Efficacy of Pivmecillinam for Treatment of Lower Urinary Tract Infection Caused by Extended-Spectrum β-Lactamase–Producing Escherichia coli and Klebsiella pneumoniae

Abstract

To evaluate the clinical and bacteriological efficacy of pivmecillinam against lower urinary tract infection (UTI) caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae, patients treated for lower UTI with pivmecillinam (n=8) were studied. Patients treated with nitrofurantoin (n=3) and trimethoprim (n=3) or a combination of these agents with pivmecillinam (n=3) were included as a control group. Antimicrobial susceptibility was determined with EUCAST methodology. Bacteriologic cure was defined as <10³ CFU/ml at follow-up (30 days), and clinical cure as resolved UTI symptoms after completed treatment. All patients receiving pivmecillinam had good clinical response (8/8), but bacteriological cure rates were low (2/8). However, none of the patients with persisting bacteriuria had a relapse of UTI symptoms within 6 months. All isolates were susceptible to the given antimicrobial. Most isolates belonged to the CTX-M-1 group (n=11, 65%) or CTX-M-9-group (n=4, 24%). Four E. coli isolates belonged to the international clone O25b-ST131 (25%). In conclusion, pivmecillinam had good clinical activity against lower UTI caused by ESBL-producing Enterobacteriaceae, but bacteriological cure rates were low. The persistent bacteriuria appears to be of little clinical importance, but larger clinical studies are needed to determine the usefulness of pivmecillinam in infections caused by ESBL-producing bacteria.

Introduction

Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae have become important causes of community-onset urinary tract infection (UTI), and the lack of effective oral antimicrobial agents is a matter of concern. As the high level of coresistance to trimethoprim and fluoroquinolones has compromised these alternatives, few therapeutic options are available. Minimal inhibitory concentrations for nitrofurantoin, fosfomycin, and mecillinam are usually low in ESBL-producing E. coli,¹¹ although acquired resistance to fosfomycin has been described among the E. coli clone O25b-ST131.⁹ Previous reports support the clinical efficacy of fosfomycin and nitrofurantoin against lower UTI caused by ESBL-producing E. coli and K. pneumoniae,⁴ but clinical data for pivmecillinam are scarce.

Pivmecillinam is an amidinopenicillin with selective and high activity against Gram-negative organisms, especially E. coli. It is well documented that pivmecillinam is effective and well tolerated for the treatment of acute uncomplicated cystitis in women,⁷ and long-term clinical experience from the Nordic countries supports the efficacy of this agent. The in vitro activity of mecillinam is high also against ESBL-producing isolates.¹¹ One case report suggests that pivmecillinam could be effective against pyelonephritis caused by ESBL-producing E. coli,⁸ but apart from that there is no data on the clinical outcome for pivmecillinam against ESBL-producing bacteria. This antimicrobial agent is not available in many countries outside of Scandinavia but could represent a possible treatment alternative for lower UTI caused by ESBL-producing Enterobacteriaceae also in countries that traditionally have not had access to the agent.

In this study we evaluate the clinical and bacteriological activity of pivmecillinam against lower UTI caused by ESBL-producing E. coli and K. pneumoniae.

Materials and Methods

Study design

This study was part of a larger prospective study on the dynamics of fecal carriage of ESBL-producing bacteria after first-time infection. Patients (n=65) were included during 2009 and followed up with ESBL screening of fecal samples at 1, 3, 6, and 12 months after diagnosis. Urinary samples were collected at the one-month follow-up.

Study population

Sixty-five patients were included in the larger study. Of these 22 women had been treated for lower UTI. Seventeen patients had retrievable isolates and had received antimicrobial agents considered first- or second-line treatment for uncomplicated cystitis according to the national Swedish guidelines¹⁰: pivmecillinam (n=8), nitrofurantoin (n=3), and trimethoprim (n=3), or a combination of these agents (n=3). The patients who had received other agents than pivmecillinam were included as a control group. Before inclusion their medical records were studied for information on the treatment, dosage, symptoms of acute cystitis (≥1 of the following symptoms: frequency, urgency, dysuria, and suprapubic pain), and absence of signs of upper UTI (fever ≥38°C or back pain).

Follow-up

At the point of inclusion the patients were asked to fill in a questionnaire on received antimicrobial treatment, various comorbidities, and history of travel to be sent in together with a urine specimen ∼30 days after the original urinary sample. Another questionnaire regarding relapse of UTI symptoms and treatment for a possible new UTI was completed 3 and 6 months after the original urinary sample.

Outcome measures and definitions

The study outcome was antimicrobial efficacy based on bacteriological and clinical cure. Prestudy urine cultures were considered bacteriologically positive if there were ≥10³ CFU/ml of E. coli or K. pneumoniae.⁶ Bacteriologic cure was defined as <10³ CFU/ml at follow-up. Patients were considered clinically cured if the urinary symptoms had resolved after completed treatment according to the medical record. Relapse of UTI was defined as symptoms of acute cystitis, and/or signs of upper UTI, presenting within 6 months after clinical cure.

ESBL, MIC, and susceptibility testing

Production of ESBL in the prestudy was confirmed with ESBL combination disks (Oxoid) or ESBL Etest (AB BIODISK) according to the manufacturers' instructions.

Susceptibility for pivmecillinam, nitrofurantoin, and trimethoprim was determined with disk diffusion according to EUCAST³ and MICs determined with Etest (bioMérieux) according to the manufacturer's instructions, and interpreted according to EUCAST MIC breakpoints (www.eucast.org).

ESBL-producing bacteria in the follow-up urinary samples were detected with ESBL ChromID ESBL (bioMérieux). The detection limit was 10³ CFU/ml.

Determination of ESBL genotype and PCR detection of pabB

A previously described real-time MGB probe–based PCR was used for typing of bla_CTX-M to the phylogenetic subgroups.¹ Further, the E. coli isolates were analyzed with an O25b-ST131 allele-specific PCR assay of the pabB gene according to Clermont et al.²

Results

The results are displayed in Table 1. The majority of the isolates belonged to the CTX-M-1 group (n=11), and 4 isolates to the CTX-M-9 group. Four of the E. coli isolates belonged to the international clone O25b-ST131. All patients receiving pivmecillinam had good clinical response (8/8); however, the bacteriological cure rate was low (2/8). Interestingly, none of the patients with persisting bacteriuria after 30 days had a relapse of UTI within 6 months, whereas one of the patients with bacteriological cure did. There was no indication that the received dose of pivmecillinam, in the range of 200 mg twice daily (b.i.d, i.e., bis in die, latin) to 200 mg three times daily (t.i.d, i.e., ter in die, latin), affected the clinical or the bacteriological outcome. One of the patients with and one of the patients without bacteriological cure had no risk factors for ESBL colonization apart from travel abroad, whereas the other patients had one or several risk factors such as previous antimicrobial treatment, hospitalization, urinary catheter, and abnormalities within the urinary tract.

Table 1.

Women with Cystitis: Susceptibility and Response to Antimicrobial Treatment, and Risk Factors for Extended-Spectrum β-Lactamase

										Risk factors for ESBL infection
Age	Species (CTX-M-group) ^a	Antimicrobial treatment	Dosing regimen	Susceptibility to given antimicrobial(s) (MIC; mg/L/zone diameter; mm) ^b	Bacteriological cure ^c	Clinical cure	Relapse of UTI within 6 months	Additional antimicrobial treatment	Hospitalization ^d	Previous antimicrobial treatment ^d	Urinary catheter ^d	Abnormality in urinary tract	Travel abroad ^d (country)	Hospitalization abroad ^d
27	Escherichia coli (CTX-M-1)	MEC	200 mg t.i.d. 5d	S (0.25/25)	Yes	Yes	No	-	-	-	-	-	Cambodia	-
60	E. coli (CTX-M-1)	MEC	Data missing	S (1/18)	No	Yes	No	AMX	-	-	-	-	Italy	-
26	E. coli (CTX-M-9)	MEC	200 mg b.i.d. 7d, 400 mg b.i.d 7d	S (0.25/28)	No	Yes	No	-	-	Unknown agent (cystitis)	Yes	Recurrent cystitis	-	-
62	E. coli (CTX-M-9)	MEC	200 mg b.i.d. 7d	S (0.5/22)	No	Yes	No	AMX	-	AMX, DOX	-	Incontinence	-	-
55	E. coli (CTX-M-1)	MEC	200 mg t.i.d. 7d	S (2/17)	No	Yes	No	-	Yes	FLU, NIT	-	-	-	-
51	E. coli (CTX-M-1)	MEC	200 mg t.i.d 7d	S (0.25/25)	No	Yes	No	-	Yes	Unknown agent	Yes	MS, bladder dysfunction, chronic catheter	-	-
77	E. coli (CTX-M-8/25)	MEC	200 mg b.i.d. 7d	S (0.25/26)	No	Yes	No	-	-	-	-	-	Spain	-
43	Klebsiella pneumoniae (CTX-M-9)	MEC	200 mg b.i.d. 7d	S (0.5/23)	Yes	Yes	Yes (After 5 weeks)	-	Yes	PcV	-	Extracorporeal shock wave lithotripsy −08	-	-
56	E. coli (CTX-M-1)	NIT	50 mg t.i.d 5d	S (8/20)	Yes	Yes	No	-	-	2 unknown agents (sinusitis)	-	-	Germany, India, USA, Middle east	-
77	E. coli (CTX-M-1)	NIT	50 mg t.i.d 5d	S (16/20)	Yes	Yes	No	-	-	-	-	-	Egypt	-
41	E. coli (CTX-M-1)	NIT	50 mg t.i.d. 5d	S (16/18)	No	Yes	Yes (after 6 weeks)	-	-	-	-	-	-	-
32	E. coli (CTX-M-1)	NIT+MEC	NIT 50 mg t.i.d 7d+MEC 200 mg b.i.d 2d	NIT: S (16/21) MEC: S (0.5/21)	Yes	No. After 2d of MEC pyelitis	No	-	-	-	-	Pregnant	-	-
78	E. coli (non-CTX-M)	MEC+TMP+NIT	200 mg t.i.d. 2d+160 mg b.i.d. 7d+50 mg t.i.d. 7d	MEC: R (8/12) TMP: R (8/15) NIT: S (32/16)	Yes	MEC+TMP:partial response, relapse after 4 weeks NIT:Yes	No	-	Yes	-	Yes	Uterine prolapse, op 1965	-	-
86	E. coli (CTX-M-9)	TMP+MEC+NIT	200 mg b.i.d. 7d	TMP:R (>32/6) MEC:S (0.25/27) NIT:S (8/21)	Yes	Yes	No	-	Yes	-	Yes	Recurrent cystitis	-	-
67	E. coli (CTX-M-1)	TMP	160 mg b.i.d 7d	R (>32/6)	Yes	Yes	No	AMX	Yes	DOX	-	Recurrent cystitis	-	-
71	E. coli (CTX-M-1)	TMP	160 mg b.i.d. 7d	S (0.25/28)	No	Yes	No	MZL	-	-	-	-	-	-
60	E. coli (CTX-M-1)	TMP	160 mg b.i.d. 7d	R (>32/6)	No	Yes	Yes, 2 episodes	-	Yes	-	-	Chronic interstitial nephritis	-	-

Bold face, the isolate belongs to the international clone E. coli ST131.

MIC breakpoints according to EUCAST (zone diameter breakpoint) (S ≤/ R>): MEC 8/8 (15/15), NIT 64/64 (11/11), TMP 2/4 (18/15).

<1,000 CFU/ml, urine sample one month after initial culture.

Within 6 months before diagnosis.

MEC, pivmecillinam; NIT, nitrofurantoin; TMP, trimethoprim; B.i.d (bis in die, latin), twice daily; t.i.d (ter in die, latin), three times daily; AMX, amoxicillin; DOX, doxycycline; FLU, flucloxacillin; PcV, fenoxymetyl penicillin; MZL, metronidazole; UTI, urinary tract infection; ESBL, extended-spectrum β-lactamase.

Discussion

The use of pivmecillinam as treatment for uncomplicated cystitis is recommended both by the Infectious Diseases Society of America and the European Society for Clinical Microbiology and Infectious Diseases,⁵ and its efficacy is well documented.⁷ However, half of the patients in this study could not be classified as uncomplicated as they had functional or structural abnormalities of the genitourinary tract (9/17 in total; 4/8 who received pivmecillinam). Although the evaluation of comparative trials for complicated lower UTI is compromised by the variability in study subjects, equivalent outcomes for the compared agents are generally reported. The selection of an antimicrobial for clinical therapy should in each case be individualized considering patient tolerance, clinical presentation, recent prior antimicrobial treatment, prior urine culture results, and known or suspected susceptibilities. Oral therapy for 7 days is recommended, but patients with chronic urological devices should receive as short a duration as possible to limit antimicrobial pressure leading to resistance. Because of the variability in factors that could influence the outcome of the treatment, it is difficult to find comparative data for those of our study subjects for whom UTIs could not be classified as uncomplicated (9/17).

Although the number of patients in this study is limited, our results give a clear indication that clinical cure rates with pivmecillinam are high, whereas bacteriological eradication is low for lower UTI with ESBL-producing isolates. However, the clinical importance of persisting bacteriuria maybe questioned when clinical cure is achieved, and relapse of UTI does not occur. It is known that bacteriological cure rates are somewhat lower with β-lactams than with fluoroquinolones and trimethoprim-sulfamethoxazole for wild-type isolates, although cure rates of >90% have been reported with various pivmecillinam regimens (200 mg b.i.d, 200 mg t.i.d, and 400 mg b.i.d for 3–7 days).⁷ The lower bacteriological cure rate with β-lactams is usually considered of little clinical importance, and the advantages of using pivmecillinam in terms of low rate of resistance and high tolerance outweigh this potential problem.¹² It is also known that patients with structural or anatomical problems within the urinary tract are less likely to experience bacterial eradication after infection, and it is possible that the high rate of persisting bacteriuria in our collection to some extent reflects the underlying complicating factors of the patients.

This study, although the number of isolates is low, indicates that pivmecillinam has good clinical activity against lower UTI with ESBL-producing bacteria, but that the bacteriological activity is questionable, at least with the current dosage regimens in patients with underlying complicating factors. Potentially, this agent could also have a place in the antimicrobial armamentarium in countries where it has not previously been licensed. However, our data also suggest that persisting bacteriuria is of little clinical importance, although larger clinical studies are needed to confirm this.

Footnotes

Acknowledgments

The authors thank Noha Flefel and Muhammad Asif Habeeb for excellent technical assistance.

Disclosure Statement

This work was financed through grants from the Swedish Strategic Programme against Antibiotic Resistance (Strama) and the Scandinavian Society for Antimicrobial Chemotherapy (SSAC). C.G.G. has received speaker's honoraria from Wyeth and Meda, and chairperson's honorarium from Pfizer. Other authors: none to declare.

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