
UK
NR 25% China Gil et al.
(2021)
NR 2% China (Hospital 99, Chen et al.
203) (2020b)
NR 4.8% USA Arentz et al.
(2020)
NR 20% China Hospital 20 Xia et al.
(children) (2020)
NR – not reported

A report released from one of the Italian hospitals indicated that 19%
positive CPKP cases were obtained using blood cultures collected from the
critically ill COVID patients (Arcari et al., 2021). Other hospitals of the same
country reported rises in the spread of CPKP that were attributed to related
factors comparable to CRAB outbreak, and to some of the health-care
personnel involved to handle hypoxic COVID-19 patients (Belvisi et al.,
2021; Tiri et al., 2020). A report released from one of the France hospitals
indicated that an outbreak of NDM-producing E. coli in an ICU associated
with COVID-19 patients that was attributed to a shortage of standard
personal protections and contact precautions, inexperienced ICU staff,
 BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 11

Table 2. Major reports of MDR co-infections in COVID-19 patients.

Prescribed antibiotics Prevalence
which showed of the
resistance Bacterial pathogens Locations Co-infection References
Moxifloxacin P. aeruginosa, Mycobacterium Wuhan, China 62% Pongpirul et al.
tuberculosis Clostridium difficile, (2020), Wang
Neisseria gonorrhoeae et al. (2020a)
Cefoxatime, ESBL-Producing Enterobacteriaceae, Wuhan, China 33% Pongpirul et al.
Ceftriaxone N. gonorrhoeae, P. aeruginosa (2020), Wang
et al. (2020a)
Linezolid Enterococcus faecalis, Enterococcus Italy 17% Barrasa et al.
faecium, Staphylococcus (2020),
epidermidis Kosecka-
Strojek et al.
(2020)
Meropenem K. pneumoniae, Enterobacteriaceae Hong Kong 25% Malchione et al.
sp. (2019)
levofloxacin E. coli Spain 35% Girijan et al.
(2020)
Carbapenem Carbapenem-resistant A. baumannii New Jersey, 34 patients Perez et al.
(CRAB) USA (2020)
Carbapenem Enterobacter cloacae (E. cloacae) New York 0.095% Ayoub
Resistance (3/3152) Moubareck
and
Hammoudi
Halat (2022)
Carbapenem K. pneumoniae Italy 34.14 Ayoub
Resistance (14/41) Moubareck
and
Hammoudi
Halat (2022)
Carbapenem P. aeruginosa Egypt 1.5% Ayoub
(4/260) Moubareck
and
Hammoudi
Halat (2022)
Carbapenem Carbapenem-resistant A. baumanni China More than Zhang et al.
half of (2020a)
the ICU
patients
Pan-drug resistant Providencia rettgeri USA NA Mc Gann et al.
(2021)
Carbapenem K. pneumoniae Romania 36% (9/25) Ayoub
Moubareck
and
Hammoudi
Halat (2022)
Carbapenem Stenotrophomonas maltophilia United Arab NA Senok et al.
Carbapenem-resistant Emirates (2021)
A. baumanni
Amikacin, gentamycin, Acinetobacter spp. and Klebsiella Mazandaran nine corona Jamnani et al.
cefixime, and spp. Heart patients (2022)
imipenem Center (41%)
antibiotics. Hospital,
Sari, Iran
NA NA Zimbabwe NA Chitungo et al.
(2022)
Carbapenem, Carbapenem-Resistant South Korea NA Jeon et al.
Vancomycin, A. Baumannii, P. aeruginosa, (2022)
Methicillin Vancomycin-Resistant
Enterococcus, Methicillin-
Resistant S. aureus
(Continued)
12 A. D. TEKLEMARIAM ET AL.

Table 2. (Continued).
Prescribed antibiotics Prevalence
which showed of the
resistance Bacterial pathogens Locations Co-infection References
Cephalosporin Stenotrophomonas Maltophilia, King Salman Different at Aldhwaihi et al.
antibiotics, E. cloacae, S. aureus, Providnice Hospital in different (2021)
Penicillin, stuartii, P. aeruginosa, Riyadh, settings
Aminoglycosides, P. mirabillis, klebsiella spp., Saudi
Fluoroquinolones, E. faecalis Arabia

overworked work place and lack of accurate diagnosis for MDR carriers
(Farfour et al., 2020).
Apart from the above-mentioned antibiotics macrolides are among the
top five antimicrobial classes distributed by drugstores, with known devel­
opment of resistance throughout the globe (Kow & Hasan, 2020). Most
COVID-19 patients received azithromycin (macrolide) with known rising
resistance to both Gram-negative and Gram-positive infections. Co-
infection with Chlamydia pneumoniae and Mycoplasma pneumoniae could
indicate the use of azithromycin in COVID-19 patients (De Francesco et al.,
2021). In one study, resistance to erythromycin has been observed in
S. aureus (26 vs. 43%), and this could be related to excessive azithromycin
use (Chowdhary et al., 2020).

6. Challenges of AMR containment associated with the COVID-19

pandemics
COVID-19 affects efficiency of well-organized antimicrobial stewardship
(AMS) programs and AMR surveillance which have been delayed, deprior­
itized, or ceased with downgrading of the resources allocated to the health
system as part of the response to the global pandemic (Rodríguez-Baño
et al., 2021). The AMR control approach was redirected to COVID-19
response including contact tracking, and diagnosing (Rodríguez-Baño
et al., 2021) while AMR surveillance data are crucial to support physicians
and researchers to better investigation of antibiotic resistance pattern and
effect of antibiotic use associated with COVID-19 and co-infections as well
as secondary infections. This highlights failures in AMR mitigation and
containment approaches that necessitate warrant quick response from clin­
ical and scientific communities. These comprise evaluation of the worldwide
prevalence of co-infections and secondary infections in COVID-19 patients
to identify patients who are most in need of drugs as well as the way how
treatment can be safely terminated, withheld, or de-escalated (Rodríguez-
Baño et al., 2021).
The global COVID-19 pandemics has clearly showed how the world
especially the health-care structures vulnerable are. This incidence is more
visible and severe in hospitals that lack qualified personnel and
 BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 13

infrastructures are also lack preparedness to mitigate the pandemic inci­

dences (Rodríguez-Baño et al., 2021). Sustainable surveillance of the con­
sumption of antibiotics at the different clinical settings and resistance trends
is necessary to predict the changes in the epidemiology of AMR while
mitigating shortage of antibiotics and ensuring constant supply.

7. Diagnosis of bacterial co-infection

Little attention has been given for bacterial co-infection in the diagnosis of
COVID-19 patients. Clinical and radiological diagnostic approaches are not
efficient in distinguishing the bacterial pathogens from the existing viral
pneumonia (Azoulay et al., 2020). Calcitonin is one of the auxiliary detec­
tion mechanism of bacterial co-infection as the level of IL-6, interleukin
(IL)-1β and tumor necrosis factor (TNF)-α rises which lead to high level of
synthesis and release of parathyroid-derived calcitonin during bacterial
infection (Wiegers et al., 2019). Nevertheless, the increase in the secretion
of TNF-γ during viral infection inhibit the secretion of parathyroid-derived
calcitonin (Lippi & Plebani, 2020). Hence, the huge rise of calcitonin
indicates the presence of bacteria and severe diseases, leading to more
serious clinical conditions (Martins-Filho et al., 2020). Microbiological
investigation of bacterial pathogens, particularly sputum and/or blood cul­
ture is another means of diagnosis of bacterial co-infection with SARS-CoV
-2 (Budayanti et al., 2019). However, this approach may expose technicians
to SARS-CoV-2 as the disease spread via virus-laden aerosols (Peng et al.,
2020; Xu et al., 2020). Hence, it is crucial to create a rational detection
platform to provide suitable protective measures for the personnel who are
working in the laboratory.

8. Conclusive remarks
The current review describes co-infection between SARS-COV-2 and bac­
teria from different perspectives. The bacterial co-infection recognized to be
one of the serious problems in the COVID-19 pandemic. The bacterial co-
infection is significantly higher in severely infected SARS-CoV-2 patient’s
than those who have not been seriously affected. On top of theses, the
overlapping nature of bacterial and viral pneumonia lead to the adminis­
tration of unnecessary antibiotic which ultimately increase the occurrence
of MDR bacterial pathogens in the clinics. The clinical data of these scenario
is very crucial for rational treatment of COVID-19. Hence, to investigate the
co-infection of patients with COVID-19, a solid platform must be built to
investigate the disease and for proper handling of the cases.
In 2020, COVID-19 infection significantly changed the context of anti­
microbial stewardship, especially in primary care. In response to the
14 A. D. TEKLEMARIAM ET AL.

excessive and misuse of antibiotics during the initial wave of the pandemic,
the World Health Organization issued guidance on COVID-19 clinical
management, recommending that antibiotics should not be used to treat
mild COVID-19 infections. The ongoing global crisis of antimicrobial
resistance should not be neglected, and efforts should be made to promote
antimicrobial stewardship during and following pandemic and post-
pandemic periods. Hence, to evaluate the effectiveness of these interven­
tions and preventive measures, it would be helpful to collect data and
records about the prevalence of AMR before and after the pandemic.
Additionally, a microbial genomics comparative sequence analysis particu­
larly the genes responsible or involved in drug resistance during, before, and
after the pandemic would offer valuable insight into how genetic alterations
occur and possible mechanisms behind the development of AMR.

9. Limitation of this review

Some of the reports released from different countries are not consistent and
vary from hospital to hospital and the information is fragmented. In some
cases, due to the fatality of the disease and the lack of a diagnostic tool, the
presence of a bacterial co-infection associated with COVID-19 infection was
not reported. During the pandemic, some reports on antibiotic resistance
related to bacterial co-infections were limited to specific clinics or hospitals for
a limited period, which did not represent the entire prevalence of infections.

Acknowledgement
The work was supported by the Scientific Grant Agency of the Ministry of Education,
Science, Research, and Sport of the Slovak Republic and the Slovak Academy Sciences
[IFPDP-100-22].

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
This research work was funded by the Institutional Fund projects under grant no. (IFPDP-
100-22). Therefore, the authors gratefully acknowledge technical and financial support from
the Ministry of Education and King Abdulaziz University, Deanship of Scientific Research,
Jeddah, Saudi Arabia.
 BIOTECHNOLOGY AND GENETIC ENGINEERING REVIEWS 15

ORCID
Steve Harakeh http://orcid.org/0000-0001-7512-8787

Consent for publication

All authors have provided consent for the manuscript to be published.

Credit authorship contribution statement

Addisu D. Teklemariam, Anwar M. Hashem, Saber H. Saber, Mohammed S. Almuhayawi,
Shafiul Haque, Turki S. Abujamel, Steve Harakeh: Writing and revision the manuscript.

Data availability statement

All data generated or analyzed during this study are included in this published article.

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