Antimicrobial resistance trend of bacterial uropathogens at the university of Gondar comprehensive specialized hospital, northwest Ethiopia: A 10 years retrospective study

Desie Kasew; Blen Desalegn; Mihret Aynalem; Sosina Tila; Dureti Diriba; Beimnet Afework; Michael Getie; Sirak Biset; Habtamu Wondifraw Baynes

doi:10.1371/journal.pone.0266878

. 2022 Apr 11;17(4):e0266878. doi: 10.1371/journal.pone.0266878

Antimicrobial resistance trend of bacterial uropathogens at the university of Gondar comprehensive specialized hospital, northwest Ethiopia: A 10 years retrospective study

Desie Kasew ^1,^*, Blen Desalegn ², Mihret Aynalem ², Sosina Tila ², Dureti Diriba ², Beimnet Afework ², Michael Getie ³, Sirak Biset ¹, Habtamu Wondifraw Baynes ⁴

Editor: Simon Clegg⁵

PMCID: PMC9000029 PMID: 35404978

Abstract

Urinary tract infection and antimicrobial resistance remains the major problem, with significant health and socioeconomic burden, particularly in developing countries. This infection is commonly caused by Gram-negative bacteria, principally by Escherichia coli. So, this study aimed to determine bacterial isolates and antimicrobial resistance trend among patients with urinary tract infection at the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. A retrospective study was conducted from January 1^st to February 28^th. A ten years (2010–2019) record of urine culture results, the biochemical test and antimicrobial susceptibility test results of isolates were collected from the medical microbiology laboratory register using a checklist. Data quality was checked, entered, and analyzed using SPSS version 23. We have presented results through descriptive tables and graphs. The overall prevalence of urinary tract infection among 4441 patients was 24.1%. Escherichia coli (37.7%), Klebsiella pneumoniae (11.4%), and Staphylococcus aureus (9.1%) were the predominant uropathogens. The infection rate was nearly similar across both sexes but highest in the age group above 60 years. Above 75% of Gram-negative isolates were resistant to ampicillin (92.5%), amoxicillin-clavulanate (80.1%), tetracycline (79.3%), cefuroxime (79.2%), and Trimethoprim-sulfamethoxazole (78.3%). Over 2/3 of Gram-positive isolates also showed increased resistance to tetracycline (84.8%) and penicillin (71.6%). Moreover, more than 44% of the isolates were multidrug-resistant (MDR). We have seen an inconsistent trend of antimicrobial resistance, with an overall resistance rate of above 50%. In conclusion, the overall prevalence of urinary tract infection was high and elderly patients were most affected. More than 70% of both Gram positive and gram-negative isolates were resistant to penicillin, ampicillin, amoxicillin-clavulanate, tetracycline, cefuroxime, Trimethoprim-sulfamethoxazole. Above than 44% of the isolates were multidrug-resistant (MDR). The increasing rate of antimicrobial resistance calls for routine diagnosis and antimicrobial susceptibility testing. A prospective multicenter study indicating the status of resistance should be encouraged.

Introduction

Urinary tract infection (UTI) is one of the most common infectious diseases, particularly in developing countries, overwhelmed with healthcare and economic constraints [1]. Urinary tract infection can be called pyelonephritis (kidney infection), or cystitis (bladder infection). The infection has clinical signs and symptoms such as dysuria, frequency, urgency, suprapubic tenderness, fever, chills, nausea, and vomiting [2, 3]. The bacterial causes of UTI include Escherichia coli (E. coli) (which causes 80% of the UTI), Klebsiella pneumoniae (K. pneumoniae), Citrobacter species, Enterobacter species, Pseudomonas aeruginosa (P. aeruginosa), and Staphylococcus species [4–6]. The mechanism of pathogenesis of the mentioned pathogens include adhesion to the host cell epithelium, invasion, immune evasion via cell wall lipopolysaccharide, capsule, and fimbriae [7]. The infection is higher in females due to biological factors such as the short urethra, anal-genital proximity, and use of spermicides [8].

Urinary tract infection is associated with increased resistance to antimicrobial agents such as multidrug resistance (MDR) with substantial medical and a financial burden [9, 10]. Antimicrobial resistance is a thoughtful medical problem in which microorganisms use varied resistance mechanisms such as horizontal gene transfer (such as plasmids and bacteriophages), genetic recombination, and mutations [11]. In addition, self-medication [12], empirical therapy, misuse, and overuse of antimicrobials which are highly practiced in Ethiopia, hasten antimicrobial resistance (AMR) end up in prolonged illness, disability, increased health care costs, and death [1, 13, 14]. In the era of rising antimicrobial resistance, current longitudinal studies revealing the prevalence and AMR trend of uropathogens are crucial to coming up with this problem [15]. This up-to-date evidence will support clinicians to identify the etiology of UTI, ensure appropriate empirical treatment for a reasonable period and an affordable cost. Moreover, it helps health policymakers in implementing locally efficient therapy and preventive guidelines. Although there are snapshot studies on the prevalence of UTI and associated AMR, data showing results of longitudinal studies lacked in the study area. Hence, this study aimed to assess the prevalence and AMR trend of bacterial uropathogens over 10 years between 2010 and 2019 among patients with UTI at the University of Gondar Comprehensive Specialized Hospital (UoGCSH), Northwest Ethiopia.

Materials and methods

Study area, design and period

A Hospital-based retrospective study was conducted by retrieving laboratory record of ten years (2010–2019) data from January 1^st to February 28^th, 2020 at the UoGCSH, Gondar, Ethiopia. The University hospital is one of the pioneering tertiary level referral and teaching hospitals in the country, which serves more than 5 million people in Gondar province and neighboring regions. It has different service centers in inpatient and outpatient settings such as fistula, cancer, dialysis, psychiatric and ophthalmology clinics. It also has an organized laboratory such as microbiology and mycobacteriology sections [16]. We have collected manually, a ten years (2010–2019) retrospective data from the microbiology laboratory logbook which is a paper-based record of the laboratory results. We have collected data complete record of the variables mentioned in the exclusion criteria.

All recorded urine culture results of patients who visited the UoGCSH and were suspected of UTI were the source. Moreover, the recorded urine culture results of those UTI suspected patients who visited the hospital from 2010–2019 were the study population and analyzed.

Inclusion and exclusion criteria: We have included the records of patients’ data which contains the patients’ age, sex, urine culture result including antimicrobial susceptibility test (AST) results for significant bacteriuria (10⁵ CFU/ml) of monomorphic organisms which have been processed and recorded from 2010 to 2019. However, records lacking at least one of the variables age, sex, urine culture results, and AST results of cultures with significant bacteriuria were excluded.

Ethical approval letter was obtained from ethical review committee (ERC) of school of Biomedical and Laboratory Sciences, College of medicine and health sciences, University of Gondar. We explained the study objectives to the heads of the hospital director and laboratory personnel who worked in the hospital. Consent from patients was not obtained as a waiver of consent by the ERC. In addition, we extracted our research data from a record in which patients’ name was anonymous.

Data collection and analysis

We have collected variables such as age, sex, urine culture result, isolated uropathogens, and their AST results from the UoGCSH Microbiology laboratory record book by using a data collection checklist. The urine specimen was first collected with sterile wide mouthed cup and inoculated on Cysteine-Lactose-Electrolyte-Deficient (CLED) agar. Colonies with a significant number (10⁵ CFU/ml) from CLED agar were subjected to Gram staining and then sub-cultured on MacConkey (Gram negative) and Blood agar plates (gram positive) (BIO MARK Laboratories, India) for identification. Cultures were incubated at 37⁰c for 24 hours. After a series of biochemical tests were performed to identify Gram-negative isolates (performed using Triple sugar iron agar, Urea agar, Citrate agar, Lysine iron agar, Motility medium and Indole test) and Gram-positive isolates (Catalase, coagulase, bile-esculin hydrolysis, and optochin sensitivity). Then, the Kirby-Bauer disk-diffusion method of AST commences on Muller-Hinton agar (BIO MARK Laboratories, India) to determine its susceptibility to antimicrobial agents by incubating at 37⁰c for 18 hours. Antimicrobial discs used were ampicillin (10 μg), amoxicillin-clavulanic acid (20/10 μg), cefoxitin (30 μg), ciprofloxacin (5 μg), gentamycin (10 μg), nitrofurantoin (300 μg), norfloxacin (10 μg), amikacin (30 μg), kanamycin (30 μg), tetracycline (30 μg), tobramycin(10 μg), ceftriaxone (30 μg), nalidixic acid (30 μg), cefuroxime (30 μg), cefotaxime (30 μg), ceftazidime (30 μg), vancomycin(30 μg), meropenem (10 μg), Trimethoprim-Sulfamethoxazole (1.25/23.75 μg), chloramphenicol (30 μg), and penicillin (10 units) (HI Media Laboratories, India). The AST results were collected, and multidrug-resistant (MDR) isolates were identified. Multidrug resistance is the in vitro non-susceptibility to at least one drug in more than two classes of antimicrobial agents [17]. The antimicrobial discs were selected, and AST results were interpreted, based on the clinical laboratory standards institute (CLSI) guideline [18].

The data were summarized and entered into a statistical package for social sciences (SPSS) version 23 software and were analyzed using the software (SPSS) for descriptive statistics. Then, the descriptive results were presented with tables and graphs. The trend of antimicrobial resistance was determined by dividing the number of resistant isolates to the total isolates tested in each year. The data were collected by investigators with data quality and completeness checks throughout the collection period, at the end of data collection, and after entry to SPSS for statistical analysis.

Results

Socio-demographic characteristics and rate of infection

From Jan 2010–2019, the UoGCSH bacteriology laboratory analyzed 4441 urine samples from UTI suspected patients. Of those patients, 54.8% were females. The age group 21–30 years accounts for the highest proportion (27.1%) of UTI suspected patients, while the highest prevalence of UTI (47.4%) falls in the age group 61–70 years, and the least affected (15.4%) falls in the age group 2–10 years (Table 1).

Table 1. The distribution of uropathogenic isolates with sex and age at the university of Gondar comprehensive specialized hospital, 2010–2019.

Variable	Category of variable	Frequency (%)	UTI (significant bacteriuria)
Variable	Category of variable	Frequency (%)	Positive N (%)	Negative N (%)
Sex	Male	2006(45.2)	494(24.6)	1512(75.4)
Sex	Female	2435(54.8)	578(23.7)	1857(76.3)
Age	≤ One year	307(6.9)	64(20.8)	243(79.2)
	2–10 years	702(15.8)	108(15.4)	594(84.6)
	11–20 years	555(12.5)	109(19.6)	446(80.4)
	21–30 years	1205(27.1)	268(22.2)	937(77.8)
	31–40 years	554(12.5)	123(22.2)	431(77.8)
	41–50 years	384(8.6)	97(25.3)	287(74.7)
	51–60 years	285(6.4)	96(33.7)	189(66.3)
	61–70 years	228(5.1)	108(47.4)	120(52.6)
	71 and above	221(5)	99(44.8)	122(55.2)
	Total	4441(100)	1072(24.1)	3369(75.9)

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Key: Frequency (%) column is calculated from the total sample size (4441); UTI rate of each category of variables is calculated row wise.

The proportion of uropathogenic bacterial isolates

A total of 1072 (24.1%) significant bacteriuria of monomorphic bacterial growth was recorded. Of these isolates, 879 (82%) were Gram-negative bacteria. Escherichia coli (37.7%) and K. pneumoniae (11.4%) were the predominant of all isolates while S. aureus (9.14%) was the leading Gram-positive and the third most common of all uropathogenic isolates in this study (Table 2).

Table 2. The proportion of uropathogenic isolates at the university of Gondar comprehensive specialized hospital, 2010–2019.

Species of isolates	Frequency	Percentage (from total UTI patients; 1072)
E. coli	404	37.7
K. pneumoniae	122	11.4
CONS	46	4.3
S.aureus	98	9.14
Prouteus Spp.	17	1.6
Citrobacter Spp	76	7.1
Salmonella Spp	6	0.6
GNR	111	10.34
Enterobacter Spp	37	3.45
Streptococcus Spp	26	2.42
Klebsiella Spp	36	3.35
Pseudomonas Spp	6	0.55
Providencia Spp	5	0.46
K.ozaenae	45	4.2
Shigella Spp	8	0.74
Enterococcus Spp	23	2.14
Serratia Spp	4	0.37
M.morgani	2	0.18

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Key: CONS- Coagulase Negative Staphylococci, GNR-Gram negative rods, Spp- Species.

Antimicrobial resistance pattern of Gram-positive isolates

Gram-positive isolates showed a high resistance to tetracycline (84.8%) and penicillin (71.6%). Antimicrobial agents most effective against Gram-positive uropathogens were vancomycin and nitrofurantoin. Staphylococcus aureus was the most common isolate comprising about 51% of Gram-positive isolates. It was highly resistant to tetracycline (85.7%) and trimethoprim-sulfamethoxazole (83.5%). In addition, 30% of S. aureus were resistant to cefoxitin (Table 3).

Table 3. The proportion of resistant Gram-positive isolates among UTI patients at the University of Gondar comprehensive specialized hospital, 2010–2019.

Antibiotics	CONs N (%)	S. aureus	Streptococcus spp N (%)	Enterococcus spp N (%)	Row Total N (%)
AMP	ND	ND	4/8(50)	7/7(100)	11/15(73.3)
PEN	16/19(84.2)	22/32(68.8)	7/12(58.3)	3/4(75)	48/67(71.6)
CIP	13/20(65)	36/57(63.2)	7/15(46.7)	12/20(60)	68/112(60.7)
GEN	9/24(37.5)	13/30(43.3)	7/11(63.6)	4/7(57.1)	33/72(45.8)
NIT	2/5(40)	3/21(14.3)	1/10(10)	6/12(50)	12/48(25)
NOR	11/15(73.3)	24/39(61.5)	4/6(66.7)	5/7(71.4)	44/67(65.7)
TET	22/26(84.6)	48/56(85.7)	9/12(75)	5/5(100)	84/99(84.8)
CAF	9/18(50)	11/29(37.9)	0/9(0)	1/6(16.7)	21/62(33.9)
FOX	1/1(100)	3/10(30)	1/4(25)	2/2(100)	7/17(41.2)
SXT	17/19(89.5)	33/41(80.5)	12/13(92.3)	9/12(75)	71/85 (83.5)
CRO	9/25(36)	11/35(31.4)	6/11(54.5)	2/4(50)	28/75(37.3)
VAN	ND	ND	1/8(12.5)	2/6(33.3)	3/14(21.4)

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Key: AMP-ampicillin, PEN- penicillin, AMC-amoxicillin-clavulanic acid, CIP- ciprofloxacin, GEN-gentamycin, NIT- nitrofurantoin, NOR- norfloxacin, TET- tetracycline, TOB- tobramycin, FOX- cefoxitin, CRO- ceftriaxone, VAN-vancomycin, NA- nalidixic acid, OXA-oxacillin, ND-not done.

Antimicrobial resistance pattern of Gram-negative isolates

Gram-negative isolates showed a high resistance rate to ampicillin (92.5%), amoxicillin-clavulanate (80.1%), tetracycline (79.3%), cefuroxime (79.2%) and trimethoprim-sulfamethoxazole (78.3%). Their resistance against cephalosporin drugs ranges from 50%-79.2%, while fluoroquinolone resistance was 51.5% - 66.5%. The least resistance was reported against amikacin (20%) and meropenem (26.4%). Escherichia coli, which accounted for 45.9% of Gram-negative isolates showed 88.9%, 83.6%, 76.5%, and 74% resistance to ampicillin, tetracycline, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanate, respectively. All Gram-negative isolates had a high ampicillin resistance ranging from 89–100% (Table 4).

Table 4. The proportion of resistant Gram-negative isolates among UTI patients at the University of Gondar comprehensive specialized hospital, 2010–2019.

Antibiotics	E. coli N (%)	K.pneu moniae N (%)	Proteu s spp N (%)	Citrobacter spp N (%)	Salmon ella spp N(%)	NLFGNR N (%)	Enterob acter spp N (%)	Klebsiella spp N (%)	LFGNR N (%)	Pseudo monas spp N (%)	Provid encia spp N (%)	K.ozaena e N (%)	Shigell a spp N (%)	Serratia spp N (%)	Row Total N (%)
AMP	219/246 (88.9)	64/65 (98.5)	12/13 (92)	48/49 (98)	3/4(75)	32/35 (91.4)	19/20(95.0)	27/27(100)	26/29(89.6)	ND	2/2(100)	21/22(95.5)	4/4(100)	2/2(100)	479/518 (92.5)
AMC	128/173 (74)	44/51 (86.3)	5/9 (55.6)	31/32 (96.9)	3/3(100)	20/27 (74)	9/10(90.0)	15/16(93.8)	16/21(76.2)	ND	2/2(100)	17/19(89.5)	2/2(100)	1/1(100)	293/366(80.1)
CIP	155/279 (55.6)	30/78 (38.5)	8/15 (53.3)	29/57 (50.9)	1/4(25)	20/44 (45.5)	13/20(65)	15/27(55.6)	15/32(46.9)	1/6(16.7)	2/5(40)	15/26(57.7)	5/7(71.4)	1/2(50)	309/602 (51.3)
NOR	122/179 (61.9)	19/48 (40)	4/7 (57.1)	14/34 (41.2)	1/2(50)	18/33 (54.5)	7/13(53.8)	7/17(41.2)	17/26(65.4)	1/4(25)	2/5(40)	14/20(70)	3/5(60)	1/2(50)	230/395(58.2)
NA	45/69 (65.2)	18/29 (66.7)	1/1 (100)	9/14 (64.3)	ND	7/12 (58.3)	3/8(37.5)	8/11(72.7)	10/13(76.9)	ND	ND	7/11(63.6)	1/1(100)	1/1(100)	110/170(64.7)
TOB	33/72 (45.8)	18/29 (62.1)	1/5 (20)	7/14 (50)	ND	6/9 (66.7)	3/4(75)	1/4(25)	2/7(28.6)	1/1(100)	ND	2/9(22.2)	1/3(33.3)	0/1	75/158(47.5)
GEN	103/240 (42.9)	35/58 (58.6)	7/13 (53.8)	20/36 (55.6)	2/3(66.7)	19/30 (63.3)	14/17(82.4)	8/15(53.3)	16/29(55.2)	1/4(25)	2/4(50)	15/22(68.2)	3/5(60)	ND	245/476(51.5)
AMK	6/25(24)	4/11 (36.4)	ND	0/11	ND	2/3 (66.7)	0/5	0/2	0/3	0/1	ND	1/4(25)	ND	ND	13/65(20)
KAN	7/13(53.8)	5/7 (71.4)	ND	1/1 (100)	1/1(100)	1/1 (100)	1/1(100)	ND	1/2(50)	ND	ND	1/2(50)	1/4(25)	ND	19/32(59.4)
NIT	21/133 (15.8)	13/41 (31.7)	4/4 (100)	11/21 (52.4)	ND	12/24 (50)	2/7(28.6)	6/7(85.7)	5/17(29.4)	3/3(100)	ND	0/11	0/1	1/1 (100)	78/270(28.9)
SXT	186/243 (76.5)	55/66 (83.3)	8/10 (80)	29/37 (78.4)	2/3(66.7)	33/38 (86.8)	15/17(88.2)	16/20(80)	15/21(71.4)	3/5(60)	3/3(100)	24/29(82.8)	3/7(42.9)	1/3 (33.3)	393/502(78.3)
TET	163/195 (83.6)	33/46 (71.7)	10/11 (91)	31/40 (77.5)	0/1	24/29 (82.8)	14/18(77.8)	16/18(88.9)	19/24(79.2)	2/3(66.7)	4/5(80)	12/18(66.7)	2/5(40)	2/2 (100)	332/415(79.3)
CAF	43/163 (26.4)	22/38 (57.9)	8/10 (80)	17/32 (53.1)	1/2(50)	12/20 (60)	9/15(60)	5/13(38.5)	9/18(50)	2/2(100)	1/4(25)	9/15(60)	2/5(40)	1/1 (100)	141/338(41.7)
CRX	26/38 (68.4)	15/17 (88.2)	1/3 (33.3)	5/5 (100)	1/1(100)	6/6 (100)	3/3(100)	2/2 (100)	4/6(66.7)	1/1(100)	ND	8/9(88.9)	1/1(100)	ND	73/92(79.3)
CRO	93/205 (45.4)	33/54 (61.1)	5/14 (35.7)	27/41 (65.9)	2/3(66.7)	18/27 (66.7)	9/11(81.8)	17/24(71)	14/22(63.6)	1/2(50)	2/4(50)	15/17(88.2)	3/6(50)	1/2(50)	240/432(55.6)
FOX	6/18(33.3)	¾ (75)	ND	3/5 (60)	ND	1/1(100)	1/2(50)	2/3(66.7)	2/3(66.7)	1/1(100)	ND	1/2(50)	ND	ND	20/39(51.3)
CTX	4/10(40)	4/4 (100)	ND	0/4	1/1(100)	0/1(0)	2/3(66.7)	0/1	2/2(100)	ND	ND	ND	ND	ND	13/26(50)
CAZ	14/25 (56)	6/10 (60)	0/2	1/4 (25)	ND	3/3 (100)	2/3(66.7)	1/3(33.3)	3/6(50)	ND	ND	5/5(100)	0/1	ND	35/62(56.5)
MER	9/34 (26.5)	3/17 (17.6)	0/2	2/7 (28.6)	ND	4/9 (44.4)	4/5(80)	0/2	0 /3	ND	ND	2/9(22.2)	0/3	ND	24/91(26.4)

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Key: AMP-ampicillin, AMC-amoxicillin-clavulanic acid, CIP- ciprofloxacin, GEN-gentamycin, NIT- nitrofurantoin, NOR- norfloxacin, AMK-amikacin, KAN-Kanamycin, TET- tetracycline, TOB- tobramycin, FOX- cefoxitin, CRO- ceftriaxone, NA- nalidixic acid, CRX-cefuroxime, CTX-cefotaxime, CAZ-ceftazidime, MER- meropenem, SXT-Trimethoprim-Sulfamethoxazole, CAF-chloramphenicol, LFGNR-Lactose fermenting Gram negative rods, NLFGNR- None lactose fermenting Gram negative rods, ND-not done, N- Number of organisms of a specified species tested to each antimicrobial agent. Numerators represent number of resistant bacteria to each antimicrobial while the denominators are the number of bacteria tested against each antimicrobial agent (both resistant and susceptible).

The yearly basis of resistance pattern of the classes of antimicrobial agents

The resistance rate of isolated bacteria was seen to be inconsistent to the majority of the tested antimicrobial classes. However, the resistance to cephalosporins has been rising, particularly from 2014 to 2019 (Table 5).

Table 5. Yearly basis of antimicrobial resistance to classes of antimicrobial agents, 2010–2019.

	Number N (%) of isolates tested to each class of antibiotics
Class	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019	Total
Penicillin	133/144 (92.4)	98/114(86)	148/175 (84.6)	109/119 (91.6)	81/89 (91)	71/79(90)	35/43(81.4)	42/48(87.5)	75/97(77.3)	49/58(84.5)	841/966 (87.1)
Fluoroquinolone	97/177 (54.8)	67/125 (53.6)	104/174 (59.8)	92/165(55.8)	78/126(61.9)	42/87(48.3)	29/65(44.6)	83/133(62.4)	93/160(58.1)	80/129(62)	765/1341(57)
Aminoglycoside	54/100(54)	29/58 (50)	10/23 (43.5)	39/61(63.9)	33/68(48.5)	30/63(47.6)	14/24(58.3)	26/52(50)	93/222(41.9)	57/122(46.7)	385/793(48.5)
Cephalosporin	44/56(78.6)	32/43 (74.4)	27/56(48.2)	54/94(57.4)	34/76 (44.7)	30/56(53.6)	14/25(56)	11/19(57.9)	90/127(70.9)	80/113(70.8)	416/665(62.6)
Folate pathway inhibitor (SXT)	80/95 (84.2)	51/69 (73.9)	15/22 (68.2)	26/37(70.3)	35/42 (83.3)	37/53 (69.8)	30/36 (83.3)	60/69(87)	62/79 (78.5)	68/85 (80)	464/587(79)
NIT	ND	ND	ND	ND	9/29 (31)	9/49 (18.4)	4/28 (14.3)	8/40 (20)	37/109(33.9)	23/63 (26.7)	90/318(28.3)
TET	79/102(77.5)	61/77 (79.2)	67/81 (82.7)	76/91(83.5)	39/49 (79.6)	49/56(87.5)	21/29 (72.4)	5/7 (71.4)	13/15 (86.7)	6/7 (85.7)	416/514(80.9)
CAF	41/97 (42.3)	26/66 (39.4)	7/23 (30.4)	27/43(62.8)	25/78 (32.1)	12/29(41.4)	3/15 (20)	12/31(38.7)	5/10 (50)	4/8 (50)	162/400(40.5)
Carbapenem	ND	ND	ND	ND	ND	ND	ND	ND	13/53 (20.8)	11/38 (28.9)	24/91 (26.4)
Glycopeptide (VAN)	ND	ND	ND	ND	ND	ND	ND	ND	2/9 (22.2)	1/5 (20)	3/14 (21.4)

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ND- Antimicrobial susceptibility test was not done, VAN- vancomycin.

Antimicrobial resistance (AMR) trend and multidrug resistance (MDR) rate of isolates

In the last ten consecutive years (2010–2019), the antimicrobial resistance trend of uropathogens ranges from 50 to 66.5%. The resistance rate was highest (66.5%) in 2012, and the lowest (50.2%) observed resistance was in 2016. From 2012 to 2016, there was a reduction in antibiotic resistance rates. However, there was a slight increment in the resistance rate from 2016 to 2019 (Fig 1).

Multidrug-resistant (MDR) isolates were 473 (44.1%) of the total 1072 uropathogens. E. coli 199 (42.1%) and K. pneumonia 51(10.8%) were the predominant MDR uropathogens, which together account for more than half of the total MDR isolates. Among Gram-positive uropathogens, S. aureus 31(6.6%) was the leading MDR isolate, placed 4^th among all MDR isolates (Fig 2).

Fig 2 — Key: Proteus 7(1.5%), shigella 5(1.1%), Providencia 3(0.6%), Pseudomonas 2(0.4%), Salmonella, Serratia, M. *morganii* 1(0.2%) each.

Discussion

Globally, human health is in danger from antimicrobial-resistant infection. To strengthen knowledge of AMR through surveillance and research World Health Organization (WHO) opened a program called the Global Antimicrobial Resistance Surveillance System (GLASS). Escherichia coli, K. pneumoniae, and S. aureus, which are the leading etiologic agents of UTI and common resistant bacteria, are among the GLASS targets [19]. Epidemiological studies with time in different geographic regions are the first and vital steps for selecting effective antimicrobial agents for treatment, preventive and control actions [20]. The overall prevalence of UTI in this study was 1072(24.1%) [95% CI, (22.9–25.4)], with a proportional infection rate in males (24.6%) and females (23.7%). This finding is consistent with results from studies conducted in Dessie (22.7%) [21] and Addis Ababa, Ethiopia (23.32%) [22], as well as other parts of the world such as India (22.8%) [23] and central Europe (26.9%) [24]. The age-wise distribution of the infection reveals 47.4% UTI in the elderly population above 60 years. In contrast, according to a study done in Addis Ababa the most affected age group of participants was the age group 21–30 years [22]. Similar to our study, an increased infection rate in the elderly participants has been reported elsewhere [16]. The elderly population might be at risk of acquiring UTI due to age-related weakened immunity, change in vaginal hormonal secretion, or other comorbidities [25]. On the other hand, the rate of UTI in our study was lower than studies conducted in Bahir Dar, Ethiopia (30.5%) [26], India (38.84%) [27], India ((28.2%) [28], Sudan (91%) [29], but higher than the prevalence studies conducted in Iran (15%) [20] and India (15.9%) [30]. Geographic and population differences, study design, or the laboratory method used among studies may explain the difference in the prevalence rate.

Regarding the proportion of bacterial isolates in this study, E. coli 404 (37.7%) was the leading isolate among uropathogens, followed by K. pneumoniae (11.4%) and S. aureus (9.14%). Similar findings have been reported in different geographic regions; Gondar [16], Bahir Dar [26] and Hawassa [31], and Addis Ababa, Ethiopia [27], and India [28].

The resistance rate of Gram-positive isolates was high to agents such as tetracycline (84.8%), trimethoprim-sulfamethoxazole (83.5%), fluoroquinolones (60.7–65.7%), and penicillin (71.6%). This figure is much higher than the resistance rate (34.6%) reported in Iran [20]. Moreover, more than 75% of Gram-negative isolates in this study, were resistant to ampicillin (92.3%), amoxicillin-clavulanate (80.1%), tetracycline (79.3%), cefuroxime (79.2%), and Trimethoprim-sulfamethoxazole (78.3%). Escherichia coli isolates were highly resistant to ampicillin (88.9%), tetracycline (83.6%), trimethoprim-sulfamethoxazole (76.5%), and amoxicillin-clavulanate (74%). The resistance rate continues to grow even for those antimicrobial agents including cefuroxime (68.4%) which are limited to selected tertiary hospitals. Comparable resistance rate among isolates were reported in Sudan; ampicillin (94%), amoxicillin-clavulanate (90%), tetracycline (76%), norfloxacin (74%), trimethoprim-sulfamethoxazole (88%) and ceftriaxone (68%) [31]. In this study, more than half of the Gram negative isolates were resistant to fluoroquinolones which outnumbers a report in the USA (24.3%-25.8%) [32]. Moreover, nitrofurantoin (35%), ciprofloxacin (28.8%), and ceftriaxone (25.9%) were better agents for uropathogens in another study [33].

In this study, 26.4% and 20% of Gram-negative isolates were resistant to meropenem and amikacin respectively. It is worrisome because these agents were considered the most effective agents in treating UTIs [32]. Furthermore, the rate of resistance of uropathogens to amikacin (20%), ciprofloxacin (51.3%), and cefuroxime (79.3%) in this study were lower than the resistance rate reported in Turkey [34]. Different reports showed that uropathogens are highly resistant to ampicillin, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole [33, 34]. The recommendations from national guidelines for antimicrobial use in different countries could have resulted in varying resistance among countries [35]. The resistance trend of uropathogenic isolates over ten consecutive years (January 2010–2019) ranges from 50.2% in 2016 to 66.5% in 2012. The resistance rate of isolated bacteria to antimicrobial classes was inconsistent but the resistance to cephalosporins has shown increasing pattern particularly from 2014 to 2019. Absence of uniform supply and hence, irregular use of these antibiotics in the laboratory can be mentioned for such inconsistent trend of resistance. The rising resistance to cephalosporins may be due to the rising preference and clinical use of this agent.

This study showed an inconsistent trend of the overall resistance rate with a reducing rate between 2012 and 2016, while a slight increment from 2016 to 2019. In general, the overall resistance rate surpasses 50% over the study period (Fig 1). Moreover, there were vancomycin-resistant Enterococcus species (33.3%) in this study, which was a higher prevalence than a report (14.8%) by Melese et al. in Ethiopia [36] but lower than 54% resistance reported in Sudan [29]. In addition, 6(50%) nitrofurantoin resistant Enterococcus species were isolated in this study which was higher than (9.8%) vancomycin and (0–40%) nitrofurantoin resistant Enterococcus species reported in England [37]. Methicillin-resistant S. aureus (MRSA) is an emerging threat evolving rapidly, and 30% of MRSA strains were isolated in this study which needs an urgent response [38].

Multidrug resistance is a concern of the medical community because there is a run out of effective antimicrobial agents to relieve the suffering of patients and save lives [39]. We found a total of 473(44.1%) MDR UTI which concords to a result reported in Tunisia (45.1%) [40]. However, our finding was higher than 25% in Portugal [41] and 36.5% in Germany [42]. The result of this study otherwise, was lower compared to results from Hawassa, southern Ethiopia (80.3%) [31], in Serra Leone (85.7%) [43], Saudi Arabia (80%) [1] and Serbia (53.8%) [44]. The Geographic variation, limited activity towards implementation of antimicrobial stewardship program, and a different definition of MDR might contribute to the observed differences. The species E. coli (42.1%), K. pneumonia (10.8%), Citrobacter species (8.7%), and S. aureus (6.6%) were the most common MDR isolates in this study. This result was lower than the 79.3% MDR in southern Ethiopia among HIV patients [45], who frequently take antibiotics and are at higher risk of MDR infections. In general, MDR, Carbapenem resistance, MRSA, and vancomycin resistance have been observed in this study. Hence, healthcare professionals and other stakeholders need to be curious about the supply and control of antimicrobial agents as we are on the verge of loss of effective agents [20]. Considering the existing resistance in the hospital from our result, healthcare providers in the hospital would selectively use the effective antibiotics. The global community would understand the burden of resistance in the area and design comprehensive policies by aggregating with reports from diverse geographic settings. Limitation, as the study was a retrospective study, we did not analyze factors contributing to resistance. The resistance trend of each species was not determined because of inconsistent use of antimicrobials to each species. In addition, it is a single-center hospital-based study among symptomatic patients. We were also not able to differentiate between inpatients and out patients and compare the rate of UTI. As the laboratory did not have any molecular based detection, this study was limited to conventional culture-based results.

Conclusions

The overall of prevalence of UTI was high and elderly patients were most affected. Escherichia coli was the most common bacterial uropathogen, followed by K. pneumonia and S. aureus. Multidrug resistance in this study is high, which alarms a need for problem resolution using routine diagnosis and antimicrobial susceptibility testing rather than empirical treatment. A continuous revision of UTI treatment guideline to replace ineffective agents with potent alternatives should be done. A prospective multicenter study including asymptomatic population is indispensable to know status of resistance.

Acknowledgments

We would like to acknowledge the Microbiology laboratory and the hospital management of UoGCSRH for their genuine cooperation to ensure this research work.

List of abbreviations

AMR: Antimicrobial resistance
AST: Antimicrobial Susceptibility Test
CLED: Cysteine Lactose Electrolyte Deficient
CLSI: Clinical Laboratory Standards Institute
CMHS: Collage of Medicine and Health Science
MDR: Multidrug Resistance
MRSA: Methicillin resistant staphylococcus aureus
SBLS: School of Biomedical and Laboratory Science
UoGCSH: University of Gondar Comprehensive Specialized Hospital
UTI: Urinary tract infection

Data Availability

Data cannot be shared publicly because of ethical restriction of human research data as the patient data is private and the ethical review committee (ERC) of School Biomedical and Laboratory Sciences, College of Medicine and Health sciences, University of Gondar limits publicly sharing the data. Data are available from the ethical review committee (ERC) (contact via the E-mail: abty12@gmail.com or deme2112@gmail.com) for researchers who meet the criteria for access to confidential data. The data underlying the results presented in the study are available from the Ethical Review Committee (ERC) of School Biomedical and Laboratory Sciences, College of Medicine and Health sciences, University of Gondar can be accessed by the E-mail abty12@gmail.com or deme2112@gmail.com.

Funding Statement

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0266878.r001

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13 Aug 2021

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Antimicrobial Resistance Trend of Bacterial Uropathogens at the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia: A 10 years retrospective study

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: dear authors

there are several lacunae in the methodology part with respect to inclusion and exclusion criteriae. more than one loose statements have been made without citations. quite a lot of errors seen in the discussion section too. kindly provide the details of analysis made for making out the the trends in antimicrobial resistance over years. kindly go through the comments and make the necessory revisions

Reviewer #2: General Comment:

Interesting topic about AMR, observing 10 years laboratory-data to establish the local guidance. Enormous number of isolate collecting in single hospital as study site.

Specific Comment:

In method section, sub-section Study area (Line 92), it is stated “We have collected ten years (2010-2019) retrospective data from the microbiology laboratory logbook”. This should describe more detailed e.g mention how does the author confirm the adequate data and represent for each year period? Moreover, the author should also mention the consistency of practical work in the laboratory for ten years, i.e. method of susceptibility testing, antimicrobial disk used. I think this is very important point as the strength of the manuscript.

In method section, sub-section population (Line 94-95), it is stated “all symptomatic patients who visited the hospital from 2010-2019 and had recorded urine culture results were the study population”. Please describe how does the author perform the screening of the patient!

This is important information to be added in the method section. Moreover, description about elaboration data with microbiology aspect is needed, as appear in Line 129-130: “The data were collected by investigators with quality and completeness checks throughout the collection period, at the end of data collection, and after entry to SPSS for statistical analysis.” Also, need to define the definition for trend of AMR in this study!

In method section, the author should mention how the percentage calculation for resistance trend among antibiotic tested. What is denominator of the calculation? This information is still missing from the method section.

In the inclusion criterion, I think it seems like “negative” statement or opposite from inclusion, please clarify!

In Line 110 – 121: Does it show microbiology procedure? Please write more clearly and elaborate with whole process of the study.

Result:

In line 134, the author mentioned about “UTI suspected patient”; but in population section, it was described “all symptomatic patients” (Line 94-95), which means not suspected patient. Please clarify for this sentence! If the author started with suspected patient, then provide the number of patient being suspected and mentioned how many of this become symptomatic patient with culture-proven UTI.

In table 2: the percentage is confusing and need to defined properly in method section (see the method comment). There is number of 4441, which indicate the number of total specimen, and number of 1072, which indicate the isolate included based on study criteria. Please explain for this two-different information!

Lot of mistype for species name i.e Prouteus, Klebsella. Author need to check all the typing for species name. Also, consistency for using italic formatting.

In table 3 and 4: what does the number in bracket indicate? Please provide clear calculation for this table. What is the denominator for the calculation?

I think the figure 1 and 2 is main finding of this study and should be attached in the body of manuscript, instead as supplementary figure. the result should more address the trend of bacterial and antimicrobial from 10 years observation, instead of mentioned single species with resistance profile.

Discussion:

I don’t see the discussion related with trend as the main title of the manuscript. Please correlate the finding with the term of Trend as mentioned with title of this study.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2022 Apr 11;17(4):e0266878. doi: 10.1371/journal.pone.0266878.r002

Author response to Decision Letter 0

17 Sep 2021

Response to reviewer(s)

A. To PLOS ONE RVIEW

We are pleased that you, the PLOS ONE editorial team, offered us an invitation to revise our manuscript for the PLOS ONE journal. Also, we appreciate you for assigning such talented and qualified reviewers to our manuscript. We believed that their valuable comments helped us to improve our work.

1. Line 60- Pyelonephritis and kidney infection are almost same.

Response: Yeah, these terms are referring to infections of the upper urinary tract. We have revised and corrected it.

2. Line 61.62- suprapubic tenderness is a sign.

Response: “Suprapubic tender ness” has been included in a list of signs in many articles including the cited article. But now we have amended as sign and symptoms.

3. 62.63- could be corrected as bacterial causes as UTI can be due to fungal species like candida

Response: Thanks for your suggestion, and now we have amended it.

4. 68- Adherence to urethral mucosa? is it unique for female sex alone?

Response: Thank you for raising this issue. It is not unique for female sex alone, therefore, we have amended the sentence

5. 69- Kindly clarify the usage of the term “directly associated”. Doesn’t sound right.

Response: Thanks! We have revised and amended. As UTIs are among the most frequently treated infections, especially among women, it is obvious that exposure or usage of antibiotics will be increased, which intern hastens the emergence of antibiotic resistance. Hence these infections and drug resistance can have direct association.

6. 74- You mean Ethiopia alone?

Response: No, we don’t mean that Ethiopia is the only one affected by these factors. The mentioned problems are also reported in many countries. These practices have been widely perpetuated in Ethiopia because of loose control system and wide availability of drugs without prescription in Ethiopia. There is a minimal attention to prevention of antimicrobial resistance in the country and awareness about the misuse or/and overuse of antibiotics in the community.

7. 78- Suggest usage of appropriate empirical treatment rather than appropriate treatment alone as most UTIs are treated empirically based on prevalent antimicrobial pattern.

Response: Thank you for your suggestion, and now we have amended it.

8. 81.82.83-sentence can be reframed to include trend over 10 years between 2009 and 2019. Response: Amended as suggested but it is from 2010 to 2019, not 2009 to 2019.

9. 86- study period should include the period from which the study sample is selected rather than the period at which the data is collected.

Response: The period is included as per the comment and the sentence is written as “A Hospital-based retrospective cross-sectional study was conducted by retrieving laboratory record of ten years (2010-2019) data from January 1st to February 28th, 2020 at the UoGCSH, Gondar, Ethiopia”

10. 92- Was it a manual retrieval or retrieval from computerized data?

Response: We have retrieved the data manually from the Laboratory paper-based record book

11. 93, 94- did the study included patients of all ages from birth to the maximum age recorded? If so any difference in the criteria for interpreting the results was applied between pediatric UTI and adult UTI? Did the study include outpatients or inpatients or both?

Response: Yes, this study included UTI patients irrespective of age group as per the inclusion criteria (having a complete record of the variables mentioned in the inclusion criteria). There were not any different criteria for interpreting UTI between pediatric and adults or any other age group. The microbiology laboratory at the UoGCSH uses growth of 105 CFU/ml as a criterion for defining significant bacteriuria. We have used a record-based data and not able to identify between outpatients and inpatients. We could not determine the number of outpatients and inpatients as the origin of specimen was not recorded in the laboratory result registration book. We know that the UoGCSH laboratory receives urine for culture from inpatient and outpatients, therefore, we believe that both inpatients and outpatients were included in this study.

12. 96- What was the total number of samples recorded in the log book and how many were excluded based on your exclusion criteria. how many were excluded because of lack of information like age and sex in spite of having positive culture reports, which can influence the analysis?

Response: We have collected and analyzed records, which have full data of our target variables but the total number of the recorded urine culture results were 4209, of which 4088(included for analysis in this study) and 121 (rejected from this study because of missing of one or more of our inclusion criteria). Herewith we have mentioned the number and reason for exclusion in a table below.

Number of samples rejected N=121 Reason for rejection

7 Age was not recorded or missed

18 Sex was not recorded or missed

83 Age and sex were not recorded or missed

11 Culture result was not recorded

2 Isolated organism was not recorded

13. 111- “organisms” would be better term rather than” colonies” with significant

Response: Thank you for your suggestion. We have changed it to “organisms”.

14. 125- Which version of CLSI guidelines? As the guidelines get revised periodically, kindly be more specific.

Response: Yes, it is known that CLSI is revised in a year basis, and the laboratory uses yearly uprated versions of the CLSI. So, a single year CLSI guideline has not been used.

15. 127. “The quality and completeness of patients’ urine culture records, as well as antimicrobial susceptibility results, were checked”. Can you clarify the statement as it is repeated again in the next sentence?

Response: Thank you for pointing this out. We have corrected it.

16. 135 UTI suspected patients? According to the exclusion criteria patients without antimicrobial susceptibility testing were excluded from the study. Then how come they are included in the results? Kindly clarify.

Response: We used “UTI suspected patients” to express those patients with urinary tract complain and for whom urine culture test was requested.

Patients without antimicrobial susceptibility testing result were excluded from the study which mean patient with significant bacteriuria but no AST recorded. This means for patients with significant bacteriuria, although records of age, sex, and significant bacteriuria were available, they were excluded if records of their antimicrobial susceptibility test results were not available, if result was “significant bacteriuria”, AST must also be recorded to include into the study. This does not mean that the isolate must be tested to all the mentioned antimicrobial agents. The isolated organisms were tested to different agents depending on their availability in the laboratory. Records without significant bacteriuria were also included if all variables age, sex and culture result (no significant bacteriuria) were recorded.

17. 152,153- There is no information about antibiotic susceptibility in table 2 while it has been cited here. Highly irrelevant.

Response: Thank you! We have modified it.

For understanding we have mentioned that “only two Morganella morganii (M. morganii), both resistant to ampicillin and amoxicillin-clavulanate, and either of which being resistant to gentamycin, trimethoprim-sulfamethoxazole, tetracycline, ciprofloxacin, tobramycin, and nalidixic acid were recorded (Table 2)”

Here, the antimicrobial susceptibility test was not written because only 2 Morganella morganii isolates were isolated and tested and their susceptibility results for the tested antibiotics was as mentioned in the text. Their susceptibility was omitted from the table 4 to minimize crowding. The table 2 was cited for the species of isolated organisms, not to the antimicrobial susceptibility testing. But now we have canceled it to avoid confusion.

18. 156 table took looks very irrelevant what is the meaning of calculating the percentage with the overall urinary samples when it is already calculated for positive cultures alone?

Response: We have used Table -2 to indicate the proportion of each bacterial species from the total isolates. However, as it is suggested, the proportion from the total number of urine sample (column 3) could have been omitted and now corrected.

19. 185 table could have been better with the explanation for numbers and percentages in the heading row (does it mean the percentage positive out of total numbers tested?)

Response: Thank you for your suggestion. We have reported the resistant isolates using frequencies and percentages. Each percentage were calculated by dividing the number of the same bacteria (e.g., E. coli) reported as resistant to a particular antibiotic agent (e.g., Ceftriaxone) from the total number of that bacteria (resistant or sensitive) tested against the same agent.

20. 192- kindly explain the methodology by which this trend is obtained in the methodology section itself. how this resistance percentage was calculated? And this is for all organisms? One should understand that CLSI guidelnies get changed every year and the antimicrobial susceptibility testing and reporting also changes. does this trend show the prevalence of MDR pathogens over years? No clear information. calculating over all prevalence for ten years doesn’t add much to the community. Not sure whether this might help in surveillance.

Response: Thank you for your questions. We have explained the trend in the method based on your suggestion. In fact, we have explained the overall resistance trend on a year basis. We have shown the plot of resistance pattern (it may be the sum of mono resistant and/or MDR isolates) reported over ten years but not the trend of MDR isolates.

21. 201. Kindly remove the statement threat as we have more severe threats than UTI S.

Response: corrected accordingly.

22. 211. there is a huge difference in prevalence from elderly in the previous study and younger age group in the current study. Did the earlier study include all patients from birth? Clarify? If so, one cannot compare.

Response: The studies we used here for comparison with our result have similar population to our study population.

23. 213,214,215 what is the relevance of these statements to the current study?

Response: These have been included to mention the possible rationale that support our result in which UTI was higher in the elderly populations.

24. 236 isolates exceeded 50 percent? Statement or poorly framed and unclear

Response: The statement has been rewritten to make it clear.

25. 244.245 seems to be a loose statement. Is there any reference for local usage of antibiotics statment?

Response: We have used the term “local usage” to refer the national guidelines for antimicrobial use (we have changed the term to national guidelines for antimicrobial use. Different countries use their own guidelines for antimicrobial use as per their countries’ situations like economic, or distribution of antimicrobial resistance. (Food E. Medicine and Healthcare Administration and Control Authority. Continuing Professional Development (CPD) Guideline for Health Professionals in Ethiopia Addis Ababa: FMoH. 2013. https://www.who.int/selection_medicines/country_lists/Ethiopia_STG_Hosp.pdf)

26. 267 again seems to be a loose statement? Any reference for usage of antibiotics in hiv patients?

Response: It is known that HIV patients are at greater risk of other infections and hence, they are likely to get antibiotics for these infections. Such a high risk of infection and resulting antibiotic treatment may increase the risk of resistance. The WHO has recommended prophylactic prescription of trimethoprim-sulfamethoxazole for HIV infected children. The cited reference itself has described it.

Reference: (https://doi.org/10.1371/ journal.pone.0243054)

27. 274 earlier it was said that age groups 20- 30 was more affected, this statement is in contradiction with that. Kindly clarify. If its elderly, then define elderly and cite the appropriate analysis for that in results and discussion.

Response: As it is described in the result and table-1, the highest proportion of UTI suspected patients were in the age group 21–30 years (27.1%). However, the rate of infection was highest in the age group 61-70 years (47.4%) followed by patients of the age group above 70 years (44.8%). So, the point we have written in line 274 or in the conclusion is not conflicting. We think you may have seen in the line number -212, “the age group 21-30 was the most affected” but that was not our result rather it was a result reported in Addis Ababa, another part of Ethiopia and used here for comparison.

B. RESPOSES TO REVIEWER(S)

1. Reviewer #1: dear authors

There are several lacunae in the methodology part with respect to inclusion and exclusion criteriae. more than one loose statement has been made without citations. quite a lot of errors seen in the discussion section too. kindly provide the details of analysis made for making out the trends in antimicrobial resistance over years. kindly go through the comments and make the necessary revisions

Response: We appreciate you for taking time to thoroughly review this manuscript and offer us your constructive comments and suggestions which will strengthen the quality of our work. We have revised the manuscript and made corrections as necessary based on your comments. We have tried to find and cite appropriate references to every information stated. We also have invited a professional English editor and so, the language and grammatical issues have been curiously amended.

2. Reviewer #2: Comments:

In method section, sub-section Study area (Line 92), it is stated “We have collected ten years (2010-2019) retrospective data from the microbiology laboratory logbook”. This should describe more detailed e.g., mention how does the author confirm the adequate data and represent for each year period? Moreover, the author should also mention the consistency of practical work in the laboratory for ten years, i.e., method of susceptibility testing, antimicrobial disk used. I think this is very important point as the strength of the manuscript.

Response: we appreciate your concern about the adequacy and representativeness of the data. We have collected patients’ records which were complete record of the variables mentioned in the inclusion criteria within the whole study period. Moreover, representativeness of the collected data should not be the concern here because we have collected all the available data processed each year and contain complete record of the required variables, we did not take a sample.

Regarding the consistency of the laboratory work: The Hospital is one of the biggest pioneering hospitals in the country, Ethiopia. The laboratory performs microbiology culture constantly throughout the year and had no interruption over the study period. We know the laboratory as we are working with the hospital and one of the authors, Mr. Michael Getie, is manager of the microbiology laboratory. The UOGCSH microbiology laboratory had been using disc diffusion method of AST has been used in the laboratory. The antimicrobial agents could have been used up for a brief period until purchased but as the national antimicrobial treatment guideline was not changed long term discontinuation of antimicrobials has not occurred and antimicrobial disk used have been are mentioned in the method section. So, commonly prescribed discs have been used consistently.

3. In method section, sub-section population (Line 94-95), it is stated “all symptomatic patients who visited the hospital from 2010-2019 and had recorded urine culture results were the study population”. Please describe how the author performs the screening of the patient! This is important information to be added in the method section. Moreover, description about elaboration data with microbiology aspect is needed, as appear in Line 129-130: “The data were collected by investigators with quality and completeness checks throughout the collection period, at the end of data collection, and after entry to SPSS for statistical analysis.” Also, need to define the definition for trend of AMR in this study!

Response: As this study is based on a retrospective data, we have retrieved the record for urine cultures and collected the data of patients whose age, sex, urine culture result, and antimicrobial susceptibility results (for those with significant bacteriuria) have fully recorded. So, we have not screened patients. We had been cross-checking and re-checking data on a daily basis for the readability, correct data transcription to the data collection checklist, complete filling of the intended variables

4. In method section, the author should mention how the percentage calculation for resistance trend among antibiotic tested. What is denominator of the calculation? This information is still missing from the method section.

Response: the percentage of resistance was tested by dividing the resistant isolates to the total number of tested isolates to each antibiotic. The percentage of resistance trend was calculated by dividing the sum of resistant isolates in a year to the sum of isolates tested to each agent in the same year. E.g., the sum of resistant isolates identified in 2019/ number of urinary pathogens isolated tested in 2019.

5. In the inclusion criterion, I think it seems like “negative” statement or opposite from inclusion, please clarify.

Response: We have included the patients’ data if the following hade ben completely recorded

� Age, Sex

� Urine culture result (both significant bacteriuria and no significant bacteriuria)

� Isolated uropathogen antimicrobial susceptibility result (for the result with significant bacteriuria)

6. In Line 110 – 121: Does it show microbiology procedure? Please write more clearly and elaborate with whole process of the study.

Response: it shows a precise procedure of the urine culture conducted in the microbiology laboratory, where the data was collected. But we have not gone through these laboratory procedures rather we have collected the result done by performing all these procedures as per the standard laboratory operating procedure and the Clinical Laboratory Standards Institute (for selection of antimicrobials and reporting result as susceptible and resistant)

7. Result:

In line 134, the author mentioned about “UTI suspected patient”; but in population section, it was described “all symptomatic patients” (Line 94-95), which means not suspected patient. Please clarify for this sentence! If the author started with suspected patient, then provide the number of patients being suspected and mentioned how many of this become symptomatic patient with culture-proven UTI.

Response: First sorry for the inconvenience, and in the study area, patients showing signs and symptoms are suspected or presumptive UTI patients and will be supposed to give urine for urine culture for microbiological confirmation. When we suspected patients, we mean patients having signs and symptoms of UTI and all suspected patients were symptomatic patients in this study. so, now we have corrected as “UTI suspected” patients.

8. In table 2: the percentage is confusing and need to defined properly in method section (see the method comment). There is number of 4441, which indicate the number of total specimens, and number of 1072, which indicate the isolate included based on study criteria. Please explain for this two-different information!

Response: The number 4441 is the total number of collected patients’ data (both with significant bacteriuria and with no significant bacteriuria), while the number 1072 represents the total number of patients with significant bacteriuria or simply confirmed UTI patients) but all 4441 patients were included in this study. The % in the 3rd column of table 2 is the percentage of each species of isolate from the total number of patients’ while the 4th column is the percentage of each species of isolate to the total number of patients with significant bacteriuria or total number or organisms isolated in this study.

9. Lot of mistypes for species name i.e Prouteus, Klebsella. Author need to check all the typing for species name. Also, consistency for using italic formatting.

Response: We have revised and corrected the misspelled organisms.

10. In table 3 and 4: what does the number in bracket indicate? Please provide clear calculation for this table. What is the denominator for the calculation?

In these tables, the denominators indicate the total number of species of isolates tested against to each antimicrobial agent and in the last column the denominator is the total number of all isolates tested to each antimicrobial agent. The denominator is not constant because number of organisms tested varies. The numerator is the percentage of isolates which were resistant from the total tested organisms to a specific antimicrobial tested in a row. The numbers in bracket of in table 3 were the total number of each species isolate and we have canceled the numbers as it is found in table 2 and to avoid repetition.

11. I think the figure 1 and 2 is main finding of this study and should be attached in the body of manuscript, instead as supplementary figure. the result should more address the trend of bacterial and antimicrobial from 10 years observation, instead of mentioned single speces with resistance profile.

The tables were included in the body of the manuscript, but figures were attached as separate file according to the journal manuscript submission guideline.

Discussion:

I don’t see the discussion related with trend as the main title of the manuscript. Please correlate the finding with the term of Trend as mentioned with title of this study.

Response: We have tried to discuss the trend as stated in the discussion part (line 253-259)

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PLoS One. doi: 10.1371/journal.pone.0266878.r003

Decision Letter 1

Monica Cartelle Gestal

14 Oct 2021

PONE-D-21-22966R1Antimicrobial resistance trend of bacterial uropathogens at the university of Gondar comprehensive specialized hospital, northwest Ethiopia: a 10 years retrospective studyPLOS ONE

Dear Dr. Kasew,

The resistance percentage is calculated for overall isolates and the trend shows it has been stable over years and has reduced now. I recommend you to clarify the exact criteria used for defining resistance isolates and whether it is applicable for all the years of the study, which is unlikely as clsi guidelines change every year.Please pay attention to all reviewer comments and submit as early as your convenience.

Please submit your revised manuscript by Nov 28 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Monica Cartelle Gestal, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Most of the errors which have been pointed out have been corrected

The calculation of trends for individual species could have been a better parameter rather than calculating for overall species. The trend pattern suggests reduction in the percentage of resistance isolates in 2019 as compared to 2010. This is in contradiction to what is seen world wide and even from the same area reported by other authors. Since the CLSI guidelines change the testing pattern of antibiotics over years it would be better if the authors can state the definition of resistant isolates, like to which antibiotics does it refer to. And is this definition kept same for all the years? In such a case this study shows that there has been no increase in the antimicrobial resistance over 10 years which is really surprising

KINDLY provide more clarification of possible

Reviewer #2: 1. Thank you for addressing all the question adequate and properly.

2. However, table 3 and table 4 are still confusing to follow, especially number and percentage. In table 3, e.g Ampicillin, the total row number was 11 isolate/organism; 4 of 11 was Streptococcus spp. and 7 of 11 refer to Entercoccus spp. The proportion of resistance (percentage) for Streptococcus spp and Enterococcus spp, were 50%, 100%, respectively. In the author explanation was stated: "the percentage of resistance was tested by dividing the resistant isolates to the total number of tested isolates to each antibiotic." Referring to table 2, if the total number of isolate per organism, e.g Streptococcus spp was 26, the percentage calculation of 50% also did not fit. Kindly clarify !

3. My suggestion for point 2: if the number of isolate different according to the tested antibiotic, mentioned e.g: 4/8 (50%) or 7/7 (100%), to make the calculation clear; and put table note to highlight the meaning of the number.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: DR. Sathyamurthy .P

Reviewer #2: No

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PLoS One. 2022 Apr 11;17(4):e0266878. doi: 10.1371/journal.pone.0266878.r004

Author response to Decision Letter 1

9 Nov 2021

We would like to thank both reviewers for their valuable comments to see the limitations of our manuscript and having us the chance to improve such limitations.

Response to reviewer(s)

Academic Editor/Reviewer 1:

Response: Thank you for your concern.

The criteria, that has been used to interpret the antimicrobial resistance by the laboratory in which our study was done, is the CLSI guideline. In fact, the CLSI is updated on a yearly basis and the laboratory uses the newly updated versions of CLSI each year. So, the results were reported as susceptible or resistant to the antimicrobial agents used as per the CLSI’s criteria and still no other criteria have been used in the laboratory. Up on release of new versions the CLSI the laboratory gets new versions timely each year and reports as per the new guideline. We are confident that the results are reported following the CLSI guideline and will not deviate the CLSI. E.g., in 2010 antimicrobial susceptibility test (AST) results were interpreted and reported based on 2010’s CLSI AST reporting criteria and that of 2019 results were reported following 2019’s version of CLSI. The number of organisms tested, the number and class of antimicrobial agents used could have a role in the slightly reducing resistance trend. The antimicrobial stewardship program is currently being implemented in the university of Gondar comprehensive specialized hospital and it might also be bringing the intended outcomes in reducing the antimicrobial resistance.

Reviewer #1:

1. Most of the errors which have been pointed out have been corrected the calculation of trends for individual species could have been a better parameter rather than calculating for overall species. The trend pattern suggests reduction in the percentage of resistance isolates in 2019 as compared to 2010. This is in contradiction to what is seen worldwide and even from the same area reported by other authors. Since the CLSI guidelines change the testing pattern of antibiotics over years it would be better if the authors can state the definition of resistant isolates, like to which antibiotics does it refer to. And is this definition kept same for all the years? In such a case this study shows that there has been no increase in the antimicrobial resistance over 10 years which is really surprising.

KINDLY provide more clarification of possible

Response: first we want thank you for considering our previous response. We also acknowledge your attention and critical review to make our work scientifically valuable.

2. The calculation of trends for individual species could have been a better parameter rather than calculating for overall species

Response:

This study was a retrospective study done by collecting a ten years laboratory data. The laboratory the antimicrobial discs used for antimicrobial susceptibility test (AST) were not consistently used throughout 10 years due to supply interruptions of the discs. In the absence of full stock of antimicrobial discs, the laboratory uses only few discs which are available at hand. The other is the frequency of species isolated and tested shows huge difference from too few (e.g., Serratia species = 4, Providencia species =5) to hundreds (e.g., E. coli =404) which makes the trend by species difficult to compare and conclude. So, calculating the species wise trend by species will not be important for conclusion. That is why we were not interested in analysis of species wise trend of resistance, but we have mentioned this as limitation.

3. The trend pattern suggests reduction in the percentage of resistance isolates in 2019 as compared to 2010. This is in contradiction to what is seen worldwide and even from the same area reported by other authors.

Response:

Yes, the trend was inconsistent and it seems that the percentage of resistance reported in 2010 was a little higher than the percentage of resistance reported in 2019. Multiple factors could have contributed for this seemingly contradiction. To mention some, the number of organisms tested, the number and class of antimicrobial agents used could have a role in the slightly reducing resistance trend. The tendency to replace antimicrobial agents with more potent discs could have reduced or maintain the resistance rate at steady level. For instance, there were higher frequency of ampicillin, amoxicillin use in 2010, 2011 and reduced the frequency of using these agents in recent years. Conversely, nitrofurantoin, which is a potent antibiotic used in the treatment of urinary tract infection, has not been used until 2014 and become increasingly used in the recent years. Moreover, 90.53% of meropenem disks were used for AST in the last two years (2018-2019). Amikacin has been used since 2017 and kanamycin has been used in 2018& 2019, which indicates drugs used for AST are changing. So, this phenomenon could have reduced the pooled percentage of resistance. The antimicrobial stewardship program is currently being implemented in the university of Gondar comprehensive specialized hospital and it might also be bringing the intended outcomes in reducing the antimicrobial resistance.

4. Since the CLSI guidelines change the testing pattern of antibiotics over years it would be better if the authors can state the definition of resistant isolates, like to which antibiotics does it refer to. And is this definition kept same for all the years? In such a case this study shows that there has been no increase in the antimicrobial resistance over 10 years which is really surprising.

Response:

We have collected data which have already been processed and recorded by the laboratory. So, we have collected antimicrobial susceptibility test (AST) results which have been reported as susceptible or resistant in each year and the laboratory uses each year’s update of the CLSI for interpretation of AST results as susceptible or resistant. E.g., in 2010 antimicrobial susceptibility test (AST) results were interpreted and reported based on 2010’s CLSI AST reporting criteria and that of 2019 results were reported following 2019’s version of CLSI.

Reviewer #2:

1. Thank you for addressing all the question adequate and properly.

2. However, table 3 and table 4 are still confusing to follow, especially number and percentage. In table 3, e.g Ampicillin, the total row number was 11 isolate/organism; 4 of 11 was Streptococcus spp. and 7 of 11 refer to Entercoccus spp. The proportion of resistance (percentage) for Streptococcus spp and Enterococcus spp, were 50%, 100%, respectively. In the author explanation was stated: "the percentage of resistance was tested by dividing the resistant isolates to the total number of tested isolates to each antibiotic." Referring to table 2, if the total number of isolates per organism, e.g Streptococcus spp was 26, the percentage calculation of 50% also did not fit. Kindly clarify! 3. My suggestion for point 2: if the number of isolate different according to the tested antibiotic, mentioned e.g: 4/8 (50%) or 7/7 (100%), to make the calculation clear; and put table note to highlight the meaning of the number.

Response: Thank you dear reviewer.

We have stated in our previous revision of the comments percentage of resistance was determined by dividing number of resistant isolates to the number of isolates. It is important to note that all isolates could have not been tested to each antibiotic. For instance, the total number of Streptococcus spp isolated in this study were 26, among these isolates only were 8 were tested against ampicillin and 50% of which were resistant to ampicillin. Why all isolated organisms were not tested could be due to availability of antibiotic discs, probably due to stock out or selection of priority agents.

We intended to minimize space if it is confusing, to avoid such a confusion we have corrected tables as per your comment.

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PLoS One. doi: 10.1371/journal.pone.0266878.r005

Decision Letter 2

Monica Cartelle Gestal

16 Dec 2021

PONE-D-21-22966R2Antimicrobial resistance trend of bacterial uropathogens at the university of Gondar comprehensive specialized hospital, northwest Ethiopia: a 10 years retrospective studyPLOS ONE

Dear Dr. Kasew,

Thanks for this revised version of the manuscript. It has significantly improve. There are however some suggestions that need to be addressed before moving forward, as one of the reviewers has major concerns with the manuscript in its current form. Please carefully address all the comments here provided.Looking forward to seeing the next submission

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: N/A

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: Thank you for addressing the question properly. The last comment for reviewer2 has been answered properly, however refer to other reviewer comment to the different trend pattern, my suggestion is author can explain the outbreak occurrence and/or surveillance method approach which may be useful as important point for discussion.

Reviewer #3: Manuscript number PONE-D-21-22966R2

The authors tried to address most comments or concerns raised by the previous reviewers; however, still the authors should address the following comments to improve the quality of the manuscript:

Methods

The authors mentioned that the culture media and biochemical tests used. Since the laboratory logbook has been documented only patients’ age, sex, address, urine culture results and antimicrobial susceptibility test (AST) results and over the years the hospital may use different culture media and biochemical tests, so how did you trace the type of the media and biochemical tests used?

The authors are advised to perform PCR-based detection of the antimicrobial resistance genes in multidrug-resistant strains if applicable. (On the other hand, address this point to the study limitations).

Population: I think the study populations are not the patients that visited the hospital over the 10-year period rather it could be the urine culture results records. Please kindly explain about it.

Results:

One of the main of the study was to show the drug resistance patterns of the isolates over the specified time. However, the study lacks to reveal antibiotics/ class of antibiotics have a trend of increasing resistance over 10 years period. So, kindly request the authors to show the trend of resistance for each class of antibiotics on a yearly basis.

Still the calculation of trend over the years is not clear. It could be a better parameter and more explanatory if the calculation is based on the isolated species and a yearly base rather than considering the overall isolates.

Antimicrobial resistance (AMR)

It could be better the study showed that MDR, XDR and PDR isolates from each class of the antimicrobials and please illustrate each class of antibiotics used and resistance patterns.

In figure 2, it showed the overall resistance species; it could be better if it depicts the resistance species and its trend over the years.

There are some calculations errors. For example, table three, the first row the denominators should be 15 not 13. Please curiously address such issues.

In this table, I recommend to make one last row, label total isolates, and work out the total resistance isolates for each species. For example, for CoNS, total tested isolates 172, resistance isolates 109 and rate of resistant was 63.37%.

The same is true for table 4. This table somewhat congested and please make it clear.

When the authors say LFGNR and NLFGNR, what it means? The authors mention LFGNR including E. coli, Klebsiella species, and Citrobacter and Enterobacter species. So, what it stands? The same is true for NLFGNR. Unless you grouped together or indicated other that the stated species, please avoid such jargon terminologies.

Discussions:

The authors are advised to illustrate the real impact of their findings in the managements of UTI in hospital as well as in the global community at large without repetition of results.

Minor issues:

LINE 51: More than 70% of isolates were resistant to…. Which isolates GPB or GNB?

LINE 69: 9) What is it number?

LINE88: …. retrospective cross-sectional…. What kind of study design?

LINE 113-121: Where did the authors find the information/data? Did the data collected at the time of the tested performed? Please kindly explain where the source is.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

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PLoS One. 2022 Apr 11;17(4):e0266878. doi: 10.1371/journal.pone.0266878.r006

Author response to Decision Letter 2

9 Jan 2022

Response to Reviewers

First we would like to acknowledge the reviewers for the valuable comments and questions so that our manuscript will be mature scientific.

Response to Reviewer-2

Response: Thank you for considering our previous responses and your current suggestion! But this study was done to determine the burden of urinary tract infection (UTI) over a long (ten years) period retrospectively but outbreak was not seen nor surveillance of that outbreak were used to investigate occurrence of the disease. So, we have determined the prevalence of infection and resistance pattern of isolates retrospectively.

Response to Reviewer-3

I must acknowledge you for your comments and suggestions to improve the quality of our manuscript.

Methods

1. The authors mentioned that the culture media and biochemical tests used. Since the laboratory logbook has been documented only patients’ age, sex, address, urine culture results and antimicrobial susceptibility test (AST) results and over the years the hospital may use different culture media and biochemical tests, so how did you trace the type of the media and biochemical tests used?

Response: Thank you for the concern: The laboratory has standard operating procedure (SPO) in which the culture media used in the University of Gondar comprehensive specialized hospital laboratory and preparation of culture media is documented there and we have used that document as our source.

2. The authors are advised to perform PCR-based detection of the antimicrobial resistance genes in multidrug-resistant strains if applicable. (On the other hand, address this point to the study limitations).

Response: The study was retrospective and we directly took the record of the data. Even the laboratory has no molecular detection methods.

We have accepted the comment and included in the limitation

3. Population: I think the study populations are not the patients that visited the hospital over 10-year period rather it could be the urine culture results records. Please kindly explain about it.

Response: We have accepted your comment and corrected

Results:

4. One of the main of the study was to show the drug resistance patterns of the isolates over the specified time. However, the study lacks to reveal antibiotics/ class of antibiotics have a trend of increasing resistance over 10 years period. So, kindly request the authors to show the trend of resistance for each class of antibiotics on a yearly basis.

Response: It is done in a class of antimicrobial agents on a yearly basis in table 5.

5. Still the calculation of trend over the years is not clear. It could be a better parameter and more explanatory if the calculation is based on the isolated species and a yearly base rather than considering the overall isolates.

Response: the resistance trend in species was not done. Because, as it can be seen in table 5, antimicrobial agents were inconsistently used. E.g., carbapenem drugs were used only in the last two years. Isolates tested against penicillin (144) were not tested against aminoglycosides (100) and even among these isolates one could be tested to one but not to the other. This limited our analysis of trend on a species basis. Hence, it is more informative to analyze on a yearly basis and made a pooled resistance rate on a yearly basis can be conclusive.

Antimicrobial resistance (AMR)

6. It could be better the study showed that MDR, XDR and PDR isolates from each class of the antimicrobials and please illustrate each classes of antibiotics used and resistance patterns.

Response: Thank you!

To minimize congested nature of table, we have canceled the column of antimicrobial classes in other tables and mentioned classes of antimicrobial agents in Table 5.

As there are antimicrobial classes (such as Glycylcyclines, Monobactams…), that were not available in the laboratory and AST was not done to these agents, it is difficult to report XDR and PDR isolates. The definition is “MDR is defined as non-susceptibility to at least one agent in three or more antimicrobial categories. XDR is defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories). PDR is defined as non-susceptibility to all agents in all antimicrobial categories (i.e., no agents tested as susceptible for that organism)”. Hence, according to the definition we have only MDR isolates. The research is a retrospective study and we have analyzed and reported what had been done and recorded.

(Reference: Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clinical microbiology and infection. 2012 Mar 1;18(3):268-81. https://doi.org/10.1111/j.1469-0691.2011.03570.x)

7. In figure 2, it showed the overall resistance species; it could be better if it depicts the resistance species and its trend over the years.

Response: The resistant species were mentioned in table -3 and table 4, but the trend of resistance to each species was not done because antimicrobial agents were not consistently used to test each isolates and over years. So, we showing the trend of resistance over the years was done. Seen in No 5.

8. There are some calculations errors. For example, table three, the first row the denominators should be 15 not 13. Please curiously address such issues.

Response: tables were revised and corrected as per the comment

9. In this table, I recommend to make one last row, label total isolates, and work out the total resistance isolates for each species. For example, for CONS, total tested isolates 172, resistance isolates 109 and rate of resistant was 63.37%

Response: It can be seen in the table different denominators indicating different number of isolates were tested against each antimicrobial agent. So, different antibiotics are difficult to add up. For example, only one isolate of CONs was tested against Cefoxitin while 17 were tested against Trimethoprim-sulfamethoxazole (SXT) and that one isolate could or could not be tested against SXT.

10. The same is true for table 4. This table somewhat congested and please make it clear.

Response: we understand that the table is congested because of the number of drugs used and species of isolates were diverse. It could be good to cancel the denominators, it was submitted that way in our 1st submission and changed to the current form with comment.

11. When the authors say LFGNR and NLFGNR, what it means? The authors mention LFGNR including E. coli, Klebsiella species, and Citrobacter and Enterobacter species. So, what it stands? The same is true for NLFGNR. Unless you grouped together or indicated other that the stated species, please avoid such jargon terminologies.

Response: LFGNR-Lactose fermenting Gram negative rods, NLFGNR- None lactose fermenting Gram negative rods.

There were records in which the genus and species isolated was not specified and were reported as LFGNR and NLFGNR. This is a retrospective study done by copying the record from the laboratory. Hence it is difficult to add to the specified species and we put these isolates in separate columns.

Discussions:

12. The authors are advised to illustrate the real impact of their findings in the managements of UTI in hospital as well as in the global community at large without repetition of results.

Response:

This study figures out the burden of UTI and the rate of antimicrobial resistance to the available antimicrobials. So, the hospitals in the locality can understand which antibiotics can be used in imperial treatment and which agent should not be prescribed. The global community can also get the figure in the region.

The expected impact of the study was stated in the introduction part line 77-81, line 285-293 as well as in the conclusion (line 303-307).

Minor issues:

LINE 51: More than 70% of isolates were resistant to…. Which isolates GPB or GNB?

Response: Done as per the comment. It includes both gram positive and gram-negative isolates.

LINE 69: 9) What is it number?

Response: It was a typographical error and now corrected.

LINE88: …. retrospective cross-sectional…. What kind of study design?

Response: the study design is a retrospective study design and cross sectional was added to indicate the data collected period. it is corrected as retrospective study.

LINE 113-121: Where did the authors find the information/data? Did the data collected at the time of the tested performed? Please kindly explain where the source is.

Response: The data were collected from the University of Gondar comprehensive specialized hospital microbiology laboratory record book.

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PLoS One. doi: 10.1371/journal.pone.0266878.r007

Decision Letter 3

Simon Clegg

30 Mar 2022

Antimicrobial resistance trend of bacterial uropathogens at the university of Gondar comprehensive specialized hospital, northwest Ethiopia: a 10 years retrospective study

PONE-D-21-22966R3

Dear Dr. Kasew,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Simon Clegg, PhD

Academic Editor

PLOS ONE

Additional Editor Comments:

Many thanks for resubmitting your manuscript to PLOS One

As you have addressed all the comments and the manuscript reads well, I have recommended it for publication

You should hear from the Editorial Office shortly.

It was a pleasure working with you and I wish you the best of luck for your future research

Hope you are keeping safe and well in these difficult times

Thanks

Simon

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: N/A

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: Thank you for addressing the previous comment clearly, at this moment I don't have specific question referring to the manuscript, except:

1. Consistency of percentage calculation in Table 1, e.g in Frequency column, the percentage was calculated between male (45.2%, 2006 of 4441) to female (54.8%, 2435 of 4441) (column as total column of denominator); but percentage between UTI positive and negative was using total row, shown in the table for male, positive UTI = 24.6%, 494 of 2006 an negative UTI = 75.4%, 1512 of 2006. My suggestion, it will be better to use the total column as the denominator of the percentage, or please give some footnote that declare the different denominator of percentage calculation.

2. In table 5, please consistent with antibiotic class/group name, e.g SXT = folate pathway inhibitor. The antibiotic group/class can be referred to reference no.18 (Magiorakos et. al.)

Reviewer #3: Overall, the author tried to address all questions and comments.

Thank you for addressing the question properly

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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PLoS One. doi: 10.1371/journal.pone.0266878.r008

Acceptance letter

Simon Clegg

1 Apr 2022

PONE-D-21-22966R3

Antimicrobial resistance trend of bacterial uropathogens at the university of Gondar comprehensive specialized hospital, northwest Ethiopia: a 10 years retrospective study

Dear Dr. Kasew:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Simon Clegg

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

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Data Availability Statement

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PERMALINK

Antimicrobial resistance trend of bacterial uropathogens at the university of Gondar comprehensive specialized hospital, northwest Ethiopia: A 10 years retrospective study

Desie Kasew

Blen Desalegn

Mihret Aynalem

Sosina Tila

Dureti Diriba

Beimnet Afework

Michael Getie

Sirak Biset

Habtamu Wondifraw Baynes

Roles

Abstract

Introduction

Materials and methods

Study area, design and period

Data collection and analysis

Results

Socio-demographic characteristics and rate of infection

Table 1. The distribution of uropathogenic isolates with sex and age at the university of Gondar comprehensive specialized hospital, 2010–2019.

The proportion of uropathogenic bacterial isolates

Table 2. The proportion of uropathogenic isolates at the university of Gondar comprehensive specialized hospital, 2010–2019.

Antimicrobial resistance pattern of Gram-positive isolates

Table 3. The proportion of resistant Gram-positive isolates among UTI patients at the University of Gondar comprehensive specialized hospital, 2010–2019.

Antimicrobial resistance pattern of Gram-negative isolates

Table 4. The proportion of resistant Gram-negative isolates among UTI patients at the University of Gondar comprehensive specialized hospital, 2010–2019.

The yearly basis of resistance pattern of the classes of antimicrobial agents

Table 5. Yearly basis of antimicrobial resistance to classes of antimicrobial agents, 2010–2019.

Antimicrobial resistance (AMR) trend and multidrug resistance (MDR) rate of isolates

Fig 1. The overall trend of antimicrobial resistance of isolates to the tested antibiotics among UTI patients at the University of Gondar comprehensive specialized Hospital, 2010–2019.

Fig 2. Frequency of MDR species isolated in 10 years retrospective study (473/1072 = 44.1%).

Discussion

Conclusions

Acknowledgments

List of abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Monica Cartelle Gestal

Roles

Author response to Decision Letter 0

Decision Letter 1

Monica Cartelle Gestal

Roles

Author response to Decision Letter 1

Decision Letter 2

Monica Cartelle Gestal

Roles

Author response to Decision Letter 2

Decision Letter 3

Simon Clegg

Roles

Acceptance letter

Simon Clegg

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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