A prospective observational treatment study of aerococcal urinary tract infection

A prospective observational treatment study of aerococcal urinary tract infection

Accepted Manuscript Title: A prospective observational treatment study of aerococcal urinary tract infection Author: Mohammad Oskooi, Torgny Sunnerhag...

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Accepted Manuscript Title: A prospective observational treatment study of aerococcal urinary tract infection Author: Mohammad Oskooi, Torgny Sunnerhagen, Erik Senneby, Magnus Rasmussen PII: DOI: Reference:

S0163-4453(17)30406-1 https://doi.org/10.1016/j.jinf.2017.12.009 YJINF 4032

To appear in:

Journal of Infection

Accepted date:

12-12-2017

Please cite this article as: Mohammad Oskooi, Torgny Sunnerhagen, Erik Senneby, Magnus Rasmussen, A prospective observational treatment study of aerococcal urinary tract infection, Journal of Infection (2017), https://doi.org/10.1016/j.jinf.2017.12.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A prospective observational treatment study of aerococcal urinary tract infection By: Mohammad Oskooia, Torgny Sunnerhagena, Erik Sennebya,b, and Magnus Rasmussena,c* a

Lund University, Faculty of Medicine, Department of Clinical Sciences, Division of Infection Medicine, Tornavägen 10 BMC B14, S-22363 Lund, Sweden. [email protected], [email protected], [email protected], [email protected]. 2

Clinical Microbiology, Laboratory, Region Skåne, Sölvegatan 23, S-22185 Lund, Sweden.

3

Skåne University Hospital, Division of Infection Medicine, Hälsogatan 3, S22100 Lund, Sweden * Corresponding author: Magnus Rasmussen Division of Infection Medicine BMC B14, Tornavägen 10 223 63, Lund, Sweden Phone: +46 704 970132 Fax: +46 46 171556 [email protected]

Running title: Treatment of UTI caused by aerococci

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Highlights     

A prospective observational trial on treatment of aerococcal UTI was conducted Persons with aerococcal bacteruria were older and a majority had UTI Nitrofurantoin was the most commonly prescribed antibiotic Overall clinical success was 84 % for A. urinae UTI and 68 % for A. sanguinicola UTI Microbiological sucess was 78 % for A. urinae UTI and 58 % for A. sanguinicola UTI

Summary Objectives: Aerococcus urinae and Aerococcus sanguinicola cause urinary tract infections (UTIs) and antibiotic treatment recommendations are solely based on in vitro findings and limited clinical experience. Our objective was to investigate the effectiveness of different treatment strategies in aerococcal UTI through a prospective observational study. Methods: Urine samples with aerococci were identified and patients were enrolled. The aerococci were subjected to Etests. Information on clinical symptoms and the treatment given, was collected. Patients were interviewed after the conclusion of treatment to assess clinical cure and a control urine culture assessed the microbiological cure. Results: Of 31 629 urine samples, 144 grew aerococci and fulfilled the inclusion criteria. 91 patients gave consent and the 72 patients with UTI were assessed for treatment outcome. 53 patients had A. urinae UTI, while 19 had A. sanguinicola UTI. Nitrofurantoin was most commonly prescribed, achieving clinical and microbiological success in 71/76% of cases of A. urinae UTI, and 42/50% of cases of A. sanguinicola UTI. Pivmecillinam achieved success in patients with A. urinae cystitis and ciprofloxacin in patients with pyelonephritis.

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Conclusions: Our results support that nitrofurantoin is a valid option for the treatment of cystitis caused by A. urinae.

Keywords: Aerococcus, urinary tract infection, observational trial, nitrofurantoin

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Introduction Aerococci are Gram-positive, catalase-negative, alpha-hemolytic cocci which grow in clusters and have been shown to cause urinary tract infections (UTIs) [1-6]. The two species, A. sanguinicola and A. urinae, can also cause invasive infections such as bacteraemia and infective endocarditis, typically in elderly persons with underlying urological conditions [713]. Aerococci have often been misidentified in clinical microbiology laboratories and long been regarded as rare human pathogens. Improved methods for species determination, especially matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), have revealed that aerococci are more common in clinical samples than previously thought, being identified in 0.2-0.8% of urinary cultures [2-6,14]. There have been no clinical studies on antibiotic treatment options for aerococcal infections and current recommendations are based solely on in vitro susceptibility testing and limited clinical experience [15,16]. In general, both A. urinae and A. sanguinicola are sensitive to beta-lactam antibiotics and to vancomycin [11,17-20]. Most A. urinae isolates are sensitive to fluoroquinolones with low minimum inhibitory concentration (MIC) values, while high MICs for these antibiotics are typically recorded for A. sanguinicola [11,14,17,18,20]. A. urinae is resistant to trimethoprim and trimethoprim-sulphamethoxazole when standard solid media are used [6,21]. However, it has been shown to be sensitive to these antibiotics when lysed horse blood is added to the medium [22]. Both A. urinae and A. sanguinicola are sensitive to nitrofurantoin which, together with pivmecillinam and ampicillin, could be reasonable treatment options for uncomplicated aerococcal UTIs [4,6,14]. Recently, EUCAST suggested breakpoints for some aerococci for some relevant antibiotics [23]. We performed a prospective observational study of aerococcal bacteriuria in the south of Sweden with the aim

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of determining the effectiveness of different antibiotic treatment regimens in obtaining clinical and microbiological cure.

Methods Isolates Aerococcal isolates were identified at the clinical microbiology laboratory in Lund, Sweden. All clinical samples in the entire Skåne region (approx. 1.3 million inhabitants) are sent to this laboratory. Ten µl of well-mixed urine was inoculated onto one half of a plate containing blood agar supplemented with colistin (10 mg/L) and nalidixic acid (15 mg/L), and 10 µl of urine was plated onto the other half containing Uriselect 4 agar (Bio-Rad Laboratories AB, Solna, Sweden). Species identification of bacteria was performed using MALDI-TOF MS as described [11]. During the period January 25th to March 25th 2016, isolates from urine cultures fulfilling the all of the following criteria were prospectively collected: (1) growth of at least 10 CFU/L, (2) identified as aerococcal species with a MALDI-TOF MS score 7

of ≥2.0, (3) no more than 1 additional species, and (4) the additional species was not a primary uropathogen (Escherichia coli or Staphylococcus saprophyticus). All isolates were transferred to tubes containing horse serum and glycerol and stored at −80 °C. Patient inclusion The study was approved by the Regional Ethical Review Board in Lund, Sweden (2015/868). The unique personal-identification number of the patient and information regarding the referring physician, was obtained from the clinical microbiology laboratory. The physician was contacted by telephone and a standardized interview (Appendix A) was performed where details about the patient's symptoms, underlying conditions, cognitive state, past medical history, and prescribed treatment were acquired. The investigators did not influence the

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choice of treatment which had been instituted at the discretion of the treating physician. The patient was then contacted by letter, and shortly thereafter by telephone. Informed consent to participate was given by the patient, or in cases where the patient was unable to give consent due to cognitive impairment, by a close relative or fiduciary. Information from the patient’s medical charts was gathered. At the time of therapy completion, the patient was again contacted by telephone and a standardized interview (Appendix B) was performed with the patient (or a caregiver) to determine the clinical outcome of the treatment. The patient was instructed in the clean-catch method and required to leave a follow-up urine sample 1 week after therapy completion in order to determine the microbiological outcome of the treatment. This urine sample was treated as described above. The timeline of the study is visualized in figure 1. Definitions UTI was defined according to criteria set by the Centers for Disease Control and Prevention [24]. For a UTI diagnosis, the patient had to: (1) have had at least one of the following signs or symptoms: fever (>38 °C), suprapubic tenderness, costovertebral angle pain or tenderness (with no other recognized cause), dysuria, new onset urinary urgency, or frequency, and (2) have had a positive urine culture as defined above. The symptoms of urgency, frequency and dysuria in a patient with an indwelling catheter in place for >2 days were not used to define a UTI as the presence of an indwelling catheter can in itself cause such symptoms. A diagnosis of pyelonephritis required a positive urine culture, and the presence of systemic symptoms such as fever >38 °C, chills, and costovertebral angle pain or tenderness, with no other recognized cause. Patients with only local urinary tract symptoms such as dysuria, urinary urgency, urinary frequency, and suprapubic tenderness were diagnosed with cystitis.

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Clinical success was defined as the disappearance of all symptoms related to the infection. Persistence of such signs and symptoms after the completion of therapy was defined as a clinical failure. The microbiological outcome was assessed on the basis of results from urine cultures performed before and after antibiotic therapy. A microbiological success was defined as no growth (<105 CFU/L) of the aerococcal species which grew in the pre-therapy culture. Persistence of such organisms in the follow-up urine culture was defined as a microbiological failure. The microbiological outcome was not assessed in cases where the follow-up culture grew mixed flora or was not obtained. Antibiotic susceptibility testing Minimum inhibitory concentration (MIC) values for mecillinam, nitrofurantoin, ciprofloxacin, trimethoprim, cephalotin, and ceftibuten were determined using Etests (BioMérieux, Marcy l’Etoile, France) according to the instructions by the manufacturer. Müller Hinton agar with 5% horse blood and 20 mg/l ß-NAD (Müller-Hinton fastidious, MHF) was used, and MICs were determined after incubation for 24–48 h at 37 °C in 5% CO . 2

Statistical analysis For comparisons, the Mann-Whitney U, and Fisher’s exact tests were used. Values were calculated using the IBM SPSS v. 23 and statistical significance was defined as p ≤ 0.05.

Results Patient inclusion During the study period, a total of 31 629 urine samples were sent to the laboratory and 311 (1 %) of the samples grew aerococci, of which, 144 met the inclusion criteria specified above. Of these, 53 did not give their consent to participate or could not be reached, leaving 91

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patients to be enrolled in the study (Figure 2). A. urinae was encountered in cultures from 66 patients (51 in pure culture; 15 in mixed culture), and A. sanguinicola in 25 patients (18 in pure culture; 7 in mixed culture). The additional species identified were Klebsiella pneumoniae (n=5), Proteus mirabilis (n=5), Klebsiella oxytoca (n=3), Proteus vulgaris (n=2), Streptococcus agalactiae (n=2), Enterobacter cloacae (n=2), Enterobacter aerogenes (n=1), Enterococcus faecalis (n=1) and Pseudomonas aeruginosa (n=1). Patient characteristics Patients with aerococcal bacteriuria (n=91) had a median age of 79 years (range 50-101). In total, 72 (79%) patients met the criteria for a UTI. The characteristics of the patients are displayed in Table 1. There was a female dominance in the A. sanguinicola UTI group compared to the A. urinae UTI group (p = 0.004 Fisher’s exact test). A. urinae treatment outcomes The clinical and microbiological outcomes for the 53 patients with a UTI caused by A. urinae are presented in Table 2. In total, a clinical failure occurred in eight cases, of which only one had growth of A. urinae in the control urine sample. Of the remaining seven patients with clinical failure, four control urine samples grew another uropathogen (E. coli in two, P. mirabilis in one and E. faecalis in one), whereas there was no growth of bacteria in two and in one case a control sample could not be obtained. Microbiological failure occurred in five cases of which three had clinical success. Seven control urine samples could not be assessed for microbiological outcome due to growth of mixed flora or the control sample not being obtained. The clinical and microbiological outcomes were not evaluated for three patients who did not receive any antibiotic treatment.

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A. sanguinicola treatment outcomes The clinical and microbiological outcomes for the 19 patients with a UTI caused by A. sanguinicola are displayed in Table 3. A clinical failure occurred in six cases, of which two had continued growth of A. sanguinicola in the control urine sample. Of the remaining four control urine samples, one grew S. agalactiae, one did not contain bacteria, and two could not be obtained. Microbiological failure occurred in three cases of which one had clinical success. Five control samples could not be assessed for microbiological outcome due to growth of mixed flora or the control sample not being obtained. MIC values and relation to treatment outcome MIC values for the tested antibiotics are displayed in Table 4. Isolates from eleven patients could not be retrieved from the laboratory. For patients treated with nitrofurantoin, there was no significant difference in MIC values between those with clinical or microbiological success and those with clinical or microbiological failure.

Discussion Although aerococci have long been regarded as rare causes of human infections, an increasing number of studies show that they are human pathogens of clinical relevance, causing UTI and in some cases invasive infections [16]. There have been no previous treatment studies on aerococcal infections. In this prospective observational treatment study, most aerococcal UTIs were treated with nitrofurantoin. This observation was expected as, according to Swedish guidelines, nitrofurantoin and pivmecillinam are first-choice drugs in the treatment of cystitis while ciprofloxacin is recommended only for pyelonephritis.

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Our results suggest that nitrofurantoin is an appropriate treatment option for A. urinae cystitis, achieving clinical and microbiological success in 71% and 76% of cases, respectively. Previous studies on nitrofurantoin in the treatment of UTIs caused by other pathogens than aerococci, report clinical and microbiological success rates ranging between 74 and 93% [2528]. However, in contrast to our study, the patients in these studies were considerably younger and underlying conditions were rare. A study on a patient population with characteristics similar to ours evaluated nitrofurantoin in the treatment of cystitis caused by extendedspectrum beta-lactamase-producing E. coli, and observed clinical and microbiological success in 69% and 68% of cases, respectively [29]. Moreover, in our study, there was growth of A. urinae in the control urine sample of only one of six patients with clinical failure. The remaining patients had growth of other uropathogens to which the persistence of symptoms could be attributed, or had sterile urine, indicating the possibility that the symptoms were not caused by an infection. Thus, the success rates observed in the present study seem acceptable. Our results suggest ciprofloxacin to be another appropriate treatment option for A. urinae UTI. The patients treated with ciprofloxacin were generally male and a majority had pyelonephritis. Pivmecillinam, a commonly used antibiotic for UTIs in Sweden, achieved a clinical success in all patients, though it did not eradicate A. urinae from the urine in all cases. Although all A. urinae isolates had relatively low MICs to mecillinam in vitro, it is difficult to draw definite conclusions regarding pivmecillinam as the number of patients was low. In this study, UTI with A. sanguinicola was less common than with A. urinae. Patients in the A. sanguinicola group were more likely to be women and UTI caused by A. sanguinicola seemed to be more difficult to treat with nitrofurantoin, with considerably lower clinical and microbiological success rates than for A. urinae. These results must, however, be interpreted with caution as a high proportion of control urine samples were unassessable and the number of patients in this group was low. Nevertheless, since all A. sanguinicola isolates tested had

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low MICs for nitrofurantoin in vitro, and as only two patients with clinical failure had growth of A. sanguinicola in the control sample, nitrofurantoin could still be considered as a reasonable treatment option. Our results suggest that both cefadroxil and amoxicillin could be other feasible treatment options, although the low number of patients treated with these antibiotics in our study makes it difficult to draw definite conclusions. Nineteen patients did not meet the UTI criteria and were not assessed for clinical or microbiological cure. Five of these patients did not receive any treatment and had growth of aerococci in their control urine samples, demonstrating that they had asymptomatic bacteriuria. Thus, asymptomatic bacteriuria with aerococci occurs, though the frequency of this condition remains to be studied. In line with previous results [15,16], we found that most patients with aerococcal bacteriuria were elderly. In addition, a majority of these patients (75 %) had at least one underlying condition in the urinary tract. In an earlier study by our group, aerococci were identified in 0.27% of urinary cultures collected during a 3-month period in 2012 [6]. In the present study, aerococci were isolated from approximately 1% of the total number of urinary cultures sent to the same clinical microbiology laboratory. This apparent increase is probably due to higher awareness of aerococci in the laboratory, although an actual increase due to other factors cannot be ruled out. Interestingly, in a previous study, our group observed an equal distribution between men and women in patients with A. sanguinicola bacteriuria, while the distribution was significantly skewed towards women in this study. However, a larger proportion of the bacteria were in pure culture in the previous study (98%) as compared to this study (72%) [6]. This contrast could possibly also be linked to increased awareness of aerococci since the publication of the first study, causing more aerococci in mixed cultures to be species determined instead of being discarded as presumed contamination.

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This study has several limitations. Firstly, although the optimal study design for evaluating treatment efficacy is the randomized controlled trial design, we chose a prospective observational design. To conduct a randomized controlled trial in the setting of aerococcal UTIs would be extremely difficult due to the relative rarity of aerococci, and the fact that most physicians begin antibiotic treatment for a UTI before urine culture results are available. Moreover the retrospective design makes us unable to assess the success of treatment strategies other than those outlined in the guidelines for empirical treatment of UTI. Secondly, a number of follow-up urine samples (n = 12) could not be assessed due to contamination or due the patient failing to provide with a follow-up urine sample. This caused loss to followup, and therefore a discrepancy between the number of cases available for evaluation of clinical and microbiological outcome. The A. sanguinicola UTI group was particularly affected due to the lower number of patients. As the patients were generally elderly, many with low baseline function, this loss is understandable. Future studies on the treatment of aerococcal bacteriuria should attempt to minimize such losses, perhaps by having professional health care workers assist in the collection of urine samples. Thirdly, the patient interviews conducted in this study were performed shortly after the conclusion of treatment, and no further follow-up of patient symptoms was done. As UTI can relapse, a second follow-up of patient symptoms 15-30 days after the conclusion of treatment would have allowed the efficacy of different treatments to be evaluated over a longer period of time. We conclude that cystitis caused by A. urinae can be treated with nitrofurantoin and pyelonephritis with ciprofloxacin. Future studies need to be performed on a larger number of patients in order to establish treatment guidelines for other antibiotics and for patients with A. sanguinicola UTI.

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Acknowledgements We acknowledge Dr Bo Nilsson and Mrs Gisela Hovold, for valuable intellectual and technical support. This work was financed by the Swedish Government Fund for Clinical Research (ALF); the Royal Physiographic Society in Lund; the foundations of Marianne and Marcus Wallenberg, Crafoord, Österlund, Lundgren and Tornspiran; and the Skåne University Hospital.

Transparency declaration The authors declare that they have no conflicts of interest. Part of this work was presented at the meeting for infectious diseases specialists in June 2017, Karlskrona, Sweden,

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Iravani A, Klimberg I, Briefer C, Munera C, Kowalsky SF, Echols RM. A trial comparing low-dose, short-course ciprofloxacin and standard 7 day therapy with co-trimoxazole or nitrofurantoin in the treatment of uncomplicated urinary tract infection. J Antimicrob Chemother 1999;43 Suppl A:67–75. Stein GE. Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection. Clin Ther 1999;21:1864–72. doi:10.1016/S0149-2918(00)86734-X. Christiaens TCM, De Meyere M, Verschraegen G, Peersman W, Heytens S, De Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract 2002;52:729–34. Tasbakan MI, Pullukcu H, Sipahi OR, Yamazhan T, Ulusoy S. Nitrofurantoin in the treatment of extended-spectrum β-lactamase-producing Escherichia coli-related lower urinary tract infection. Int J Antimicrob Agents 2012;40:554–6. doi:10.1016/j.ijantimicag.2012.08.003.

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Legends to figures Figure 1. Timeline showing the process conducted for each patient. The given intervals are the median number of days between the different activities Figure 2. Flowchart showing the total number of urine cultures sent to the microbiology laboratory, those excluded, those eligible for inclusion, and the species encountered in the ptients that were included.

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Table 1. Features of the patients with urinary cultures containing aerococci Total (n = 91)

A. urinae (n = 66)

A. sanguinicola (n = 25)

59%

50%

84%

Sex % female Age, years Median (range)

79 (50-101) 78 (50-101)

82 (53-96)

Setting % hospital UTI, n (%) Cystitis Pyelonephritis No UTI Culture % in pure culture

31%

32%

28%

58 (64) 14 (15) 19 (21)

41 (62) 12 (18) 13 (20)

17 (68) 2 (8) 6 (24)

76%

77%

72%

Underlying conditions, n (%) 68 (75) 50 (76) 18 (72) Urogenitala b 54 (59) 37 (56) 17 (68) Extra-urogenital c 18 (20) 10 (15) 8 (32) History of recurrent UTIs 7 (8) 7 (11) 0 None a Including but not limited to, urolithiasis, prostatic hyperplasia, long-term and intermittent urinary catheter treatment, urological surgery, postvoid residual volume >100ml, neurogenic bladder, renal failure, vaginal prolapse, and malignancy in the urinary tract bIncluding but not limited to, diabetes, dementia, cerebrovascular disease, rheumatoid arthritis, multiple sclerosis, liver cirrhosis, immunosuppressive medication, and malignancy. c ≥3 episodes in 12 months with no other structural or functional abnormality in the urinary tract

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Table 2. Clinical and microbiological outcomes after treatment for 50 patients with A. urinae UTI. NITa

CIPa

PMECa

AMXa

CFRa

>1b

15/21 (71)

9/9 (100)

6/6 (100)

3/3 (100)

1/1 (100)

8/10 (80)

16/21 (76)

8/9 (89)

2/6 (33)

3/3 (100)

0

9/10 (90)

2/21 (10)

1/9 (11)

2/6 (33)

0

1/1 (100)

1/10 (10)

Clinical, n/N (%) Success Microbiological, n/N (%) Success NA

c

a

Median dosing regimens as follows: NIT: 50mg three times daily for 5 days; CIP: 500mg two times daily for 10 days; PMEC: 200mg three times daily for 7 days; AMX: 750mg two times daily for 10 days; CFR: 500mg two times daily for 7 days. b More than one antibiotic in the following combinations: PMEC and NIT (n=5); NIT and CIP (n=1); NIT and AMX (n=1); PMEC and CFR (n=1); VAN and AMX (n=1); CTX, IPM, AMX and CIP (n=1). c Not assessable due to mixed flora or follow-up culture not obtained.

Table 3. Clinical and microbiological outcomes after treatment for 19 patients with A. sanguinicola UTI. NITa

CFRa

AMXa

>1b

Clinical, n/N (%) Success

6/12 (50) 3/3 (100) 1/1 (100) 3/3 (100)

Microbiological, n/N (%) Success NA

c

5/12 (42) 2/3 (67) 1/1 (100) 3/3 (100) 4/12 (33) 1/3 (33)

0

0

a

Median dosing regimens as follows: NIT: 50mg three times daily for 5 days; CFR: 500mg twice daily for 7 days; AMX: 500mg twice daily for 3 days. b More than one antibiotic in the following combinations: CTX and AMX (n=1); NIT, PMEC and AMX (n=1); CTX, AMX and PMEC (n=1). c Not assessable due to mixed flora or follow-up culture not obtained.

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Table 4. MIC values for A. urinae and A. sanguinicola MIC (mg/L) 10th percentile Median 90th percentile

Range

A. urinae (n = 58) Ciprofloxacin Nitrofurantoin Trimethoprim Cefalotin Mecillinam Ceftibuten

0.094 0.094 >32 0.064 0.75 >32

0.25 0.38 >32 0.19 1.5 >32

0.75 3 >32 0.38 3 >32

0.047 to >32 0.047 to 6 12 to >32 0.023 to 0.5 0.19 to 16 >32

A. sanguinicola (n = 22) Ciprofloxacin Nitrofurantoin Trimethoprim Cefalotin Mecillinam Ceftibuten

0.75 2 >32 0.19 1 >32

>32 3 >32 0.38 2 >32

>32 6 >32 1 4 >32

0.25 to >32 0.25 to 8 >32 0.094 to 1.5 1 to 6 >32

Figure 1

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Figure 2

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