Antimicrobial Susceptibility Trends Observed in Urinary Pathogens Obtained From New York State

Abstract

International guidelines recommend using local susceptibility data to direct empiric therapy for acute uncomplicated cystitis. We evaluated outpatient urinary isolate susceptibility trends in New York State. Nitrofurantoin had the lowest resistance prevalence whereas trimethoprim-sulfamethoxazole and fluoroquinolones had higher prevalences. This study highlights the need for local outpatient antimicrobial stewardship programs.

Acute uncomplicated cystitis is a prevalent outpatient condition [1, 2]. It is estimated that there are approximately 6–8 million annual visits to a physician or clinic by patients for treatment of an acute uncomplicated cystitis event [3, 4]. Treatment guidelines for acute uncomplicated cystitis in premenopausal, nonpregnant women are well defined in international guidelines [2]. In these international guidelines, empiric treatment recommendations are provided, but these empiric recommendations are accompanied by the caveat that empiric antibiotic selection should be guided by local organism susceptibility data and patient-specific risk factors.

Although treatment selection for acute uncomplicated cystitis was straightforward in the past, management of these conditions has been complicated by reports of rising antibiotic resistance rates for several key urinary pathogens. It is important to note that much of the data that describe rising rates of resistance for uncomplicated cystitis pathogens were derived from hospitalized inpatients with urinary tract infections. Data that describe outpatient resistance rates are consistent with published inpatient reports but are limited [5]. It is also unclear if resistance rates among acute uncomplicated cystitis pathogens are applicable to all age groups, and to both men and women. Given these gaps in the literature, this study sought to describe the prevalence and resistance patterns of urinary pathogens in New York State in the outpatient setting. The intent was to use these data to help inform treatment decisions for patients who present with uncomplicated cystitis in the outpatient setting and to assess the appropriateness of empiric treatment recommendations found in national guidelines for New York State.

METHODS

A retrospective analysis was conducted on all urine cultures received from outpatient settings (defined as physician offices or outpatient clinics), with antimicrobial susceptibility testing performed from January 1, 2016, to December 31, 2016, at a major clinical microbiology reference laboratory (Quest Diagnostics Laboratory, Teterboro, NJ). As antimicrobial testing is not routinely recommended for Streptococcus agalactiae and Staphylococcus saprophyticus, these organisms were not included in the analysis. Data from 17 New York State counties were included in the overall sample (Table 1). Urine cultures demonstrating 1 or 2 bacterial isolates at >10⁵ colony-forming units/mL were included (only the first reported isolate from dual infections was included). In accordance with standards for summarizing antimicrobial susceptibilities for antibiograms, each species required a minimum of 30 isolates for inclusion in antimicrobial susceptibility estimates.

Table 1. .

Summary of Urinary Isolate Antibiotic Susceptibility From New York State

Microorganism	Na	Ampicillin	Ceftazidime	Cefazolin	Ciprofloxacin	Nitrofurantoin	Pip-Tazo	Tobramycin	TMP-SMX	Tetracycline
Overallb
Gram-negative
Citrobacter diversus	933		100		99	90	99	100	99
Citrobacter freundii	316		93		95	95	94	98	85
Enterobacter aerogenes	785		93		99	30	97	100	99
Enterobacter cloacae	404		91		94	44		96	86
Escherichia coli	50 900	53	99	95	78	97	97	90	73
Klebsiella pneumoniae	7734		100	98	95	42	95	96	90
Proteus mirabilis	3389	79	99	91	90		100	95	87
Providencia rettgeri	43		93		85		95
Pseudomonas aeruginosa	1051		94		76		92	95
Serratia marcescens	264		100		98			88	97
Stenotrophomonas maltophila	53								100
Gram-positive
Methicillin-sensitive Staphylococcus aureus	825				85	98			98	89
Methicillin-resistant Staphylococcus aureus	326				25	97			96	83
Vancomycin-sensitive Enterococcus spp.	9281	100				99
Vancomycin-resistant Enterococcus faecium	35	94				97
Females <18 yc
Gram-negative
Escherichia coli	3872	41	99	97	91	98		91	74
Klebsiella pneumoniae	281		100	97	97	46		98	92
Proteus mirabilis	264	80	100	89	96			94	88
Pseudomonas aeruginosa	71		97		100			100
Gram-positive
Enterococcus spp.	441	100				100
Methicillin-sensitive Staphylococcus aureus	61				93	98			97	92
Females 18–64 yd
Gram-negative
Citrobacter diversus	498		100		100	92		100	99
Citrobacter freundii	91		99		97	96		98	88
Enterobacter aerogenes	433		96		99	16		100	100
Enterobacter cloacae	126		91		98	46		98	86
Escherichia coli	29 180	57	99	97	84	98		92	75
Klebsiella pneumoniae	3642		100	97	86	38		87	80
Proteus mirabilis	1486	84	100	94	96			97	91
Pseudomonas aeruginosa	109		94		84			95
Serratia marcescens	67		100		100			88	97
Gram-positive
Methicillin-sensitive Staphylococcus aureus	430				92	98			99	87
Methicillin-resistant Staphylococcus aureus	105				54	94			98	65
Vancomycin-sensitive Enterococcus spp.	4425	100				99
Females >64 ye
Gram-negative
Citrobacter diversus	190		98		98	86		99	97
Citrobacter freundii	140		91		93	97		100	88
Enterobacter aerogenes	154		88		100	55		100	99
Enterobacter cloacae	123		92		98	47		96	88
Escherichia coli	13 156	53	99	92	67	96		88	71
Klebsiella pneumoniae	2781				46	21		43	34
Proteus mirabilis	978	76	99	88	84			95	83
Pseudomonas aeruginosa	312		97		85			98
Serratia marcescens	37		100		97			86	100
Gram-positive
Methicillin-sensitive Staphylococcus aureus	106				74	98			100	91
Methicillin-resistant Staphylococcus aureus	79				11	99			94	94
Vancomycin-sensitive Enterococcus spp.	1843	100				98
Males <18 yf
Gram-negative
Escherichia coli	126	52	99	94	91	98		92	72
Klebsiella pneumoniae	21		100	97	99	46		100	91
Proteus mirabilis	108	70	100	86	96			93	85
Gram-positive
Vancomycin-sensitive Enterococcus spp.	124	99				100
Males 18–64 yg
Gram-negative
Citrobacter diversus	96		100		100	95		100	100
Enterobacter aerogenes	83		87		98	30		100	94
Enterobacter cloacae	34		97		94	38		97	88
Escherichia coli	1862	48	99	96	70	97		85	69
Klebsiella pneumoniae	318		100	98	99	41		99	94
Proteus mirabilis	157	72	99	85	83			93	80
Pseudomonas aeruginosa	139		93		65			93
Serratia marcescens	54		100		98			89	96
Gram-positive
Methicillin-sensitive Staphylococcus aureus	68				84	100			97	93
Vancomycin-sensitive Enterococcus spp.	990	100				99
Males >64 yh
Gram-negative
Citrobacter diversus	104		100		97	88		99	97
Citrobacter freundii	49		86		96	90		94	72
Enterobacter aerogenes	93		89		97	23		100	99
Enterobacter cloacae	91		89		85	37		93	81
Escherichia coli	2704	43	98	92	51	94		82	64
Klebsiella pneumoniae	691		100	98	95	45		97	92
Proteus mirabilis	396	74	98	87	75			92	82
Pseudomonas aeruginosa	405		92		66			93
Serratia marcescens	90		100		97			90	97
Gram-positive
Methicillin-sensitive Staphylococcus aureus	145				70	99			98	94
Methicillin-resistant Staphylococcus aureus	110				7	99			96	92
Vancomycin-sensitive Enterococcus spp.	1458	100				99

The 17 New York counties are Albany, Bronx, Dutchess, Fulton, Greene, Kings, Nassau, New York, Orange, Putnam, Queens, Richmond, Rockland, Suffolk, Sullivan, Ulster, and Westchester.

Abbreviations: Pip-Tazo, piperacillin-tazobactam; TMP-SMX, trimethoprim/sulfamethoxazole.

^aN = total number of antimicrobial testing results.

^bData not shown for 1739 coagulase-negative staphylococci.

Organisms not reported due to <30 isolates in the reporting group:

^cFemales <18 years: Citrobacter diversus (29 isolates), Citrobacter freundii (11), Enterobacter aerogenes (19), Enterobacter cloacae (27), methicillin-resistant S. aureus (5), Providencia rettgeri (1), Serratia marcescens (7), Staphylococcus haemolyticus (9), Staphylococcus hominis spp. hominis (4), Staphylococcus ludgunensis (1), Staphylococcus simulans (25), Stenotrophomonas maltophila (2), vancomycin-resistant Enterococcus faecium (0).

^dFemales 18–64 years: Providencia rettgeri (5), Providencia stuartii (4), Staphylococcus hominis spp. hominis (9), Staphylococcus ludgunensis (29), Stenotrophomonas maltophila (8), vancomycin-resistant Enterococcus faecium (3).

^eFemales >64 years: Providencia rettgeri (16), Providencia stuartii (13), Staphylococcus hominis spp. hominis (10), Staphylococcus ludgunensis (25), Staphylococcus simulans (28), Stenotrophomonas maltophila (10), vancomycin-resistant Enterococcus faecium (11).

^fMales <18 years: Citrobacter diversus (16), Citrobacter freundii (4), Enterobacter aerogenes (3), Enterobacter cloacae (3), Klebsiella pneumoniae (21), methicillin-resistant S. aureus (0), methicillin-sensitive S. aureus (15), Providencia rettgeri (1), Pseudomonas aeruginosa (15), Serratia marcescens (9), Staphylococcus haemolyticus (9), Staphylococcus hominis spp. hominis (3), Staphylococcus ludgunensis (0), Staphylococcus simulans (24), Stenotrophomonas maltophila (1), vancomycin-resistant Enterococcus faecium (0).

^gMales 18–64 years: Citrobacter freundii (21), methicillin-resistant S. aureus (27), Providencia rettgeri (2), Providencia stuartii (2), Staphylococcus hominis spp. hominis (11), Staphylococcus ludgunensis (7), Staphylococcus simulans (1), Stenotrophomonas maltophila (8), vancomycin-resistant Enterococcus faecium (2).

^hMales >64 years: Providencia rettgeri (18), Providencia stuartii (13), Staphylococcus hominis spp. hominis (28), Staphylococcus ludgunensis (25), Staphylococcus simulans (16), Stenotrophomonas maltophila (24), vancomycin-resistant Enterococcus faecium (19).

Urine pathogens were isolated from bi-plates of Trypticase Soy Agar with 5% Sheep Blood (TSA II) and MacConkey II Agar, followed by identification and automated drug susceptibility testing (Vitek-2). Antimicrobials tested included ampicillin, ceftazidime, cefazolin, ciprofloxacin, nitrofurantoin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, tetracycline, oxacillin, and vancomycin, as appropriate. Minimum inhibitory concentration (MIC) susceptibility interpretations were derived from CLSI M100 S-25 [6]. Antibiotic sensitivity percentages are reported as number of susceptible isolates divided by number of isolates tested. Susceptibility was reported overall and by sex and age (children: ≤17 years; adults: 18–64 years; and older adults: ≥65 years). Chi-square tests or Fisher exact tests were used to compare the overall prevalence of bacterial resistance within and between agents tested and between age and sex groups.

RESULTS

A total of 78 078 urine culture susceptibility reports were included (Table 1). The majority of the urine cultures were obtained from female patients. The most frequently recovered isolates were Escherichia coli, 65.1%; Enterococcus spp., 11.9%; and Klebsiella pneumoniae, 10.0%. Among isolates recovered from females, the distribution was consistent with the overall study population. In men, the prevalence of E. coli was lower (40.3 %) relative to the overall population, whereas the prevalence of Enterococcus was higher (22.1%). In children, E. coli was the most prevalent isolate (73.7%), followed by Enterococcus (10.4%) and Proteus species (6.8%). The distribution of pathogens in adult (age 18–64 years) patients was similar to the overall population: E. coli (68.5%), Enterococcus (11.2%), and K. pneumoniae (8.7%). In older adults, the prevalence of E. coli was lower (58.7%), whereas the prevalence rates of Enterococcus and Klebsiella were higher (12.2% and 12.8%, respectively).

Of all the isolates tested for nitrofurantoin sensitivity (n = 73 191), 90.4% were susceptible. Nitrofurantoin resistance was more commonly noted in males as compared with females (10.6% vs 9.1%, P < .001) and older adults as compared with all other ages combined (12.3% vs 8.1%, P < .001). High overall rates of susceptibility were reported for isolates tested for cefazolin sensitivity (90.4%). However, due to the high prevalence of Enterococcus spp. (which is intrinsically resistant to cefazolin), cefazolin only has activity against 68.2% of the isolates. Only 77.2% of all isolates tested (n = 67711) were trimethoprim-sulfamethoxazole susceptible. Resistance to trimethoprim-sulfamethoxazole was more prevalent in men than women (26.3% vs 22.7%, P < .001) and in older adults than all other age groups combined (25.1% vs 22.1%, P < .001). Of the isolates tested for ciprofloxacin sensitivity (n = 68 709), 80.2% were susceptible. Resistance to ciprofloxacin was more frequent in males than females (35.0% vs 17.3%, P < .001) and in older adults than in all other ages combined (30. % vs 14.0%, P < .001). Additional data on pathogen-specific sensitivity overall and by sex and age groups are presented in Table 1. County-specific data are provided in the Supplementary Data.

DISCUSSION

The current Infectious Disease Society of America (IDSA) guidelines for acute uncomplicated cystitis recommend nitrofurantoin, trimethoprim-sulfamethoxazole, or fosfomycin as firstline agents for treatment [2]. Overall, we found that bacterial isolates in the outpatient setting in New York State were 90% sensitive in vitro to nitrofurantoin. The high probability of in vitro activity with nitrofurantoin is likely due to the high prevalence and susceptibility rates for E. coli. Although the IDSA guidelines do not define a resistance prevalence threshold for assessing the appropriateness of nitrofurantoin for empiric use in treating acute uncomplicated cystitis, if we apply the trimethoprim-sulfamethoxazole threshold (20%, per the IDSA guidelines), our data support the utilization of nitrofurantoin in the New York State outpatient setting for this condition. In contrast, trimethoprim-sulfamethoxazole appears to have more limited utility as an empiric treatment regimen for acute uncomplicated cystitis as the overall prevalence of trimethoprim-sulfamethoxazole resistance exceeded 20%. Unfortunately, fosfomycin susceptibility data were unavailable in this data set as testing was not routinely performed. Given the limited activity of trimethoprim-sulfamethoxazole and ciprofloxacin for acute uncomplicated cystitis, it would be prudent for laboratories to consider testing of fosfomycin in urinary isolates, especially for Escherichia coli and Enterococcus faecalis. In species other than Escherichia coli and Enteroccocus faecalis, the utility and validity of susceptibility results for fosfomycin have yet to be determined [6]. Importantly, recent data show that 1 day of fosfomycin is inferior to 5 days of nitrofurantoin for acute uncomplicated cystitis [7]. As such, fosfomycin should be used with caution when treating acute uncomplicated cystitis.

Susceptibility results from this study were also unfavorable to the empiric use of fluoroquinolones and β-lactam antibiotics. The overall prevalence of ciprofloxacin resistance was 19.8%, exceeding the IDSA-recommended 10% resistance threshold for empiric use. In light of the relatively high prevalence of fluoroquinolone resistance as well as growing concerns about fluoroquinolone-associated disability, our study supports the recent Food and Drug Administration recommendation to avoid empiric fluoroquinolone use unless no other alternative agents are available [7]. We also examined cefazolin as a surrogate for cephalexin susceptibility. When only Gram-negative bacterial species were isolated, cefazolin appeared to be an appropriate empiric agent. However, the utility of cefazolin as an empiric agent is less than favorable due to the high prevalence of Enterococcus, an organism that is intrinsically resistant to cefazolin. Given that β-lactam medications require longer duration of treatment as compared with other therapies and are associated with lower efficacy [8], our data suggest that β-lactam drugs should be considered as empiric agents only when potential benefits outweigh risks.

These data also indicate that the overall antimicrobial susceptibility percentages of antimicrobials are significantly lower for individuals in the ≥65 age group compared with all other ages combined and among males of all ages compared with females. These findings highlight the need to not rely exclusively on overall susceptibility results and to consider sex, age, and prior urine culture results when selecting an agent for a given patient. As susceptibility rates varied by age and sex, subsequent adjustment of therapy based on individualized culture and susceptibility reports should be performed in an effort to promote use of narrow-spectrum antibiotics where possible.

There are several caveats to be considered with respect to these findings. We did not include coagulase-negative staphylococci in this analysis due to its questionable pathogenicity. However, our conclusions would be affected minimally by the inclusion of coagulase-negative staphylococci because coagulase-negative staphylococci only accounted for 2% of isolates. Another potential limitation of this study is lack of data on clinical presentation of the patients. We did not determine whether these were symptomatic urinary tract infections or asymptomatic bacteriuria. Last, this study may overrepresent antimicrobial resistance rates as practitioners may only send urine cultures for patients with recurrent infections or treatment failure.

Although these data are from New York State, there are several generalizable aspects of this study. First, this project highlights the framework for creating a regional antibiogram. Regional antibiograms are important tools that could be used by health departments and other regional authorities to help influence prescribing and/or track antimicrobial resistance for key pathogens. Second, New York State (especially Kings, Queens, New York, Bronx, and Richmond counties, the 5 New York City counties) is unique in that it has an incredibly high population density [9]. Along with antimicrobial utilization, population density has been shown to be associated with antimicrobial resistance prevalence [10]. Hence, it stands to reason that New York State can be thought of as a regional bellwether for antimicrobial resistance.

In summary, we conducted a 1-year retrospective analysis of outpatient urine isolates collected from patients in New York State. Data indicated that nitrofurantoin has retained activity against many of the urinary pathogens since the publication of the 2011 IDSA guidelines and has a high prevalence of in vitro activity. In contrast, we found that the overall prevalence of resistance in bacterial urinary isolates exceeded the predefined IDSA empiric therapy thresholds of 20% for trimethoprim-sulfamethoxazole and 10% for fluoroquinolones, with resistance rates being highest in patients ≥65 years. These data highlight the need in outpatient settings for (1) urinary culture specimen submission, (2) antimicrobial stewardship efforts, and (3) assembly of local susceptibility data to guide empiric therapy in acute uncomplicated cystitis. Finally, these data also support the desperate need for new oral antimicrobials to treat acute uncomplicated cystitis in the outpatient setting.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.