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.
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.