Antimicrobial Resistance Pattern of Moraxella catarrhalis and Haemophilus

influenza in Iran; a Systematic review

Firouze Hatami
Shahid Beheshti University of Medical Sciences
Hadi Allahverdi Nazhand
Shahid Beheshti University of Medical Sciences
Hadi Ebadi
Shahid Beheshti University of Medical Sciences
Amir Hossein Zeininasab
Shahid Beheshti University of Medical Sciences
Farid Javandoust Gharehbagh
Shahid Beheshti University of Medical Sciences
Shahrzad Shahrokhi
Shahid Beheshti University of Medical Sciences
Mohammad Mahdi Rabiei
Shahid Beheshti University of Medical Sciences
Legha Lotfollahi
Shahid Beheshti University of Medical Sciences
Neda Kazeminia
Shahid Beheshti University of Medical Sciences
Ilad Alavi Darazam (  ilad13@yahoo.com )
Shahid Beheshti University of Medical Sciences

Research Article

Keywords: Moraxella Catarrhalis, Haemophilus Influenza, Respiratory Tract Infection, Drug Resistance, Antimicrobial Resistance

Posted Date: August 29th, 2022

DOI: https://doi.org/10.21203/rs.3.rs-1989291/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License

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Abstract
Introduction: Haemophilus. influenzae and Moraxella. catarrhalis are two common pathogens in respiratory tract infections. Antimicrobial resistance to these
pathogens occurs over years. Therefore, we decided to carry out a systematic review to investigate the antibiotic resistance and sensitivity of these pathogens
in Iran.

Material and method: All recent original articles and studies related to the antimicrobial resistance in H. influenza and M. cattarhalis in Iran up to 2022 were
investigated in English and Persian databases.

Result: The prevalence of antibiotic susceptibility in H. influenza to levofloxacin (100%), cefotaxim (78.8%), clarithromycin (71.4%) and ceftriaxone (71.4-80%)
was upmost. Resistances to ciprofloxacin were varied. In addition, about 50% of isolated had resistant to ampicillin. The prevalence of M. cattarhalis
resistance in Iran including penicillin was 70-100%, erythromycin was 0%, and in three of our study of our studies, the resistance rate of ciprofloxacin was 0%
whereas in one study 70% of isolated M.cattarhalis had resistance to ciprofloxacin also, resistances to amoxicillin/clavulanate were varied.

Conclusion:

According to the study, most isolates of H. influenzae are sensitive to levofloxacin, but resistance to macrolides and third generation cephalosporins are
increasing; and the majority of M. cattarhalis was resistant to penicillin.

Introduction
Haemophilus influenzae and Moraxella catarrhalis are two common microorganisms found in community-acquired pneumonia and other upper and lower
respiratory tract infections. These bacteria are gram-negative and mostly found in the nasopharynx and oropharynx [1]. The incidence of H. influenza
(Haemophilus influenzae) varies between industrial and non-industrial communities. H. influenza type b rates have declined throughout the vaccination era,
but the predominance of non-typeable strains has increased the incidence of invasive Haemophilus influenza [2–4]. Colonization of M. catarrhalis is much
more common in healthy infants, especially in the first year of life [2, 3].

The main diseases caused by H. influenzae and M. catarrhalis are meningitis, bacteremia, community-acquired pneumonia (CAP), septic arthritis, acute otitis
media (AOM), acute sinusitis and exacerbation of chronic obstructive pulmonary disease (COPD)[1, 2, 4].

With the emergence of resistance to some antimicrobials, antibiotic recommendations have changed over the years. According to previous studies, most
isolates of M. catarrhalis carry β-lactamase enzymes and are resistant to penicillin and amoxicillin. Second- and third- generations of cephalosporins or β-
lactam antibiotics with β-lactamase inhibitors are used in the treatment of some resistant strains of H. influenzae and M. catarrhalis [2, 4]. Empirical treatment
usually is required because the causative agents are often difficult to be identified in clinical settings [5]. Therefore, knowledge of the susceptibility and
resistance patterns of each bacterium in local areas plays an important role in treatment.

Due to the rise in detection of these organisms in various syndromes particularly pneumonia, and upper respiratory tract infections, the diversity of resistance
mechanisms and the lack of enough supporting data to treat our patients, we decided to carry out a systematic review to discuss the drug resistance and
susceptibility of these pathogens in order to establish a thorough viewpoint for the treatment of suspected infections caused by these etiologies in Iran.

Method
Study design

Eligible studies were identified through a search of PubMed, Scopus, Google Scholar, Magiran, SID, and Irandoc with the following keywords: (antimicrobial
resistance OR Drug Resistance, Microbial OR antibiotic resistance) AND Moraxella catarrhalis AND Iran for investigation of antimicrobial resistance of M.
cattarhalis; and (antimicrobial resistance OR Drug Resistance, Microbial OR antibiotic resistance) AND Haemophilus influenza AND Iran for investigation of
antimicrobial resistance of H. influenza in Iran. Since we aimed to investigate recent antibiotic resistance patterns the search strategy was restricted to the last
5 years up to 2022. However, the number of studies regarding M. cattarhalis during the previous five years was not remarkable therefore we extended it to the
recent decade. Publications during the last 5 years up to 2022 in the case of H. influenza were retrieved.

Study Selection

Studies were included in the analysis if they met the following criteria: (1) published in English or Persian, and (2) done in Iran. The exclusion criteria were (1)
secondary research articles, including reviews, case reports, editorials, and articles that did not report primary research findings (2) studies that did not conduct
on human.

Data Extraction and Definitions

Data from each eligible study were extracted by two investigators. The main extracted data from the included studies were the name of first author,
publication year, study design, study population, sample size, number of isolated M. catarrhalis or H. influenzae strains, antibiotic susceptibility testing, and
number of resistant strains to different antibiotics.

Quality Assessment

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The risk of bias for every study was assessed independently by a reviewer (FJ) using the revised Cochrane Risk of Bias Tool (RoB 2.0). Any disagreements
were resolved by consensus with reviewer (IAD).

Results
M. catarrhalis

Figure 1 shows the steps taken to select relevant studies. First, we identified 34 potentially related studies from the database. According to the research
method, 5 out of 34 studies were relevant and qualified as a result of detailed evaluation. Reviewers performed systematic searches, study selections, and
data extraction from the included studies.

Table 1 summarizes data obtained from patients, including study design; study population, sample size, number of isolated M. catarrhalis antibiotic
susceptibility tests, and number of strains resistant to various antibiotics. These samples were taken from sputum, sinuses, pharynx, and media otitis
effusion. The antibiotics tested were penicillin, ampicillin, amoxicillin/clavulanate, tetracycline, clarithromycin, azithromycin, trimethoprim-sulfamethoxazole,
cefazolin, ceftazidime and fluoroquinolones (FQ), etc. The details about different antibiotics were described in table 2.

H. influenzae

By searching for keywords in the database mentioned above, 44 studies were identified. Six of the 44 studies were duplicated in search of unique studies.
After the abstract screening, there were 14 studies. An abstract screening was performed to determine the relevance of H. influenzae antibiotic resistance in
Iran. The full text of the remaining studies was read and four studies were eligible for inclusion in this review (Figure 2). These four studies provided a total of
646 samples. These samples were taken from sputum, cerebrospinal fluid (CSF), sinuses, and pharynx. Of all, 98-129 samples were recognized as H.
influenzae based on different detection methods (PCR or culture). Antibiotic susceptibility testing was performed according to CLSI guidelines.

The tested antibiotics were ciprofloxacin, levofloxacin, co-trimoxazole, clarithromycin, azithromycin, ceftriaxone, cefotaxim, chloramphenicol, ampicillin,
amoxicillin/clavulanate and tetracycline.

Among these antibiotics, susceptibility to levofloxacin (100%), cefotaxim (78.8%), clarithromycin (71.4%) and ceftriaxone (71.4-80%) was the highest[6].
Resistances to ciprofloxacin were reported 57.1, 100, and 0% in various studies [6-8]. In addition, 7.8% of the isolates had intermediate susceptibility to
ciprofloxacin[6]. Other antibiotics showed more resistance rate (Table 2).

Discussion
M. catarrhalis

Researches on the antibiotic resistance of M. catarrhalis during the last decade were limit in Iran. As a result, antibiotic resistance to penicillin and amoxicillin
were very high. Susceptibility to amoxicillin-clavulanate was controversial in one study in comparison the others, however, it seems this antibiotic is usually
effective agent. The best susceptibility pattern was related to advanced form of macrolides (azithromycin and clarithromycin) and despite of limited data
respiratory FQs (levofloxacin).

Antimicrobial resistance prevalence varies by country, which may be due to a variety of factors, including different patterns of antimicrobial use, which results
in variable selective pressure on resistance. Another factor could be the distribution of specific serotypes and the spread of resistant clones within certain
regions [9].

Penicillin resistance was 100% and 70% in two of our studies [10, 11], and even though one of our studies did not refer to the percentage of penicillin
resistance, it did show that the majority of microorganisms were penicillin-resistant. [12]. This microorganism was identified using phenotyping as well as
genotyping methods in one of our studies, and phenotypic and PCR techniques were used to confirm the β -lactamase activity and presence of the Bro gene.
Since all the isolates had β-lactamase enzymes, the results showed that they were all penicillin-resistant. In addition, resistance to other antibiotics was
different[10]. In accordance with these findings, 95 percent of M. catarrhalis isolates produced beta-lactamase[12], and another study found that penicillin
resistance in M. cattarhalis was 100%[13].

There was a relationship between the Bro gene and antibiotic resistance to ampicillin, amoxicillin, cefazolin, and cefuroxime[10]. The Bro gene was found in
90.6 percent of M. catarrhalis. There was also a link between the acrA gene and resistance to ampicillin, amoxicillin, cefazolin, cefuroxime, and
chloramphenicol [10]. According to previous researches, the M. catarrhalis Bro gene was present in 87%, 73.3%, and 99.4% of the strains and was fully
resistant to penicillin, ampicillin, and cefalotin [14-16]. Only in one of our studies, most bacterial isolates were sensitive to ampicillin[17].

The susceptibility to amoxicillin/ clavulanate varied; in two studies, the most of isolates were sensitive to amoxicillin/clavulanate [11, 17] whereas, in another,
the majority were resistant to amoxicillin/clavulanate [18], although without detail data and widespread statistics.

A study assessed resistance trends for M. catarrhalis in Twain, showed that all isolates were susceptible to amoxicillin/clavulanate, chloramphenicol,
cefixime, ciprofloxacin, erythromycin, levofloxacin[19]. Based on our studies all or majority of isolated M. catarrhalis had susceptibility to
amoxicillin/clavulanate and erythromycin [10, 11, 17], and in two of our study study the susebility to ciprofloxacin was high [10, 17] while in another study 70%
of isolated M. catarrhalis had resistancy to ciprofloxacin[11]. In another study were conducted in Pakistan, about 45% of the cultures showed resistance to
macrolides and 59% showed resistance to quinolones[20], nerveless, in our study majority of isolated M.cattarhalis had susceptibility to macrolides and
quinolones.

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The resistance to cefazolin, ceftazidime, tetracycline, chloramphenicol, and ciprofloxacin antibiotics was also dependent on the efflux pump. The growth
inhibition zone in cefazolin, ceftazidime, ciprofloxacin, chloramphenicol, and tetracycline antibiotics changed after the addition of the efflux pump inhibitor to
the growth medium compared to the first antibiogram. [11]. This finding suggested that the efflux pump is an important antimicrobial resistance mechanism
in M. cattarhalis. Perhaps, higher doses of particular antimicrobials could be more effective.

Unfortunately, the antibiotics had been used in the above-mentioned studies during the last years were not similar in all of them. Moreover, respiratory FQs
including levofloxacin, moxifloxacin, etc. are one of the most common antibiotics used for respiratory tract infections had not been evaluated in the most of
research studies.

H. influenza

We concluded from a review of included articles that the most effective antibiotics for H. influenzae in Iran are levofloxacin, cefotaxim, ceftriaxone, and
clarithromycin. According to one study, levofloxacin is completely effective (100%) in isolated strains. In these studies, the resistance of isolates to
ciprofloxacin was thoroughly different, form zero percent to 57.1% of the isolates to 100% resistance [6-8]. One of the important limitations was the small
sample size of the studies performed on ciprofloxacin.

One of the studies showed that clarithromycin was an effective antibiotic with a resistance rate of 28.6%.[7]. For tetracycline, two studies had quantitative
data, of which the first showed 33.3% resistance with a sample size of 3 and the second showed 90% resistance and 3.3% intermediate resistance with a
sample size of 108. [6, 8]. In conclusion, tetracycline is not a reliable prescription for the treatment of H. influenzae.

One of the studies investigated the genes involved in antibiotic resistance in H. influenzae and identified the TEM1 gene in 2 out of 11 samples (18.2%)
expressing β-lactamase. This study did not find any samples with ROB1 gene (0/11) [21].

In Pakistan, a country in the southeast of Iran, in 2015, Zafar A, et.al. showed the rate of susceptibility to ciprofloxacin (years: 2007-2009) and levofloxacin
(years: 2014-15) was 95.9%, and 86.6%, respectively. They also found 29% of sensitivity to chloramphenicol [22]. Moreover, Mather M.W. and his colleagues in
2019 indicated that the effectiveness of amoxicillin, amoxicillin/clavulanate , penicillin and erythromycin in strains isolated from acute otitis media patients
were 82%, 98%, 43%, and 53% in respect between 1980 and 2017 [23].

A meta-analysis study in Iran by Vaez H, et.al. found that during 1998 to 2013, resistance rate to ampicillin was 54.6%, to amoxicillin was 66.6%, and to
cefotaxim, ceftriaxone, ciprofloxacin, chloramphenicol, tetracycline, erythromycin and trimethoprim/sulfamethoxazole were 22.3%, 33.1%, 30.8%, 27.7%,
46.7%, 40.3%, and 53%, respectively [24]. Of these, the results for ceftriaxone, and cefotaxim were close to our results. Therefore, cefotaxim and ceftriaxone are
two effective drugs to treat H. influenzae in Iran. Results of Hamid Vaez et.al. on chloramphenicol were different and they did not evaluate levofloxacin, the
most common respiratory FQ in Iran, because this antibiotic has been recently introduced in Iran marketing. In general, ciprofloxacin is known as an effective
antibiotic against H. influenzae. In extracted studies, the rate of resistance to co-trimoxazole was more than 40% (42.9, 66.6, and 57.7%) and this rate for Vaez
H, et.al. study was 53%. This suggests that co-trimoxazole is not an effective empiric regimen.

In our study we encountered with few data after exclusion of studies that did not provide the inclusion criteria. In addition, the absence of full text of some
studies and missing statistical data was another reason for the limited data in this review.

It seems that respiratory FQs (e.g. levofloxacin available in Iran) or macrolides are effective for both H. influenza and M. cattarhalis. However, in only one of
our study the majority of isolated M.cattarhalis had high resistance to amoxicillin-clavulanate but it could be consider as a treatment for M.cattarhalis.
Although most different guidelines recommend monotherapy in respiratory tract infections in the outpatient setting as well as the most of non-severe
hospitalized patients with pneumonia, according to the limited data and various susceptibility patterns of resistance in Iran, probably combination therapy of
respiratory FQs or advanced macrolides with amoxicillin-clavulanate could be confident regimen. Even though, the prevalence of underlying pathogens in
respiratory tract infections is an important factor in the high-level recommendation. It means the trend of changes in the epidemiology of causative etiologies
as well as the trend of antimicrobial resistance is two main factors in the management of respiratory tract infections.

Conclusion
Based on the results of the studies reviewed, most isolates of H. influenzae are sensitive to levofloxacin and ceftriaxone and resistant to ampicillin and
amoxicillin. Therefore, to treat patients, it is more effective to prescribe levofloxacin or ceftriaxone. Also, most isolates of M. cattarhalis were resistant to
penicillin and amoxicillin and were sensitive to ampicillin, Amoxicillin/Clavulanate.

Declarations
Ethics approval: The study was confirmed by the Ethics in Medical Research Committee of the Shahid Beheshti University of Medical Sciences,
IR.SBMU.RETECH.REC.1399.1362.

Consent for publication: Not applicable

Availability of data and materials: The datasets generated during and/or analysed during the current study are available from the corresponding author on
reasonable request.

Competing interests: We declare no competing interests.

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Funding: Not applicable.

Authorship contribution: All authors contributed to the conception and design of the study; FH, IAD, HAN, HE, AHZ, and SHSH contributed to the acquisition of
data; FH, IAD, HAN, FJ, MMR, LL, NK, authors contributed to the drafting of the article and/or critical revision; and all authors contributed to the final approval
of the manuscript.

Acknowledgments: The authors would like to thank the Clinical Research Development Unit (CRDU) of Loghman Hakim Hospital, Shahid Beheshti University
of Medical Sciences, Tehran, Iran for their help and support in conducting this study.

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AcrAB-OprM Efflux Pump in Multidrug-resistant in Clinical Isolates of Moraxella catarrhalis in Kazerun City, Iran. Iranian Journal of Medical Microbiology.
2020;14(5):388–407.
12. Sharifi Yazdi M, Heidarzadeh S, Vahedi S, Rahimi Forushani A, SoltanDallal M. Identification and determination antimicrobial resistance pattern of
Staphylococcus aureus and Pseudomonas aeruginosa isolated from patients with otitis media in Amir alam Hospital. 2015.
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years of age in kindergartens in Mashhad and determination of antibiotic resistance pattern in isolated moraxella catarrhalis. Iran J Otorhinolaryngol.
2007;18(46):169–73.
14. Kadry AA, Fouda SI, Elkhizzi NA, Shibl AM. Correlation between susceptibility and BRO type enzyme of Moraxella catarrhalis strains. International journal
of antimicrobial agents. 2003;22(5):532–6.
15. Mohager MO, El Hassan MM, Elmekki MA. Molecular detection of BRO β-lactamase gene of Moraxella catarrhalis isolated from Sudanese patients.
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16. Feng G, Xie T, Wang X, Bai J, Tang L, Zhao H, et al. Metagenomic analysis of microbial community and function involved in cd-contaminated soil. BMC
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17. Khoramrooz SS, Mirsalehian A, Emaneini M, Jabalameli F, Aligholi M, Saedi B, et al. Frequency of Alloicoccus otitidis, Streptococcus pneumoniae,
Moraxella catarrhalis and Haemophilus influenzae in children with otitis media with effusion (OME) in Iranian patients. Auris Nasus Larynx.
2012;39(4):369–73.
18. Hashemi SH, Soozanchi G, Jamal-Omidi S, Yousefi-Mashouf R, Mamani M, Seif-Rabiei M-A. Bacterial aetiology and antimicrobial resistance of
community-acquired pneumonia in the elderly and younger adults. Tropical doctor. 2010;40(2):89–91.
19. Hsu S-F, Lin Y-T, Chen T-L, Siu L, Hsueh P-R, Huang S-T, et al. Antimicrobial resistance of Moraxella catarrhalis isolates in Taiwan. Journal of Microbiology,
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genes in Haemophilus influenzae isolated from sinusitis samples. Reviews in Medical Microbiology. 2019;30(1):56–61.
22. Zafar A, Hasan R, Nizamuddin S, Mahmood N, Mukhtar S, Ali F, et al. Antibiotic susceptibility in Streptococcus pneumoniae, Haemophilus influenzae and
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24. Vaez H, Sahebkar A, Pourfarzi F, Yousefi-Avarvand A, Khademi F. Prevalence of antibiotic resistance of Haemophilus Influenzae in Iran-a meta-analysis.
Iranian journal of otorhinolaryngology. 2019;31(107):349.

Tables
Table 1. Resistance pattern in M.cattarhalis

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Number Year Author Type Population Positive Disease Sampling Antibiotic Antibiotic
from susceptibility
test

[1] 1 2020 Eghbali, M descriptive 280(intervention=400 32 respiratory Pharynx, Penicillins

at el cross- group)+120(control tract sinus,
sectional group) infection Cefazolin
Ear
discharge, Ampicillin

Pulmonary Disc Cefuroxime

secretions, diffusion
(CLSI) Amoxicillin

Chloramphenicol

Trimethoprim/sulfame

Amoxicillin/clavulanat

Ceftriaxone

Erythromycin

Cefepime

Tetracycline

Gentamycin

Ciprofloxacin

Clindamycin

Azithromycin

2[2] 2020 Mohammad descriptive 137 10 respiratory Sputum Penicillin

Shafiei,P at cross- infections
el sectional and Oral and Ampicillin
pneumonia laryngeal
pharynx Amikacin

Gentamicin

Disc Chloramphenicol
diffusion
(CLSI) Tetracycline

Ciprofloxacin

Cefazolin

Ceftazidime

Trimethoprim/sulfame

Amoxicillin/clavulanic

Azithromycin

Erythromycin

Clarithromycin

[3]3 2010 Hashemi, cross 81 elderly and 69 10 community- Sputum Amoxicillin-clavulante

SH at el sectional younger adults acquired
study pneumonia Disc
diffusion
(CLSI)

Trimethoprim-sulfamet

4[4] 2012 Khoramrooz, cross 63 6 otitis media Otitis Trimethoprim/sulfame

s at el sectional with media
study effusion effusion Rifampin

Disc Ampicillin
diffusion
(CLSI) Amoxicillin-Clavulanate

Erythromycin

Page 7/11
 Clarithromycin

Azithromycin

Ciprofloxacin
Levofloxacin

1 2 otitis media Otitis Disc Penicillin

with media diffusion
effusion effusion (CLSI) Ampicillin

Amoxicillin
Table 2. Resistance pattern in H.influenza

Page 8/11
 Number Year Author Type Population Positive Sampling Antibiotic Antibiotic Resistance
from susceptibility rate
test

Resistance
rate
(intermediate
resistance
rate)

90% (3.3 %)

Shooraj F, et. cross- 328 108 by Nasopharynx Disc 57.7%

1[6] 2019 al. sectional culture diffusion (4.45%)
(CLSI) Tetracycline
43.3%
Co-trimoxazole (31.1%)
73 by
PCR Ampicillin 42.2%
(24.4%)
Chloramphenicole
11.1% (8.9%)
Ceftriaxone
11.1% (10%)
Cefotaxim
0% (0%)
Ciprofloxacin
0% (7.8%)
Levofloxacin

2[7] Farajzadeh Amoxicillin/clavulanate 85.7%

2021 Sheykh, A Ciprofloxacin
et.al. cross- 92 57.1%
sectional 11 Co-trimoxazole
Sputum Disc 42.9%
diffusion Clarithromycin
(CLSI) 28.6%
Ceftriaxone
28.6%

3[8] Nahal, H retrospective Ciprofloxacin 100%

2019 et.al. cross-
sectional 89 3 CSF Disc ampicillin 66.6%
diffusion
(CLSI) Co-trimoxazole 66.6%
Tetracycline 33.3%

Ceftriaxone 0.0%

Azithromycin 0.0%

Chloramphenicol 0.0%

4[9] Eshaghi H, cross- 137 Sinuses Disc Β-lactams 100%

2019 et.al. sectional 11 diffusion
(CLSI)
1. Eghbali M, Baserisalehi M, Ghane M. Isolation, identification, and antibacterial susceptibility testing of Moraxella catarrhalis isolated from the
respiratory system of patients in northern Iran. Medical Laboratory Journal. 2020;14(3):19-25.

2. Mohammad Shafiei P, Baserisalehi M, Mobasherizade S. Investigating the Antibiotic Resistance Prevalence and Phenotypic and Genotypic Evaluation
of AcrAB-OprM Efflux Pump in Multidrug-resistant in Clinical Isolates of Moraxella catarrhalis in Kazerun City, Iran. Iranian Journal of Medical Microbiology.
2020;14(5):388-407.

3. Hashemi SH, Soozanchi G, Jamal-Omidi S, Yousefi-Mashouf R, Mamani M, Seif-Rabiei M-A. Bacterial aetiology and antimicrobial resistance of
community-acquired pneumonia in the elderly and younger adults. Tropical doctor. 2010;40(2):89-91.

4. Khoramrooz SS, Mirsalehian A, Emaneini M, Jabalameli F, Aligholi M, Saedi B, et al. Frequency of Alloicoccus otitidis, Streptococcus pneumoniae,
Moraxella catarrhalis and Haemophilus influenzae in children with otitis media with effusion (OME) in Iranian patients. Auris Nasus Larynx. 2012;39(4):369-

Page 9/11
73.

5. Sharifi Yazdi M, Heidarzadeh S, Vahedi S, Rahimi Forushani A, SoltanDallal M. Identification and determination antimicrobial resistance pattern of
Staphylococcus aureus and Pseudomonas aeruginosa isolated from patients with otitis media in Amir alam Hospital. 2015.

6. Shooraj F, Mirzaei B, Mousavi SF, Hosseini F. Clonal diversity of Haemophilus influenzae carriage isolated from under the age of 6 years children. BMC
research notes. 2019;12(1):1-7.

7. Farajzadeh Sheikh A, Rahimi R, Meghdadi H, Alami A, Saki M. Multiplex polymerase chain reaction detection of Streptococcus pneumoniae and
Haemophilus influenzae and their antibiotic resistance in patients with community-acquired pneumonia from southwest Iran. BMC microbiology. 2021;21(1):1-
8.

8. Hadi N, Bagheri K. A five-year retrospective multicenter study on etiology and antibiotic resistance pattern of bacterial meningitis among Iranian
children. Infection Epidemiology and Microbiology. 2019;5(4):17-24.

9. Eshaghi H, Abdolsalehi MR, Mohammadi M, Khodabandeh M, Kafshgari R, Pournajaf A, et al. Direct detection, capsular typing and β-lactamase
resistance genes in Haemophilus influenzae isolated from sinusitis samples. Reviews in Medical Microbiology. 2019;30(1):56-61.

Figures

Figure 1

Flowchart of study selection for M. cattarhalis in the systematic review

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Figure 2

Flowchart of study selection for H.influenza in the systematic

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