1.
INTRODUCTION
Antibiotic resistance is a globally continuously increasing threat to patient
management (Paul, 2018). Urinary tract infections (UTIs) are recorded to
be the most common infections leading to clinical intervention all over the
world (Flores-Mireles et al., 2015). UTIs may lead to a high rate of mortality
and morbidity in a number of infected groups, such as immunocompromised
patients (Eliakim-Raz et al., 2019), women, older patients, diabetes,
obesity, and people who have frequent intercourse (Sabih & Leslie, 2023) as
well as those with long-term catheters (Nagaraj, 2023) and frequent sexual
activity (Seid et al., 2023).
A wide range of Gram-negative and ----positive pathogens
was isolated from patients with UTI. Based on the epidemiology of UTIs, uropathogenic E.
coli is the most common causative agent (Naqid et al., 2020a),
followed by Klebsiella pneumoniae, Staphylococcus saprophyticus,
Enterococcus faecalis, group B Streptococcus (GBS), Proteus
mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus, in addition to other
bacteria cause opportunistic UTIs (Flores-Mireles
et al., 2015) as well as fungi (Nyirjesy et al., 2022).
All UTI patients face serious problems associated
with bacterial-antibiotic resistance (Nickel, 2007). According
to Guclu et al., the initial bacterial antibiotic resistance was
detected in patients with diabetes or renal reflux (2021). Resistance later
broadened to include other nosocomial pathogens. However, nowadays, a large
number of community-acquired infections with resistance to antimicrobials are
noticed (Mares et al., 2024). Bacterial antibiotic resistance is not
limited to any particular country, but it is a global phenomenon.
Antibiotics
are the mainstay of treatment for any bacterial infection, and UTIs are no
exception. Nevertheless, the relentless and misused use of antibiotics for
human and veterinary or agro-industrial purposes (Tiseo et al., 2020) in
the last decades has given rise to a severe public health issue: the drastic
rise in the antibiotic-resistance of bacteria (Wiedemann et al., 2014; Alhazmi
et al., 2023). The occurrence of antibiotic-resistant bacteria in UTIs
exceeds the garden homogeneity of the European Union, with over half a million
cases (WHO and ECDC report, 2023). The European Center for Disease Prevention
and Control (ECDC) and WHO report occasional emergence of antibiotic resistance
blazing across these strains for quick and effective action.
Unfortunately,
Iraq, including the Kurdistan region, has one of the highest rates of
antibiotic consumption in the Middle East, with low knowledge of the
appropriate use of antibiotics by the public. As a consequence, recent data
bring to light the burden of antimicrobial resistance in this country and the
necessity of monitoring the prudent use of these categories of drugs (Qurbani et
al., 2024). Bacterial-antibiotics resistance studies in the local setting also
showed increased resistance of bacteria to ampicillin, aztreonam, and
nitrofurantoin. In contrast, the integrity of amikacin, ciprofloxacin,
imipenem, and nitrofurantoin sensitivity is still preserved (Osman, 2019).
Current
research evaluates the recent evolution of antimicrobial resistance in female
patients. It updates the knowledge regarding the resistance and sensitivity of
uropathogens to antimicrobials in Kurdistan of Iraq, associated with the
presentation of relevant clinical data of patients that may constitute risk
factors in the context of antibiotic-resistance UTIs. This work aimed to
assess the activity of a wide range of antibiotics against several common UTI
causative agents and to discuss the susceptibility pattern of antimicrobials based
on urine-culture sensitivity assay. By studying bacterial sensitivity patterns
to antibiotics in indicated pathogens, a new review could be proposed for
treatment protocol in such patients.
2. MATERIALS
AND METHODS
Study design and
sample collection:
This retrospective
study was carried out among females for a period of four years (Jan 2016 to Dec
2019), including 1730 urine samples at the Microbiology Laboratories in Zakho
Emergency Hospital, located in the Kurdistan region of Iraq. To prevent
contamination, first, midstream morning urine samples were collected from
female patients of all ages in sterile containers. All participants exhibited
one or more symptoms indicative of UTI, including pain or a burning sensation
during urination (dysuria), increased frequency of urination during both the
day and night (nocturia), urgent or sudden urges to urinate, and the presence
of cloudy or bloody urine.
Bacterial identification:
Bacteria
isolates were initially identified by their morphological characteristics post-culturing
on blood agar, mannitol salt agar, and MacConkey agar based on standard
microbiological culture as per the Clinical and Laboratory Standards Institute
(CLSI, 2020) guidelines. Each
sample was cultured immediately on an appropriate agar and then incubated in
aerobic conditions at 37 °C for 24 to 48 hours with aeration (Giuliano et al.,
2019).
Antimicrobial
susceptibility test:
Antibiotic
susceptibility was assessed using the disk diffusion (Kirby-Bauer) method. Upon
collection, samples were promptly analyzed microbiologically. Initially,
samples were incubated overnight at 37 °C on blood agar. In samples yielding uniform
bacterial growth, microorganisms were transferred and spread on Mueller-Hinton
agar plates using a sterile cotton swab. Antibiotic discs were applied on
plates seeded with bacterial lawn and incubated at 37 °C for 24-48 h. The
results were interpreted based on the size of the inhibition zone around the
antibiotic disc according to the guidelines that are provided by (CLSI, 2020). Vaginal yeast infection agents were excluded from this
research. The data analysis concentrated on four prevalent uropathogens: Staphylococcus
spp., Streptococcus spp., strains of E. coli, and Klebsiella
spp. Antibiotic
types, abbreviations, and concentrations are shown below.
Ethical approval:
The study design and procedure were approved by the College
of Medicine, University of Zakho, Kurdistan region, Iraq. Ethics considerations,
including the privacy of personal data, were considered during all steps of the
study. Written informed consent was acquired from each subject before sampling.
3. RESULTS
Out of 1,730 urine samples, they were collected
from females for bacterial identification and antibiotic resistance profiling.
Of those, 1,045 (60.4%) exhibited bacterial growth on various microbiological
media. This study specifically examined different strains of Staphylococcus
spp and Streptococcus spp as representatives of gram-positive bacteria,
as well as E. coli and Klebsiella spp as examples of
gram-negative bacteria (see Table 1). The bacterial isolates were tested
against a comprehensive array of Bioanalyse® ATS antibiotic discs (manufactured
in Turkey), each containing the same concentration of their respective
antibiotics.
The most significant number of isolates was
observed for Staphylococcus spp (460 samples, 44.01%), followed by E.
coli strains (265 samples, 25.35%), Klebsiella spp (165 samples,
15.78%), and then Streptococcus spp, in that order (Table 1). The
identification of Klebsiella and Streptococcus species (155
samples, 14.83%), along with E. coli strains and Staphylococcus
spp, was excluded from the bacterial-antibiotic analysis unless specifically
requested by physicians. Based on years, the total number of bacteria isolated
was highest in 2016 (n=493), followed by 2019 (n=461), 2018 (n=409), and then
2017 (n=367).
4. DISCUSSION
All
tested bacterial strains demonstrated significant resistance to a broad
spectrum of antibiotics, with each genus showing resistance to at least ten
different antibiotics. This resistance presents a severe challenge in combating
bacterial infections. Most antibiotics were ineffective, failing to kill or
inhibit bacterial growth in at least 75% of the cases tested. Conversely, only
a few antibiotics, such as AK, IMP, MEM, VA, DX, RF, and GN, showed lethal
effects in ≥75% of the tested cases, with no more than four effective
antibiotics per genus. Unfortunately, these findings highlight the alarming
rate of antibiotic resistance among uropathogenic bacteria.
Staphylococcus, especially S.
aureus, has become adept at resisting antibiotics through a variety of
mechanisms. This resistance is especially concerning with strains like MRSA
(Methicillin-Resistant S. aureus), which can cause serious infections
that are hard to treat
(Nandhini
et al., 2022). In line with our results, Staphylococcus species
previously obtained from the upper respiratory tract exhibited susceptibility
to MEM, IMP, and AK (Ullah et al., 2022), as well as to VA (Ali et al.,
2022). Nonetheless, as suggested in various earlier studies, Staphylococcus
species were also identified as resistant to a broad spectrum of antibiotics
(Van et al., 2024).
These
findings align with a previous study conducted in Kurdistan-Iraq, where Staphylococcus
spp were observed to be resistant to VA (Abdulrahman & Taher, 2018) NIT and
P but yet remained susceptible to AK (Mohamed, 2023). However, research by
Abduljabar and Naqid (2022) indicates that Staphylococcus spp found in
the nasal passages of athletes are highly susceptible to RF, GN, and fusidic
acid.
Moreover,
and consistent with current work presented findings, strains of E. coli
isolated from hospitalized patients with various infections demonstrated
susceptibility to AK, MEM, and IMP (Esfahani et al., 2024). Conversely,
some E. coli strains derived from children were identified as resistant
to these antibiotics (Luo et al., 2023). This variation in antibiotic
response could be linked to several factors, including bacterial population
density, genetic variation, or prior exposure to pathogens. Similar to the
current study’s findings, E. coli strains in research conducted in the
Kurdistan region were found to be resistant to P and E but showed sensitivity
to IMP and MEM (Assafi & Ali, 2022).
The
present antibiotic susceptibility profile of Streptococcus species
aligns with findings from a previous study by Alhamadani and Oudah (2022).
Their research indicated that Streptococcus spp showed complete
resistance to NOR, marking it as the least effective antibiotic against this
pathogen. On the other hand, among the antibiotics evaluated in this study, VA
showed the most excellent effectiveness against Streptococcus spp.,
consistent with the results of a study by Chiorescu et al. (2024).
Furthermore, the current findings of Klebsiella spp are parallel with those of
other research conducted in the Kurdistan region, where K. pneumoniae
was found to be resistant to a broad range of antimicrobials, especially AMP.
At the same time, IMP showed complete lethality against the isolates (Naqid et
al., 2020b). In another study by Mhawesh et al., 2021, Klebsiella
strains were observed to be resistant to VA and RF but sensitive to AK and MEM.
However, the pattern of antibiotic resistance in Klebsiella spp appears
to vary between studies due to differences in pathogen strains, antibiotic
concentrations, and the bacteria's resistance capabilities. Klebsiella-mediated
biofilms contribute to the failure of antibiotic treatments by obstructing
access to the cells in the deeper layers of the biofilm matrix and creating
drug resistance (Sharma et al., 2023). Klebsiella strains were
also found to be resistant to multiple antimicrobials due to plasmid-mediated properties
(Li et al., 2023).
Bacteria
have developed multiple methods to resist antibiotics, including breaking down antibiotic
molecules through enzymes (Pathak et al., 2023) and altering their internal
targets. Hence, the drugs are ineffective (Varela et al., 2021), using
broad-spectrum efflux pumps to remove antibiotics from their cells (Gaurav et
al., 2023) and reducing their cell membrane permeability, which limits the
number of antibiotics that can enter (Maher & Hassan, 2023). The bacteria
studied in this work might employ one or more of the previously mentioned
antibiotic resistance mechanisms to survive in environments heavily saturated
with antimicrobial agents.
Several risk factors contribute to
the emergence of an antibiotic-resistance problem. However, the primary reasons
for the rise in bacterial-antibiotic resistance in the Kurdistan region include
the overuse of antibiotics, a common practice among the public (Ghazala et
al., 2023), incomplete treatment courses (Borek et al., 2023), and
poor infection control in some healthcare settings (Abalkhail & Alslamah,
2022). Other contributing factors are global travel and trade, environmental
contamination (Coque et al., 2023), molecular reasons such as horizontal
gene transfer (Michaelis & Grohmann, 2023), and chromosomal point mutations
(Simone et al., 2023). The differences between presented results and findings
from other studies may be due to several reasons: genetic variability from one
strain to another, environmental conditions, antibiotic concentrations,
bacterial population density, pathogens' previous exposure, susceptibility
measurement methods, and the presence of resistance mechanisms which differ from species to another. By combining
responsible antibiotic use, improved hygiene practices, international
collaboration, and continuous research, substantial progress can be achieved in
addressing the challenge of bacterial antibiotic resistance.
CONCLUSION
Meropenem
(MEM) and amikacin (AK) are recommended as the primary treatment options for
urinary tract infections (UTIs) caused by the pathogens discussed above. Among
the antibiotics tested, imipenem (IMP) and vancomycin (VA) demonstrated the
highest effectiveness against Staphylococcus species, with fatal
activity rates of 97.8% and 92.4%, respectively. Additionally, IMP is
considered the first-line treatment for infections caused by E. coli
strains and Klebsiella spp, with lethal activity levels reaching 100%
and 97.1%, respectively. For treating infections derived from Streptococcus,
vancomycin (85.2%) and meropenem (84.3%) were identified as the most potent
antimicrobials.
ACKNOWLEDGEMENT
The
author profoundly thanks the administration of the Zakho Emergency Hospital for
their providing the microbiology lab data. A special thanks to Mrs. Nasreen
Jawad, Mrs. Payman Saady, and Mr. Renas Ghazi for their kind help and
continuous technical support.
Abbreviations
and concentrations of antibiotics/μg
AK Amikacin (10), AMP
Ampicillin (10), APX Ampicillin/Cloxacillin (25/5), AUG
Amoxicillin/Clavulanic acid (Augmentin) (20/10), AX Amoxicillin (10), AZM
Azithromycin (15), C Chloramphenicol (10), CFX Cefixime (30), CIP
Ciprofloxacin 10), CL Cephalexin (30), CRO Ceftriaxone (10), CTX
Cefotaxime (10), CTZ Ceftazidime (10), CX Cloxacillin (10), DA
Clindamycin (10), DX Doxycycline (10), E Erythromycin (100), GN
Gentamycin (10), IMP Imipenem (10), KF Cephalothin (30), LEV
Levofloxacin (5), ME methicillin, MEM Meropenem (10), MTZ
Metronidazole (30), NA Naldixic acid (30), NIT Nitrofurantoin
(100), NOR Norfloxacin (30), OX Oxacillin (10), P
Penicillin (10), RF Rifampicin (5), TE Tetracycline (25), TMP
Trimethoprim (10), VA Vancomycin (10).
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