View of Antimicrobial susceptibility estimation of uncomplicated urinary tract infection pathogens to oral beta-lactam antibiotics with a mathematical model

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1 Department of Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana, Ljubljana, Slovenia

2 Department of Medical Microbiology Murska Sobota, National Laboratory of Health, Environment and Food, Maribor, Slovenia

3 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Correspondence/

Korespondenca:

Bojana Beović, e: bojana.

beovic@kclj.si Key words:

urinary tract infections;

cephalosporins; cefadroxil;

antimicrobial susceptibility Ključne besede:

okužbe sečil; cefalosporini;

cefadroksil; protimikrobna občutljivost

Received: 19. 7. 2018 Accepted: 28. 8. 2018

en article-lang

10.6016/ZdravVestn.2855 doi

19.7.2018 date-received

28.8.2018 date-accepted

Microbiology and immunology Mikrobiologija in imunologija discipline

Short scientific article Klinični primer article-type

Antimicrobial susceptibility estimation of uncomplicated urinary tract infection pathogens to oral beta-lactam antibiotics with a mathematical model

Ocena občutljivosti povzročiteljev nezapletenih okužb sečil za peroralne betalaktamske antibiotike z matematičnim modelom

article-title

Antimicrobial susceptibility estimation of

uncomplicated urinary tract infection Ocena občutljivosti povzročiteljev nezapletenih okužb sečil

alt-title urinary tract infections, cephalosporins,

cefadroxil, antimicrobial susceptibility okužbe sečil, cefalosporini, cefadroksil, protimikrobna občutljivost

kwd-group

The authors declare that there are no conflicts

of interest present. Avtorji so izjavili, da ne obstajajo nobeni

konkurenčni interesi. conflict

year volume first month last month first page last page

2019 88 9 10 458 463

name surname aff email

Bojana Beović 1,3 bojana.beovic@kclj.si

name surname aff

Kristina Nadrah 1,3

Iztok Štrumbelj 2

eng slo aff-id

Department of Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana, Ljubljana, Slovenia

Klinika za infekcijske bolezni in vročinska stanja, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija

1

Department of Medical Microbiology Murska Sobota, National Laboratory of Health, Environment and Food, Maribor, Slovenia

Oddelek za medicinsko mikrobiologijo Murska Sobota, Nacionalni laboratorij za zdravje, okolje in hrano, Maribor, Slovenija

2

Faculty of Medicine, University

of Ljubljana, Ljubljana, Slovenia Medicinska Fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija 3

Antimicrobial susceptibility estimation of uncomplicated urinary tract infection pathogens to oral beta-lactam antibiotics with a mathematical model

Ocena občutljivosti povzročiteljev nezapletenih okužb sečil za peroralne betalaktamske antibiotike z matematičnim modelom

Kristina Nadrah,¹ Iztok Štrumbelj,² Bojana Beović+

Abstract

Background: Uncomplicated urinary tract infections are among the most common infections in young healthy women. When treating such infections we use narrow-spectrum antibiotics with activity against the most common pathogens. The treatment of such infections is usually empirical, therefore in our study we estimated the susceptibility of the most common isolates to oral betalactam antibiotics to determine whether they are an acceptable alternative in case of contraindications to first-line agents.

Methods: We used a theoretical distribution of the frequency of urinary tract pathogens and antimicrobial susceptibilities from clinical urinary cultures in women to calculate an estimate of overall susceptibility of the pathogens using a mathematical model.

Results: The estimated susceptibility to ampicillin was low (50%), but much higher for cephalo- sporins of 1st to 3rd generation (88% – 90%).

Conclusion: The mathematical model for susceptibility estimation represents an interesting tool for predicting clinical efficacy of antibiotics, based on local antibiotic susceptibility and frequency of pathogens. Our results show that among betalactam antibiotics, 1st generation cephalosporins are suitable for the treatment of uncomplicated cystitis.

Izvleček

Izhodišče: Nezapletene okužbe sečil so ena najpogostejših okužb pri zdravih mladih ženskah. Za zdravljenje tovrstnih okužb izberemo antibiotike ozkega spektra z delovanjem na najpogostejše povzročitelje. Ker je zdravljenje nezapletenih okužb spodnjih sečil večinoma izkustveno, smo v raziskavi ocenili, kakšna je občutljivost najpogostejših povzročiteljev za peroralne betalaktamske antibiotike in ali so primerni za izkustveno zdravljenje nezapletenih okužb sečil v primerih, kadar ne moremo uporabiti antibiotikov izbire.

Metode: Iz teoretične porazdelitve pogostosti različnih vrst povzročiteljev okužb sečil in deležev občutljivosti resničnih izolatov urinokultur pri ženskah smo z uporabo matematičnega modela izračunali oceno skupne občutljivosti za peroralne betalaktamske antibiotike.

Rezultati: Ocenjena skupna občutljivost za ampicilin je bila slaba (50 %), za cefalosporine prve, druge in tretje generacije pa med 88 % in 90 %.

Slovenian Medical

Journal

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1 Introduction

Uncomplicated urinary tract infections occur in non-pregnant, premenopausal women with no anatomical or functional urinary tract abnormalities and no associated diseases (1). These are very common infections, which represent one of the most common reasons women visit their chosen doctor due to infection, and are particularly common in the young work- ing-age female population (2). The most common is cystitis, which is often recurrent. In healthy young women, cystitis is estimated to reoccur in the first 6 months in as many as a quarter of cases, with each recurrence increasing the likelihood of further recurrences (3). Since such infections often recur, a suitable treatment should be chosen, so that frequent use does not cause resistance to oral antibiotics and the need for unnecessary hospital- ization, associated with it. The most common cause of uncomplicated urinary tract infections is Escherichia coli, followed by other enterobacteria and Staphylococcus saprophyticus (1,3,4).

For the treatment of uncomplicated infections of the lower urinary tract, we choose a narrow-spectrum antibiotic that acts on the most common agents and is well tolerated by female patients, while trying to limit the ecological damage that taking the antibiotic will cause. Due to great ecological damage, fluoroquinolones are, in this age of dramatic increase of re-

Zaključek: Matematični model za oceno občutljivosti je zanimivo orodje, s katerim lahko na- povemo klinično učinkovitost antibiotikov na podlagi lokalne občutljivosti in pogostosti povz- ročiteljev. Na podlagi naših rezultatov ugotavljamo, da so med betalaktamskimi antibiotiki za zdravljenje cistitisa najprimernejši cefalosporini prve generacije.

Cite as/Citirajte kot: Nadrah K, Štrumbelj I, Beović B. Antimicrobial susceptibility estimation of

uncomplicated urinary tract infection pathogens to oral beta-lactam antibiotics with a mathematical model.

Zdrav Vestn. 2019;88(9–10):458–63.

DOI: https://doi.org/10.6016/ZdravVestn.2855

sistance to Gram negative bacteria, being avoided (1,3,5), and in Slovenia a sensitivity decrease of enterobacteria to fluoroquinolones has lately been noted (6).

The drugs of choice for uncomplicated infections of the lower urinary tract are nitrofurantoin or phosphomycin (1,6).

If medicines are, for any reason, inac- ceptable or poorly tolerated by female patients, beta-lactam antibiotics may be considered, although they are less effective in short-term treatment (1,7), most likely because of less favorable pharmacokinet- ics (7). Due to the frequent high resistance of E. coli to aminopenicillins, they are not recommended for empirical treatment of urinary tract infections (1,3,5,8). The Eu- ropean Association of Urology offers in its guidelines as an alternative for treating uncomplicated urinary infections oral cephalosporins or a combination of aminopenicillins with beta-lactamase inhibi- tors (1), but it is necessary to recognise the major environmental damage (9), so these antibiotics should only be used when the two drugs of choice are prohibited.

EUCAST (European Committee on Antimicrobial Susceptibility Testing) states that oral cephalosporins are not suitable for treating systemic infections, because they do not reach sufficient concen- trations in tissues for a long enough time.

They are only suitable for uncomplicated infections of the lower urinary tract (8,10).

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In order to include oral cephalosporins in the comparison of antibiotics, we limited ourselves in the study to uncomplicated infections of the lower urinary tract. Rec- ommendations for antibiotic treatment are based on the frequency of agents and their susceptibility to antibiotics.

The purpose of this article is to calculate the total susceptibility by means of a mathematical model, based on regional data on the susceptibility and frequency of agents from the literature, and thereby indirectly predict the clinical efficacy of agents of uncomplicated urinary tract infection in Pomurje for oral beta-lactam antibiotics and to discuss the model and the limitations of the results.

2 Material and Methods

Two factors were used to assess the susceptibility of the entire population of isolates: theoretical distribution of the inci- dence of different species in acute cystitis and the susceptibility percentage of true isolates to an individual antibiotic from Pomurje. We took data from the literature for the theoretical percentage of the frequency of species, taking into account the prevalence of species referred to by the Association of European Urologists as agents of uncomplicated cystitis. The most common bacteria is E. coli (79%), agents presenting 7% each being: Klebsiella pneu- moniae, Proteus mirabilis, S. saprophyticus (1).The isolates for which antibiotic susceptibility was determined by EUCAST methods are isolates from the Department for Medical Microbiology, Murska Sobota, National Laboratory of Health, Environ- ment and Food: E. coli, K. pneumoniae, P.

mirabilis from 2016 and isolates of the S.

saprophyticus type from 2014–2017 (from 2014 to October 2017).All of the isolates in the tables are the first isolates of each bacterial species from the urinary tract of female patients with urinary tract infection - isolates from men were excluded from the analysis because urinary tract in-

fections in men are not uncomplicated (1).

From the provided prevalence data and from the test results of the indicated species, we calculated the percentage of the theoretical population of isolates susceptible to an antibiotic for each bacterial species and for all isolates together. The percentage of the theoretical population of isolates susceptible to an antibiotic is the product of the proportion of antibiotic susceptibility (expressed as a percentage) and the prevalence of the species (the percentage of 1; 1 is the total population of isolates). Example: the sensitivity of the E. coli isolates to ampicillin is 49.4%, the prevalence of E. coli in the total population is 0.79, the product of E. coli is 49.4% × 0.79 = 39.9%, which is the percentage of the theoretical population of E. coli,isolates sensitive to ampicillin. The sums of percentages of the theoretical populations of all isolates sensitive to antibiotics are the total percentages of the theoretical population of isolates sensitive to an individual antibiotic, which indicates the probability of what portion of the group of these isolates is sensitive to each antibiotic.

3 Results

The percentage of the total theoretical population of isolates susceptible to ampicillin is only 50% and to amoxicillin with clavulanic acid 83%, while susceptibility to cephalosporins is higher, reaching up to about 90% for the first (cephadroxil) and third generation of cephalosporins (cefixime).

The results are shown in Table 1.

4 Discussion

In a study on treatment of urinary tract infections in US emergency centers, the resistance of an isolate to prescribed empirical oral antibiotic therapy was a significant factor in the deterioration and a return visit to the emergency center (11).

For the treatment of uncomplicated cystitis, induced by E. coli, clinical trial find-

Table 1: Estimated susceptibility and the percentage of theoretical population of isolates susceptible to an

antibiotic (theoretical composition of isolates: Escherichia coli 79%, Klebsiella pneumoniae 7%, Proteus mirabilis 7%, Staphylococcus saprophyticus 7%).

* Percentage of susceptible isolates for uncomplicated urinary tract infections (EUCAST guidelines). Percentage of susceptible isolates for uncomplicated urinary tract infections (EUCAST guidelines).

** Percentage of theoretical isolates susceptible to the antibiotic. Percentage of theoretical isolates susceptible to the antibiotic (DTPIOA).

Bacterial species Number of tested isolates

Ampicillin Amoxicillin with Clavulanic

Acid

Cefadroxil Cefuroxime

Axetil Cefixime

Percentage S (%)* DTPIOA (%)** Percentage S (%)* DTPIOA (%)** Percentage S (%)* DTPIOA (%)** Percentage S (%)* DTPIOA (%)** Percentage S (%)* DTPIOA (%)**

Escherichia coli 1,033 49.4 39.0 82.3 65.0 90.1 71.2 88.2 69.7 89.6 70.8

Klebsiella pneumoniae 137 0.0 0.0 72.3 5.1 73.7 5.2 72.3 5.1 74.5 5.2

Proteus mirabilis 127 56.7 4.0 85.0 6.0 96.9 6.8 100.0 7.0 100.0 7.0

Staphylococcus

saprophyticus 57 100 7.0 100 7.0 100 7.0 100 7.0 100 7.0

Total 1,354 / 50.0 / 83.0 / 90.1 / 88.7 / 90.0

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fections in men are not uncomplicated (1).

From the provided prevalence data and from the test results of the indicated species, we calculated the percentage of the theoretical population of isolates susceptible to an antibiotic for each bacterial species and for all isolates together. The percentage of the theoretical population of isolates susceptible to an antibiotic is the product of the proportion of antibiotic susceptibility (expressed as a percentage) and the prevalence of the species (the percentage of 1; 1 is the total population of isolates). Example: the sensitivity of the E. coli isolates to ampicillin is 49.4%, the prevalence of E. coli in the total population is 0.79, the product of E. coli is 49.4% × 0.79 = 39.9%, which is the percentage of the theoretical population of E. coli,isolates sensitive to ampicillin. The sums of percentages of the theoretical populations of all isolates sensitive to antibiotics are the total percentages of the theoretical population of isolates sensitive to an individual antibiotic, which indicates the probability of what portion of the group of these isolates is sensitive to each antibiotic.

3 Results

The percentage of the total theoretical population of isolates susceptible to ampicillin is only 50% and to amoxicillin with clavulanic acid 83%, while susceptibility to cephalosporins is higher, reaching up to about 90% for the first (cephadroxil) and third generation of cephalosporins (cefixime).

The results are shown in Table 1.

4 Discussion

In a study on treatment of urinary tract infections in US emergency centers, the resistance of an isolate to prescribed empirical oral antibiotic therapy was a significant factor in the deterioration and a return visit to the emergency center (11).

For the treatment of uncomplicated cystitis, induced by E. coli, clinical trial find-

Table 1: Estimated susceptibility and the percentage of theoretical population of isolates susceptible to an

antibiotic (theoretical composition of isolates: Escherichia coli 79%, Klebsiella pneumoniae 7%, Proteus mirabilis 7%, Staphylococcus saprophyticus 7%).

* Percentage of susceptible isolates for uncomplicated urinary tract infections (EUCAST guidelines). Percentage of susceptible isolates for uncomplicated urinary tract infections (EUCAST guidelines).

** Percentage of theoretical isolates susceptible to the antibiotic. Percentage of theoretical isolates susceptible to the antibiotic (DTPIOA).

Bacterial species Number of tested isolates

Ampicillin Amoxicillin with Clavulanic

Acid

Cefadroxil Cefuroxime

Axetil Cefixime

Percentage S (%)* DTPIOA (%)** Percentage S (%)* DTPIOA (%)** Percentage S (%)* DTPIOA (%)** Percentage S (%)* DTPIOA (%)** Percentage S (%)* DTPIOA (%)**

Escherichia coli 1,033 49.4 39.0 82.3 65.0 90.1 71.2 88.2 69.7 89.6 70.8

Klebsiella pneumoniae 137 0.0 0.0 72.3 5.1 73.7 5.2 72.3 5.1 74.5 5.2

Proteus mirabilis 127 56.7 4.0 85.0 6.0 96.9 6.8 100.0 7.0 100.0 7.0

Staphylococcus

saprophyticus 57 100 7.0 100 7.0 100 7.0 100 7.0 100 7.0

Total 1,354 / 50.0 / 83.0 / 90.1 / 88.7 / 90.0

ings, expert opinions, and mathematical models predict that empirical treatment with trimethoprim/sulfamethoxazole (TMP/SMX) is appropriate, if TMP/SMX resistance is below 20% (5). If the results of antibiotic susceptibility in Table 1 were evaluated according to this criterion, it would be found that ampicillin (the results also apply to amoxicillin) is not suitable for empirical treatment, since the percentage of the theoretical population of ampicillin-susceptible isolates is only 50%.

The percentage of the theoretical population of isolates, susceptible to amoxicillin with clavulanic acid, is 83% and the susceptibility of first- to third-generation oral cephalosporins (cefadroxil, cefuroxime axetil, cefixime) is estimated to about 90%. These antibiotics are suitable for empirical treatment, but the ecological damage using broad-spectrum antibiotics is significant. Cefadroxil is considered to be a suitable alternative for treating uncomplicated urinary tract infections, if first-

line medications are prohibited for the patient.

The European Society of Urology rec- ommends for treating cystitis with cefadroxil a three-day treatment (1), and Slo- venian recommendations for beta-lactam antibiotics advise a 3- to 7-day treatment (6). Short-term treatment of urinary tract infections with beta-lactam antibiotics is less effective than treatment with TMP/

SMX or fluoroquinolones, so it is advis- able to extend the treatment to at least 5 days (5,7). Cefadroxil is also suitable for the treatment of cystitis in pregnant women (1,12).

The advantage of the mathematical model used is that it expresses, by a single number, the total antibiotic susceptibility of all agents that are included in the model. Based on this, we can calculate the results for different proportions of individual agents from different sources. A similar concept for the calculated (concidered) selection of an empirical antibiotic is de-

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scribed in the German guidelines for the selection of an empirical antibiotic treatment of bacterial infections (13). When choosing the most appropriate empirical treatmen, the considered choice takes in- to account the local susceptibility of the pathogens, the type of bacterial infection and the patient’s characteristics (13).

Our study has several limitations.

• Isolates are not representative of uncomplicated urinary tract infections.

Since the laboratory does not have systematic data on the type of urinary tract infection, we were able to limit the origin of the isolates to the female sex alone (in males the infections are not uncomplicated), thereby reducing the proportions of isolates in patients with potentially complicated urinary tract infection.

• The results of antibiograms come from regular microbiological diagnostics, which is more commonly used in patients with more severe infections and associated diseases and/or in patients in whom empirical treatment had failed. In these patients, their isolates are more likely to be resistant to antibiotics than in female patients who develope uncomplicated urinary tract infection at home and are empirical- ly successfully treated, without urine samples being taken.

• The percentages of species among regular isolates are not representative of uncomplicated urinary tract infections either - therefore, the percentages in the calculation were based on the percentages from the literature relating to uncomplicated urinary tract infections.

• The prevalence of individual types of bacteria is estimated at European lev- el and does not necessarily reflect the prevalence in Slovenia, but we are as- suming that the percentages of pathogens in Slovenia are not significantly different.

Therefore, the results in this article do not predict the absolute value of susceptibility of a group of uncomplicated urinary

tract infection pathogens to a single antibiotic, but the results provide an indic- ative estimate of the differences between them. Since susceptibility to amoxicillin with clavulanic acid and cephalosporins is already good in this population of regular isolates, it is likely to be excellent among the uncomplicated infection pathogens.

Urine samples were taken in Pomur- je. It is not known whether the susceptibility in Slovenia is evenly distributed, or whether there are major regional differences, and therefore the applicability of the results to other regions is not known.

Despite these limitations, we believe that the method of assessment of the predicted efficacy of antibiotics shown is important for two reasons. It allows us to easily predict the clinical efficacy of antibiotics in different regions of Slovenia and elsewhere and make treatment recommendations. At the same time, the results indicate that in Slovenia narrow-spectrum cephalosporins are also suitable for the treatment of uncomplicated urinary tract infections.

5 Conclusion

The mathematical model used shows differences in susceptibility to different antibiotics, although the detected susceptibility proportions are probably not representative of uncomplicated infections of the lower urinary tract. Research is need- ed to determine, in a sufficient number of isolates, the actual susceptibility of urinary isolates in uncomplicated infections of the lower urinary tract from different regions.

Ampicillin (amoxicillin) is not a rea- sonable choice for empirical treatment, since it has the lowest susceptibility proportion. Amoxicillin with clavulanic acid, cefuroxime axetil (2nd generation cephalosporins) and cefixime (3rd generation cephalosporins) have acceptable sensitivity levels, but they are broad-spectrum antibiotics that cause ecological damage and are therefore not an acceptable choice for empirical treatment of non-threaten- ing infections. The results indicate that

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cephalosporin of the lowest-generation, cefadroxil, is the most appropriate choice for the treatment of uncomplicated lower

urinary tract infections in female patients, who cannot be treated with nitrofurantoin or phosphomycin.