This study demonstrated that E. coli, Enterococcus spp., K. pneumonia, P. aeruginosa, and A. baumannii were the most common caucuses of HA-UTIs in this geographical region. Additionally, it was demonstrated that non-E. coli strains were more prevalent in males compared to females and revealed that the prevalence of K. pneumonia was higher in those under 20 years of age.
Moreover, this research showed that the sensitivity of the isolated Gram-negative bacteria, especially A. baumannii, P. aeruginosa, and K. pneumonia strains, to the studied antibiotics was so low that the overall sensitivity of Gram-negative bacteria to potent antibiotics such as nitrofurantoin, carbapenems, and aminoglycosides were only about 70% and had a much lower sensitivity to trimethoprim-sulfamethoxazole, fourth and third generation cephalosporins, and fluoroquinolones.
Besides, the Gram-negative bacteria sensitivity to carbapenems, aminoglycosides, fluoroquinolones, and third-generation cephalosporins was higher in females than males, and sensitivity to aminoglycosides and third-generation cephalosporins was higher in those over 20 than less than 20 years of age. Also, this study indicated high resistance of the isolated Gram-positive bacteria to ampicillin, ciprofloxacin, and vancomycin and high sensitivity to linezolid and nitrofurantoin.
Overall, the study showed that a carbapenem and an aminoglycoside can be used for the empiric treatment of severe HA-UTI in the study region. In very severe cases, linezolid can also be added to treat possible Gram-positive strains.
In this study, the most common cause of HA-UTIs was
E.coli, followed by
Enterococcus spp.,
K. pneumonia,
P. aeruginosa, and
A. baumannii. According to the majority of studies conducted in this field,
E. coli is the most common causative agent of the infection (
1,
6,
9,
11,
13,
15,
16) except for a study conducted in India (
14) in which the most prevalent agent was proven to be
K. pneumonia and then
E. coli. Other common bacterial agents in other areas were similar to our findings, and the differences in various studies were merely in their positions and rankings in the list of causative agents (
1,
6,
9,
11,
13-
16).
This research demonstrated that non-E.coli strains, most of which are antibiotic-resistant organisms, were more prevalent in males than females. The majority of the studies on HA-UTIs did not adopt a gender-specific approach. In other words, the number of microorganisms and the antibiotic sensitivity of microorganisms were not separately investigated in males and females. However, in a similar study in Tehran (
7), Iran, the percentage of non-
E. coli strains in both genders were equal. This finding indicates that in our region, in the initial treatment of such infections in males, the possibility of infection with non-
E. coli resistant strains, and consequently, a more effective antibiotic treatment or combination of antibiotics should be considered.
Our study revealed that the prevalence of K. pneumonia was higher in patients under 20 than in those over 20 years old. Unfortunately, none of the studies on the same subject made any attempt to differentiate microorganisms by age group. Due to the high prevalence of antibiotic resistance in K. pneumoniae strains compared to E. coli, empiric antibiotic treatment in patients under the age of 20 should include more potent antibiotics.
This research revealed that the sensitivity of Gram-negative strains in HA-UTI to fourth and thrid generation cephalosporins, including cefotaxime, ceftriaxone, ceftazidime, and cefepime, is very low and less than 35%. Therefore, this group of antibiotics is not suitable and not recommended to treat HA-UTI in this geographical region. Our study is similar to a study conducted in southern Iran (
6) that reported similar antibiotic sensitivity results to 3rd and 4th generation cephalosporins. Other studies conducted in Tehran (
1,
7) in 2009 - 2010 and 2010 - 2014 had shown that the sensitivity of pathogens to the above cephalosporins is about 60%. Regarding other countries, the sensitivity to this class of drugs in Turkey was approximately 70% (
16), and in India, it was 90% in one study (
14) and 70% in another (
13) The heterogeneity of the findings could be due to the geographical diversity of the microbial types and their resistance.
Evidence shows that the most effective known antibiotics for the empiric treatment of HA-UTIs are carbapenems and aminoglycosides. Our findings revealed that approximately 70% of strains were sensitive to these classes of antibiotics. This finding has also been reported in most previous articles. Considering the synergistic effect of carbapenems and aminoglycosides against Gram-negative bacteria, it seems that simultaneous treatment with these two classes of antibiotics can increase the chances of responding to the treatment. This combinational therapy can be advised in severe cases, especially in males and patients under the age of 20, when strains are more likely to be multi-drug resistant.
On the other hand, the study revealed that the sensitivity of isolated Gram-negative and Gram-positive strains to nitrofurantoin was about 70%, and this drug can be used in mild cases of infection when the patients can be treated orally. In other studies, sensitivity to this drug has been reported to be different, which may be attributed to different antibiotic usage in different places (
1,
6,
7,
12-
14).
In this study, the resistance of Gram-negative bacteria to fluoroquinolones, including ciprofloxacin, ofloxacin, and levofloxacin, was observed to be very high, and more than 67% of bacteria were resistant to these antibiotics. Thus, the use of fluoroquinolones for the empiric treatment of HA-UTI in our region is not recommended. The majority of other similar studies also reported a high sensitivity to these antibiotics (
1,
6,
7,
12,
13,
16). It is noteworthy that in a study conducted in India (
14), high resistance to this class of drugs was reported. One of the reasons for the high sensitivity to these drugs in some regions and high resistance in others can be the consumption rate of the mentioned antibiotics across communities, resulting in the induction of microbial resistance among microorganisms in that region.
The study reported a 30% sensitivity of Gram-negative organisms to trimethoprim-sulfamethoxazole, which shows that this drug is not suitable for the initial treatment of HA-UTI in the region under study. In other articles that had reported the antimicrobial susceptibility of this drug, a sensitivity of about 50% was reported (
1,
6,
7,
9,
11-
13,
16). Therefore, it seems that this antibiotic is not suitable for the initial treatment of HA-UTI in most geographical regions.
This study indicated that the sensitivity of Gram-negative isolates to third generation cephalosporins, carbapenems, aminoglycosides, and fluoroquinolones was higher in females than in males. The greater level of resistance in the male population is probably due to the higher prevalence of non-E. coli strains such as K. pneumonia, P. aeruginosa, and A. baumannii is the most multidrug-resistant strain in male individuals.
In Gram-positive bacteria, resistance to vancomycin, ampicillin, and ciprofloxacin was so high that less than 35% of the isolates were sensitive to these antibiotics. These antibacterial agents are not suitable against Gram-positive causes of HA-UTIs. In most previous articles, there was no intention to assess the antibiotic susceptibility of isolates by Gram-staining groups separately. However, in a study in southern Iran (
6), the resistance of Gram-positive isolates was studied, and high resistance to ampicillin and very low resistance to vancomycin was reported. The reliability of the report, however, is low due to the limited number of studied Gram-positive strains. In another similar study conducted in Tehran (
7), high resistance of Gram-positives to ampicillin was reported.
Moreover, according to our research, all isolated Gram-positive were sensitive to linezolid, and this drug can be used for the coverage of Gram-positive bacteria in the initial treatment of HA-UTI. However, application of this antibiotic for empiric therapy should be limited to severe infections. It is also necessary to take stewardship measures to prevent nosocomial bacteria from becoming resistant to this drug and discontinuing or changing the type of antibiotic used should be considered after determining the results of the urine culture.
The limitations of this research should also be noted. First, this research was conducted only in three referral hospitals in Isfahan province, which are not representative of all the hospitals in the province or the country. Nevertheless, considering that in recent years, almost no similar research has been done in the central parts of Iran, this study can be considered a primary guide for the treatment of patients with HA-UTI in this region. Similar studies in other parts of the country and other non-referral hospitals in the province should be conducted to determine the appropriate empiric antibiotic approach.
The second limitation of the research pertained to the practical aspects of conducting it. As this study was performed during the routine work of clinical laboratories and the choice of the antibiotic kit of the laboratory was based on the type of kit that was available in the laboratory at the time of bacterial extraction, it was not possible to investigate the microbial sensitivity to all antibiotics for all isolated microorganisms.
Despite all mentioned limitations, it should be noted that this research can be considered of particular importance for the following reasons. First, in this study, accurate definitions of nosocomial infection, contamination of the culture medium, and urinary tract infection are presented, demonstrating the strength of the study in identifying real strains of HA-UTI. Second, drug resistance investigation by age, gender, and Gram staining, besides the bacterial strain types, which were considered in this research, are of particular novelty.
5.1. Conclusions
This study showed that the resistance of Gram-negative bacteria causing HA-UTI to cephalosporins, quinolones, and trimethoprim-sulfamethoxazole was very high, and these antibiotics are not suitable for the initial treatment. On the other hand, the study indicated that Gram-positive bacterial causes of HA-UTI in this region were highly resistant to vancomycin, ampicillin, and ciprofloxacin, and these antibiotics are not suitable for the empiric treatment of this infection. In addition, our study indicated that the total sensitivity of isolated bacteria, both Gram-negative and Gram-positive, to nitrofurantoin, is relatively high, and this drug can be used in mild cases of the disease that can be treated orally.