Complicated urinary tract infections: practical solutions for the treatment of multiresistant Gram-negative bacteria

Abstract

Resistance in Gram-negative bacteria has been increasing, particularly over the last 6 years. This is mainly due to the spread of strains producing extended-spectrum β-lactamases (ESBLs) such as CTX-M enzymes or AmpC β-lactamases. Many of the isolates producing these enzymes are also resistant to trimethoprim, quinolones and aminoglycosides, often due to plasmid co-expression of other resistance mechanisms. CTX-M-producing Escherichia coli often occurs in the community and as E. coli is one of the commonest organisms causing urinary tract infections (UTIs) the choice of agents to treat these infections is diminishing. Novel combinations of antibiotics are being used in the community and broad-spectrum agents such as carbapenems are being used increasingly as empirical treatment for severe infections. Of particular concern therefore are reports in the UK of organisms that produce carbapenemases. As resistance is becoming more widespread, prudent use of antimicrobials is imperative and, as asymptomatic bacteriuria is typically benign in the elderly, antibiotics should not be prescribed without clinical signs of UTI. The use of antibiotics as suppressive therapy or long-term prophylaxis may no longer be defensible.

Introduction

Urinary tract infections (UTIs) are among the most common infectious diseases occurring in either the community or healthcare setting.1 Uncomplicated UTIs typically occur in the healthy adult non-pregnant woman, while complicated UTIs (cUTIs) may occur in all sexes and age groups and are frequently associated with either structural or functional urinary tract abnormalities. Examples include foreign bodies such as calculi (stones), indwelling catheters or other drainage devices, obstruction, immunosuppression, renal failure, renal transplantation and pregnancy.2 UTI in the elderly is almost always complicated in men with prostatic hypertrophy and in post-menopausal women who may have an increased post-void residual volume.3 The likelihood of treatment failure and serious complications, particularly the development of antimicrobial resistance, is more common in cUTI. Although a broad range of pathogens can cause cUTI, Escherichia coli remains the most common; however, even this organism is becoming resistant to the agents that are normally prescribed.4 This leads to a number of management and therapeutic problems that will be discussed below. Genetic susceptibility of individual patients to UTI has been well reviewed recently and will not be discussed in this article.2

What is a symptomatic UTI?

Typical symptoms of a lower UTI include frequency and dysuria without fever, chills or back pain whereas upper UTI usually presents with symptoms of pyelonephritis such as loin pain, flank tenderness, fever or other signs of a systemic inflammatory response.3 If both dysuria and frequency are present, the probability of a UTI is >90% and antibiotic treatment is indicated.5 However, as exemplified by the case report shown in Figure 1, diagnosis of UTI can be difficult especially in the confused elderly patient because of non-specificity and misleading symptoms and signs.6 As in this case, some patients may present with signs of a chest infection or may have dual infection. The presence of delirium, urinary retention or incontinence, metabolic acidosis or respiratory alkalosis may indicate a symptomatic UTI in this group. It is recommended that a urine sample be collected before starting empirical antibiotic therapy for patients with cUTI but in the elderly it is more difficult to collect a non-contaminated sample,7 and an in–out catheter may represent the optimum approach to obtaining a reliable specimen.6 A dipstick can be used to test for the presence of leucocyte esterase and nitrites as surrogate markers for bacteriuria in the non-catheterized patient, with negative tests associated with low probability of bacteriuria—around 20% in women with minimal signs or symptoms of a UTI and <10% in symptomatic nursing home residents.5,6 In symptomatic non-catheterized elderly patients, a positive result is less reliable with the presence of leucocyte esterase having <50% positive predictive value. However, some experts consider that the detection of nitrites in the symptomatic patient should prompt initiation of treatment.6

Figure 1.

Case report 1: uncomplicated UTI in an elderly patient.Open in new tabDownload slide

Case report 1: uncomplicated UTI in an elderly patient.

Figure 1.

Case report 1: uncomplicated UTI in an elderly patient.Open in new tabDownload slide

Case report 1: uncomplicated UTI in an elderly patient.

The quantitative criterion appropriate for the microbiological identification of significant bacteriuria is generally considered to be at least 108 cfu/L. In some specific groups it is less: for men ≥106 cfu/L; and for women with symptoms of UTI it is ≥105 cfu/L.5 Asymptomatic bacteriuria (ASB) is common in the elderly, rising with age to >50% in women and >35% in men over the age of 80 years. Other co-morbidities such as diabetes mellitus or an indwelling catheter also contribute to increased frequency of this condition.8 Algorithms have been developed to optimize antimicrobial use for suspected UTI in the nursing home, recommending that in the absence of minimal signs of UTI, urine should not be cultured and antimicrobials should not be prescribed.9 Indeed a call has been made by US clinicians for a performance measure for not treating asymptomatic bacteriuria.10

The diagnosis of cUTI is particularly difficult in patients who have an indwelling catheter and present with a fever. Such a patient is described in the case report shown in Figure 2. Costovertebral tenderness or angle pain may be a helpful localizing sign and occasionally there may be suppuration around the catheter.11 Even if there are no localizing signs, because the urine culture is frequently positive the patient is assumed to have a UTI. However, a prospective study using serological markers identified only one-third of the patients with bacteriuria in a long-term care facility as having a UTI, which suggests that the diagnosis of UTI in this situation is that of exclusion. The febrile episodes often settle spontaneously (Figure 2).11

Figure 2.

Case report 2: UTI in a catheterized elderly patient.Open in new tabDownload slide

Case report 2: UTI in a catheterized elderly patient.

Figure 2.

Case report 2: UTI in a catheterized elderly patient.Open in new tabDownload slide

Case report 2: UTI in a catheterized elderly patient.

A number of excellent guidelines reviewing the diagnosis and treatment of ASB in adults are available.5,12 In essence, in the absence of genitourinary symptoms, bacteriuria should not be treated except in pregnancy or for surgical manipulation of the urinary tract. Unnecessary treatment will lead to selection of resistant organisms and puts patients at risk of adverse drug effects including infection with Clostridium difficile. Likewise there is good evidence that screening for ASB is not necessary in pre-menopausal patients who are not pregnant, older patients living in the community or long-term care facilities and patients with spinal cord injury or indwelling catheters.

It is suggested by some groups that screening for ASB should also be carried out prior to implant surgery, to determine the choice of antibiotic for peri-operative prophylaxis (Figure 3). Treatment of ASB prior to implant surgery is not recommended unless the patient is symptomatic as this will select for resistance and will make choice of the antibiotic agent for prophylaxis more difficult.

Figure 3.

Case report 3: patient with asymptomatic bacteriuria.Open in new tabDownload slide

Case report 3: patient with asymptomatic bacteriuria.

Figure 3.

Case report 3: patient with asymptomatic bacteriuria.Open in new tabDownload slide

Case report 3: patient with asymptomatic bacteriuria.

Antibiotic-resistant organisms that cause cUTI include Gram-positive cocci such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCoNS), vancomycin-resistant enterococci (VRE) and Gram-negative organisms particularly those species that produce AmpC enzymes or extended-spectrum β-lactamases (ESBLs). Urea-splitting organisms such as Proteus spp., Morganella morganii and Providencia stuartii are often found in patients with indwelling devices. Pseudomonas spp. with their intrinsic resistance are also problematic.11Candida species are frequently found as a colonizing organism and account for <5% of cUTIs. There are only isolated reports of other fungi causing cUTI.7

In the past few years the number of cUTIs due to resistant Gram-negative bacteria has risen, mainly due to the spread of ESBL-producing bacteria and these are causing a number of management problems. Before 2003 most ESBLs seen were in Klebsiella spp. and were mutants of TEM and SHV penicillinases. They occurred mainly in specialist units and were often hospital acquired.13 Recently there has been a growing problem of CTX-M ESBLs in E. coli as well as Klebsiella and many occur in the community. Prior antibiotic therapy with agents such as cephalosporins or previous international travel are recognized risk factors for the acquisition of these organisms.14,15 Most producers are resistant to a wide range of cephalosporins and penicillins including piperacillin/tazobactam and many are also resistant to non-β-lactam agents such as fluoroquinolones, trimethoprim and gentamicin due to other co-expressed resistance mechanisms.16 CTX-M-producing E. coli are often pathogenic and a high proportion of infections result in bacteraemia with resultant mortality.17

Other resistant urinary bacteria include Enterobacter cloacae that express a chromosomal AmpC β-lactamase. This enzyme is inducible on exposure to β-lactams such as cephalosporins. Plasmid-mediated AmpC β-lactamase in bacteria such as Klebsiella spp. and E. coli can also confer a wide range of resistance to penicillins and most cephalosporins apart from the fourth-generation agents cefepime and cefpirome (neither of which is available currently in the UK). These enzymes are resistant to inhibition by clavulanic acid.18 Some of these bacteria remain susceptible to trimethoprim and the quinolones.

The oral options available for the treatment of cUTI caused by ESBL or AmpC-producing bacteria are limited, particularly if susceptibility testing indicates concurrent resistance to trimethoprim and quinolones.19 Most organisms remain susceptible to nitrofurantoin; however, this agent is licensed for lower UTIs only and the authors’ personal experience has shown that resistance may develop on treatment. One alternative is an agent used more widely in the rest of Europe—fosfomycin. Fosfomycin is approved by the Food and Drug Administration in the United States for treatment of uncomplicated lower UTI and single-dose therapy (3 g oral powder) was found to be equivalent to a 7 day course of norfloxacin in a randomized open-label study.20 For treatment of cUTI, dose regimens of 3 g every 2–3 days for up to 21 days have been used but due to limited systemic absorption, fosfomycin should not be used for pyelonephritis or severe urinary sepsis. Fosfomycin is licensed in the UK but a licensed formulation is not currently marketed. Supplies are available from pharmaceutical importers but a delay of 24–48 h for a community pharmacy to obtain stock limits the usefulness of this agent in a primary care setting.

Failures have been reported when pivmecillinam has been used alone to treat infections caused by ESBL-producing organisms and in vitro studies have shown significantly raised MICs at a higher inoculum of 106 cfu/spot.21,22 However, there is evidence that the addition of clavulanic acid results in a decrease in MIC bringing it down from an intermediate/resistant range to within the susceptible range (the modal value was reduced from 8–16 to 0.03–0.06 mg/L).21 A combination of agents containing clavulanic acid (for example co-amoxiclav) with other readily available extended-spectrum oral antibiotics that resist hydrolysis by common β-lactamases, such as pivmecillinam, cefixime or cefpodoxime (Figure 3), has been used to treat UTIs caused by CTX-M ESBL-producing E. coli.23 These combinations are unlicensed and reports of such use in the literature are rare. They are not effective against AmpC-producing Enterobacteriaceae as the clavulanate induces the production of AmpC enzymes, which attack the cephalosporin. Combinations of cefepime or cefpirome (both are in intravenous form only and not available in the UK) with clavulanate could be considered, as these agents are more stable to AmpC enzymes.23 In summary, these combinations should not be used as empirical therapy but could be considered once the organism and type of resistance are known. Table 1 summarizes some of the important properties of antibiotic combinations used off-licence for the treatment of infections caused by ESBL-producing pathogens.

Table 1.

Treatment regimen

Place in therapy

Key advantages

Contraindications

Side effects/disadvantages

CFM 200 mg oral q12h uncomplicated UTI due to resistant ESBL-producing organism not requiring hospital admission salvage therapy for infection with resistant ESBL-producing organisms when NIT not effective or not tolerated penicillin allergy high risk for selecting for superadded infections such as C. difficile and Candida spp.  OR concurrent or recent infection with C. difficile CPD 100–200 mg oral q12h  OR PMEC 400 mg oral q8h  PLUS Clavulanic acid in the form of AMC 375 mg q8h clavulanic acid inhibits ESBLs and CFM, CPD and PMEC are more stable than AMX to other co-expressed β-lactamases Clavulanic acid can induce AmpC enzymes e.g. in Enterobacter spp. possibly negating the effect of inhibiting the ESBL. These are rarer in community-use as directed therapy for non-AmpC producers. Treatment regimen

Place in therapy

Key advantages

Contraindications

Side effects/disadvantages

CFM 200 mg oral q12h uncomplicated UTI due to resistant ESBL-producing organism not requiring hospital admission salvage therapy for infection with resistant ESBL-producing organisms when NIT not effective or not tolerated penicillin allergy high risk for selecting for superadded infections such as C. difficile and Candida spp.  OR concurrent or recent infection with C. difficile CPD 100–200 mg oral q12h  OR PMEC 400 mg oral q8h  PLUS Clavulanic acid in the form of AMC 375 mg q8h clavulanic acid inhibits ESBLs and CFM, CPD and PMEC are more stable than AMX to other co-expressed β-lactamases Clavulanic acid can induce AmpC enzymes e.g. in Enterobacter spp. possibly negating the effect of inhibiting the ESBL. These are rarer in community-use as directed therapy for non-AmpC producers. 
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Table 1.

Treatment regimen

Place in therapy

Key advantages

Contraindications

Side effects/disadvantages

CFM 200 mg oral q12h uncomplicated UTI due to resistant ESBL-producing organism not requiring hospital admission salvage therapy for infection with resistant ESBL-producing organisms when NIT not effective or not tolerated penicillin allergy high risk for selecting for superadded infections such as C. difficile and Candida spp.  OR concurrent or recent infection with C. difficile CPD 100–200 mg oral q12h  OR PMEC 400 mg oral q8h  PLUS Clavulanic acid in the form of AMC 375 mg q8h clavulanic acid inhibits ESBLs and CFM, CPD and PMEC are more stable than AMX to other co-expressed β-lactamases Clavulanic acid can induce AmpC enzymes e.g. in Enterobacter spp. possibly negating the effect of inhibiting the ESBL. These are rarer in community-use as directed therapy for non-AmpC producers. Treatment regimen

Place in therapy

Key advantages

Contraindications

Side effects/disadvantages

CFM 200 mg oral q12h uncomplicated UTI due to resistant ESBL-producing organism not requiring hospital admission salvage therapy for infection with resistant ESBL-producing organisms when NIT not effective or not tolerated penicillin allergy high risk for selecting for superadded infections such as C. difficile and Candida spp.  OR concurrent or recent infection with C. difficile CPD 100–200 mg oral q12h  OR PMEC 400 mg oral q8h  PLUS Clavulanic acid in the form of AMC 375 mg q8h clavulanic acid inhibits ESBLs and CFM, CPD and PMEC are more stable than AMX to other co-expressed β-lactamases Clavulanic acid can induce AmpC enzymes e.g. in Enterobacter spp. possibly negating the effect of inhibiting the ESBL. These are rarer in community-use as directed therapy for non-AmpC producers. 
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It may be possible to use intravenous agents that can be given once a day such as gentamicin (also suitable for intramuscular injection) and ertapenem on an outpatient basis.24,25 Gentamicin is contraindicated in significant renal impairment, which is more common in the elderly, and regular monitoring of pre-dose serum concentrations is required to assess further dosing. When infection is more severe (Figure 4) and the patient possibly has bacteraemia, intravenous therapy should be given. The choice of antibiotic will depend on the severity and site of the infection and whether the susceptibility pattern of the organism is known. A treatment strategy should be based on the local susceptibility pattern, so where the local pathogens remain susceptible, for instance in areas where CTX-M ESBL-producing E. coli is predominant, gentamicin may be used as empirical therapy—in combination with other agents to treat a severe infection. Amikacin has been used as an alternative where gentamicin-resistant isolates remain susceptible to it.

Figure 4.

Case report 4: systemic sepsis and bacteraemia in a patient returning from foreign travel.Open in new tabDownload slide

Case report 4: systemic sepsis and bacteraemia in a patient returning from foreign travel.

Figure 4.

Case report 4: systemic sepsis and bacteraemia in a patient returning from foreign travel.Open in new tabDownload slide

Case report 4: systemic sepsis and bacteraemia in a patient returning from foreign travel.

It is important to note that delay in adequate therapy will lead to adverse outcomes and potentially increased mortality.26 Carbapenems, such as meropenem and imipenem, are broad-spectrum agents that can be used as empirical therapy for severe sepsis that may be caused by ESBL- or AmpC-producing bacteria. Ertapenem and temocillin are reserved mainly for treatment of appropriate infections of known aetiology, as they are both inactive against Pseudomonas spp. Temocillin is also inactive against Gram-positive bacteria and Bacteroides spp. Carbapenemase-producing E. coli and Klebsiella pneumoniae have been isolated but are still uncommon in the UK, although ertapenem and temocillin resistance is slightly more common.25,27 International travel, particularly to the Indian subcontinent, is a risk factor for the acquisition of bacteria producing a newly described carbapenemase known as New Delhi metallo-β-lactamase (NDM).28

Although tigecycline has activity against ESBL-producing bacteria it is unstable in the urinary tract and thus is not a first-line antibiotic for treatment of these infections unless the source of the organisms is known to be a different site. Tigecycline has a large volume of distribution as evidenced by relatively low serum levels and is therefore not recommended for urinary tract-related bloodstream infection. It is also unreliable against Proteus and Pseudomonas spp., which are inherently resistant.24,29

Intravenous therapy with a polymyxin (colistin or colistimethate sodium) has been used to treat infections due to multiresistant Gram-negative organisms. Although recent studies have shown that it has acceptable effectiveness and fewer cases of nephrotoxicity and neurotoxicity than previously reported, at present its use is reserved mainly for ESBL-producing bacteria that are also resistant to gentamicin and carbapenems.30 Table 2 summarizes the important properties of antibiotics available in the UK for the treatment of cUTI. Once the organism has been identified and susceptibilities are known, therapy should be de-escalated if possible to a narrow-spectrum agent.7

Table 2.

Antibiotic

Place in therapy

Key advantages

Contraindications

Side effects/disadvantages

NIT: 100 mg oral q6h for 7 days minimum treatment of complicated and uncomplicated lower UTI widely available and extensive clinical experience renal impairment (GFR < 60 mL/min) nausea and vomiting (common)  peripheral neuropathy with long-term use (rare)  resistance rare in E. coli although more common in other Enterobacteriaceae  no iv formulation  G6PD    inherent resistance in Proteus spp. and Pseudomonas spp.  FOF 3 g sachet oral once every 3 days for 14 days for cUTI treatment of complicated and uncomplicated lower UTI (unlicensed) resistance rare even in Spain where it is used extensively not suitable for pyelonephritis or severe urinary sepsis due to poor systemic absorption not licensed or marketed in the UK and thus difficult to obtain urgentlyheadache or diarrhoea in 10% of patients  oral capsules and iv formulation also available    GEN 3–5 mg/kg iv daily in divided doses or 5–7 mg/kg iv once daily (consult local guidelines) option for once-daily outpatient iv therapy for complicated UTI resistance relatively uncommon severe renal impairment nephrotoxicity  vestibular and auditory toxicity  risk of resistance in certain ESBL strains  serum levels required to determine safe and effective continuing dosing  TMC 1–2 g iv q12h treatment of cUTI and other infections caused by ESBL- and good in vitro activity against multiresistant ESBLs including AmpC-producing bacteria penicillin allergy inactive against Gram-positive bacteria, Bacteroides spp. and Pseudomonas spp.  provenance outside the  AmpC-producing bacteria susceptible to this agent narrow spectrum    urinary tract to be established  limited clinical experience in the UK  ETP 1 g iv once daily option for outpatient iv therapy for cUTI caused by susceptible ESBL-producing bacteria once-daily administration history of penicillin anaphylaxis does not cover infections caused by Pseudomonas spp.  more vulnerable than other carbapenems to resistance combinations of impermeability with an ESBL or AmpC  seizure rate attributed to ertapenem 0.2% from clinical trials

36  IPM (plus cilastatin) 500 mg–1 g iv q6h–q8h (maximum 4 g/day)  treatment of cUTI and other infections caused by ESBL- and AmpC- producing bacteria broad spectrum of activity including Enterococcus faecalis, Pseudomonas spp. and ESBL-producing bacteria history of penicillin anaphylaxis seizure risk 1.5%–2% (more common with higher doses, renal impairment and in patients with a history of epilepsy)

36  renal failure (GFR < 5 mL/min)  Cilastatin is required to inhibit dehydropeptidase enzyme present on the brush border of proximal renal tubular cells that hydrolyses and inactivates IPM  MEM 500–1000 mg iv q8h treatment of cUTI and other infections caused by ESBL- and AmpC-producing bacteria relatively low seizure risk (0.08%)

37 history of penicillin anaphylaxis increased hepatic enzymes (bilirubin and transaminases) (>1% incidence)somewhat less active carbapenem against Gram-positive organisms  broad spectrum of activity including Pseudomonas spp. and ESBL-producing bacteria     DOR 500 mg iv q8h treatment of cUTI and other infections caused by ESBL- and AmpC-producing bacteria most potent agent in carbapenem class history of penicillin anaphylaxis headache very common  limited clinical experience in the UKreduce dose in renal impairment (GFR < 50 mL/min)  broad spectrum of activity including Pseudomonas spp. and ESBL-producing bacteria    relatively low seizure risk

38  TGC 100 mg iv loading dose followed by 50 mg iv q12h licensed for complicated skin and soft tissue infections and complicated intra-abdominal infections only treatment option in severe penicillin allergy cannot be given to children <8 years of age due to discolouration of teeth limited urinary excretion of active drug  nausea very common (up to one-third of patients)  salvage therapy for infection with resistant ESBL-producing organisms  relatively low serum concentrations—caution in bacteraemia

29    extensive distribution concentration in tissues  inherent resistance in Pseudomonas spp. and acquired resistance in Proteus spp.  no dosage adjustment in renal failure  reduce dose in severe hepatic impairment  CST 1–2 million units iv q8h (15 000–25 000 units/kg iv q8h if <60 kg) cUTI and bacteraemia caused by susceptible Gram-negative bacteria resistant to other agents treatment option in severe penicillin allergy Myasthenia gravis inherent resistance in Gram-positive bacteria, anaerobes, Proteeae, Serratia spp., Providencia spp.  salvage therapy for infection with resistant ESBL-producing organisms  neurotoxicity (most commonly apnoea and sensory disturbances in ∼7% of patients)nephrotoxicity (8%–20% in seriously ill hospitalized patients); reduce dose in renal impairment (GFR < 20 mL/min); monitor renal function and discontinue if nephrotoxicity occurs.  effective against wide range of resistant Gram-negative bacteria including Acinetobacter spp.    Antibiotic

Place in therapy

Key advantages

Contraindications

Side effects/disadvantages

NIT: 100 mg oral q6h for 7 days minimum treatment of complicated and uncomplicated lower UTI widely available and extensive clinical experience renal impairment (GFR < 60 mL/min) nausea and vomiting (common)  peripheral neuropathy with long-term use (rare)  resistance rare in E. coli although more common in other Enterobacteriaceae  no iv formulation  G6PD    inherent resistance in Proteus spp. and Pseudomonas spp.  FOF 3 g sachet oral once every 3 days for 14 days for cUTI treatment of complicated and uncomplicated lower UTI (unlicensed) resistance rare even in Spain where it is used extensively not suitable for pyelonephritis or severe urinary sepsis due to poor systemic absorption not licensed or marketed in the UK and thus difficult to obtain urgentlyheadache or diarrhoea in 10% of patients  oral capsules and iv formulation also available    GEN 3–5 mg/kg iv daily in divided doses or 5–7 mg/kg iv once daily (consult local guidelines) option for once-daily outpatient iv therapy for complicated UTI resistance relatively uncommon severe renal impairment nephrotoxicity  vestibular and auditory toxicity  risk of resistance in certain ESBL strains  serum levels required to determine safe and effective continuing dosing  TMC 1–2 g iv q12h treatment of cUTI and other infections caused by ESBL- and good in vitro activity against multiresistant ESBLs including AmpC-producing bacteria penicillin allergy inactive against Gram-positive bacteria, Bacteroides spp. and Pseudomonas spp.  provenance outside the  AmpC-producing bacteria susceptible to this agent narrow spectrum    urinary tract to be established  limited clinical experience in the UK  ETP 1 g iv once daily option for outpatient iv therapy for cUTI caused by susceptible ESBL-producing bacteria once-daily administration history of penicillin anaphylaxis does not cover infections caused by Pseudomonas spp.  more vulnerable than other carbapenems to resistance combinations of impermeability with an ESBL or AmpC  seizure rate attributed to ertapenem 0.2% from clinical trials

36  IPM (plus cilastatin) 500 mg–1 g iv q6h–q8h (maximum 4 g/day)  treatment of cUTI and other infections caused by ESBL- and AmpC- producing bacteria broad spectrum of activity including Enterococcus faecalis, Pseudomonas spp. and ESBL-producing bacteria history of penicillin anaphylaxis seizure risk 1.5%–2% (more common with higher doses, renal impairment and in patients with a history of epilepsy)

36  renal failure (GFR < 5 mL/min)  Cilastatin is required to inhibit dehydropeptidase enzyme present on the brush border of proximal renal tubular cells that hydrolyses and inactivates IPM  MEM 500–1000 mg iv q8h treatment of cUTI and other infections caused by ESBL- and AmpC-producing bacteria relatively low seizure risk (0.08%)

37 history of penicillin anaphylaxis increased hepatic enzymes (bilirubin and transaminases) (>1% incidence)somewhat less active carbapenem against Gram-positive organisms  broad spectrum of activity including Pseudomonas spp. and ESBL-producing bacteria     DOR 500 mg iv q8h treatment of cUTI and other infections caused by ESBL- and AmpC-producing bacteria most potent agent in carbapenem class history of penicillin anaphylaxis headache very common  limited clinical experience in the UKreduce dose in renal impairment (GFR < 50 mL/min)  broad spectrum of activity including Pseudomonas spp. and ESBL-producing bacteria    relatively low seizure risk

38  TGC 100 mg iv loading dose followed by 50 mg iv q12h licensed for complicated skin and soft tissue infections and complicated intra-abdominal infections only treatment option in severe penicillin allergy cannot be given to children <8 years of age due to discolouration of teeth limited urinary excretion of active drug  nausea very common (up to one-third of patients)  salvage therapy for infection with resistant ESBL-producing organisms  relatively low serum concentrations—caution in bacteraemia

29    extensive distribution concentration in tissues  inherent resistance in Pseudomonas spp. and acquired resistance in Proteus spp.  no dosage adjustment in renal failure  reduce dose in severe hepatic impairment  CST 1–2 million units iv q8h (15 000–25 000 units/kg iv q8h if <60 kg) cUTI and bacteraemia caused by susceptible Gram-negative bacteria resistant to other agents treatment option in severe penicillin allergy Myasthenia gravis inherent resistance in Gram-positive bacteria, anaerobes, Proteeae, Serratia spp., Providencia spp.  salvage therapy for infection with resistant ESBL-producing organisms  neurotoxicity (most commonly apnoea and sensory disturbances in ∼7% of patients)nephrotoxicity (8%–20% in seriously ill hospitalized patients); reduce dose in renal impairment (GFR < 20 mL/min); monitor renal function and discontinue if nephrotoxicity occurs.  effective against wide range of resistant Gram-negative bacteria including Acinetobacter spp.    
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Table 2.

Antibiotic

Place in therapy

Key advantages

Contraindications

Side effects/disadvantages

NIT: 100 mg oral q6h for 7 days minimum treatment of complicated and uncomplicated lower UTI widely available and extensive clinical experience renal impairment (GFR < 60 mL/min) nausea and vomiting (common)  peripheral neuropathy with long-term use (rare)  resistance rare in E. coli although more common in other Enterobacteriaceae  no iv formulation  G6PD    inherent resistance in Proteus spp. and Pseudomonas spp.  FOF 3 g sachet oral once every 3 days for 14 days for cUTI treatment of complicated and uncomplicated lower UTI (unlicensed) resistance rare even in Spain where it is used extensively not suitable for pyelonephritis or severe urinary sepsis due to poor systemic absorption not licensed or marketed in the UK and thus difficult to obtain urgentlyheadache or diarrhoea in 10% of patients  oral capsules and iv formulation also available    GEN 3–5 mg/kg iv daily in divided doses or 5–7 mg/kg iv once daily (consult local guidelines) option for once-daily outpatient iv therapy for complicated UTI resistance relatively uncommon severe renal impairment nephrotoxicity  vestibular and auditory toxicity  risk of resistance in certain ESBL strains  serum levels required to determine safe and effective continuing dosing  TMC 1–2 g iv q12h treatment of cUTI and other infections caused by ESBL- and good in vitro activity against multiresistant ESBLs including AmpC-producing bacteria penicillin allergy inactive against Gram-positive bacteria, Bacteroides spp. and Pseudomonas spp.  provenance outside the  AmpC-producing bacteria susceptible to this agent narrow spectrum    urinary tract to be established  limited clinical experience in the UK  ETP 1 g iv once daily option for outpatient iv therapy for cUTI caused by susceptible ESBL-producing bacteria once-daily administration history of penicillin anaphylaxis does not cover infections caused by Pseudomonas spp.  more vulnerable than other carbapenems to resistance combinations of impermeability with an ESBL or AmpC  seizure rate attributed to ertapenem 0.2% from clinical trials

36  IPM (plus cilastatin) 500 mg–1 g iv q6h–q8h (maximum 4 g/day)  treatment of cUTI and other infections caused by ESBL- and AmpC- producing bacteria broad spectrum of activity including Enterococcus faecalis, Pseudomonas spp. and ESBL-producing bacteria history of penicillin anaphylaxis seizure risk 1.5%–2% (more common with higher doses, renal impairment and in patients with a history of epilepsy)

36  renal failure (GFR < 5 mL/min)  Cilastatin is required to inhibit dehydropeptidase enzyme present on the brush border of proximal renal tubular cells that hydrolyses and inactivates IPM  MEM 500–1000 mg iv q8h treatment of cUTI and other infections caused by ESBL- and AmpC-producing bacteria relatively low seizure risk (0.08%)

37 history of penicillin anaphylaxis increased hepatic enzymes (bilirubin and transaminases) (>1% incidence)somewhat less active carbapenem against Gram-positive organisms  broad spectrum of activity including Pseudomonas spp. and ESBL-producing bacteria     DOR 500 mg iv q8h treatment of cUTI and other infections caused by ESBL- and AmpC-producing bacteria most potent agent in carbapenem class history of penicillin anaphylaxis headache very common  limited clinical experience in the UKreduce dose in renal impairment (GFR < 50 mL/min)  broad spectrum of activity including Pseudomonas spp. and ESBL-producing bacteria    relatively low seizure risk

38  TGC 100 mg iv loading dose followed by 50 mg iv q12h licensed for complicated skin and soft tissue infections and complicated intra-abdominal infections only treatment option in severe penicillin allergy cannot be given to children <8 years of age due to discolouration of teeth limited urinary excretion of active drug  nausea very common (up to one-third of patients)  salvage therapy for infection with resistant ESBL-producing organisms  relatively low serum concentrations—caution in bacteraemia

29    extensive distribution concentration in tissues  inherent resistance in Pseudomonas spp. and acquired resistance in Proteus spp.  no dosage adjustment in renal failure  reduce dose in severe hepatic impairment  CST 1–2 million units iv q8h (15 000–25 000 units/kg iv q8h if <60 kg) cUTI and bacteraemia caused by susceptible Gram-negative bacteria resistant to other agents treatment option in severe penicillin allergy Myasthenia gravis inherent resistance in Gram-positive bacteria, anaerobes, Proteeae, Serratia spp., Providencia spp.  salvage therapy for infection with resistant ESBL-producing organisms  neurotoxicity (most commonly apnoea and sensory disturbances in ∼7% of patients)nephrotoxicity (8%–20% in seriously ill hospitalized patients); reduce dose in renal impairment (GFR < 20 mL/min); monitor renal function and discontinue if nephrotoxicity occurs.  effective against wide range of resistant Gram-negative bacteria including Acinetobacter spp.    Antibiotic

Place in therapy

Key advantages

Contraindications

Side effects/disadvantages

NIT: 100 mg oral q6h for 7 days minimum treatment of complicated and uncomplicated lower UTI widely available and extensive clinical experience renal impairment (GFR < 60 mL/min) nausea and vomiting (common)  peripheral neuropathy with long-term use (rare)  resistance rare in E. coli although more common in other Enterobacteriaceae  no iv formulation  G6PD    inherent resistance in Proteus spp. and Pseudomonas spp.  FOF 3 g sachet oral once every 3 days for 14 days for cUTI treatment of complicated and uncomplicated lower UTI (unlicensed) resistance rare even in Spain where it is used extensively not suitable for pyelonephritis or severe urinary sepsis due to poor systemic absorption not licensed or marketed in the UK and thus difficult to obtain urgentlyheadache or diarrhoea in 10% of patients  oral capsules and iv formulation also available    GEN 3–5 mg/kg iv daily in divided doses or 5–7 mg/kg iv once daily (consult local guidelines) option for once-daily outpatient iv therapy for complicated UTI resistance relatively uncommon severe renal impairment nephrotoxicity  vestibular and auditory toxicity  risk of resistance in certain ESBL strains  serum levels required to determine safe and effective continuing dosing  TMC 1–2 g iv q12h treatment of cUTI and other infections caused by ESBL- and good in vitro activity against multiresistant ESBLs including AmpC-producing bacteria penicillin allergy inactive against Gram-positive bacteria, Bacteroides spp. and Pseudomonas spp.  provenance outside the  AmpC-producing bacteria susceptible to this agent narrow spectrum    urinary tract to be established  limited clinical experience in the UK  ETP 1 g iv once daily option for outpatient iv therapy for cUTI caused by susceptible ESBL-producing bacteria once-daily administration history of penicillin anaphylaxis does not cover infections caused by Pseudomonas spp.  more vulnerable than other carbapenems to resistance combinations of impermeability with an ESBL or AmpC  seizure rate attributed to ertapenem 0.2% from clinical trials

36  IPM (plus cilastatin) 500 mg–1 g iv q6h–q8h (maximum 4 g/day)  treatment of cUTI and other infections caused by ESBL- and AmpC- producing bacteria broad spectrum of activity including Enterococcus faecalis, Pseudomonas spp. and ESBL-producing bacteria history of penicillin anaphylaxis seizure risk 1.5%–2% (more common with higher doses, renal impairment and in patients with a history of epilepsy)

36  renal failure (GFR < 5 mL/min)  Cilastatin is required to inhibit dehydropeptidase enzyme present on the brush border of proximal renal tubular cells that hydrolyses and inactivates IPM  MEM 500–1000 mg iv q8h treatment of cUTI and other infections caused by ESBL- and AmpC-producing bacteria relatively low seizure risk (0.08%)

37 history of penicillin anaphylaxis increased hepatic enzymes (bilirubin and transaminases) (>1% incidence)somewhat less active carbapenem against Gram-positive organisms  broad spectrum of activity including Pseudomonas spp. and ESBL-producing bacteria     DOR 500 mg iv q8h treatment of cUTI and other infections caused by ESBL- and AmpC-producing bacteria most potent agent in carbapenem class history of penicillin anaphylaxis headache very common  limited clinical experience in the UKreduce dose in renal impairment (GFR < 50 mL/min)  broad spectrum of activity including Pseudomonas spp. and ESBL-producing bacteria    relatively low seizure risk

38  TGC 100 mg iv loading dose followed by 50 mg iv q12h licensed for complicated skin and soft tissue infections and complicated intra-abdominal infections only treatment option in severe penicillin allergy cannot be given to children <8 years of age due to discolouration of teeth limited urinary excretion of active drug  nausea very common (up to one-third of patients)  salvage therapy for infection with resistant ESBL-producing organisms  relatively low serum concentrations—caution in bacteraemia

29    extensive distribution concentration in tissues  inherent resistance in Pseudomonas spp. and acquired resistance in Proteus spp.  no dosage adjustment in renal failure  reduce dose in severe hepatic impairment  CST 1–2 million units iv q8h (15 000–25 000 units/kg iv q8h if <60 kg) cUTI and bacteraemia caused by susceptible Gram-negative bacteria resistant to other agents treatment option in severe penicillin allergy Myasthenia gravis inherent resistance in Gram-positive bacteria, anaerobes, Proteeae, Serratia spp., Providencia spp.  salvage therapy for infection with resistant ESBL-producing organisms  neurotoxicity (most commonly apnoea and sensory disturbances in ∼7% of patients)nephrotoxicity (8%–20% in seriously ill hospitalized patients); reduce dose in renal impairment (GFR < 20 mL/min); monitor renal function and discontinue if nephrotoxicity occurs.  effective against wide range of resistant Gram-negative bacteria including Acinetobacter spp.    
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The main aim of therapy is to combat sepsis, relieve symptoms and prevent complications. In order to achieve a cure and prevent re-infection or recurrence the obstruction must be removed. Urinary devices such as indwelling catheters become coated with a biofilm, which acts as a reservoir for organisms, protecting them from the action of antimicrobials and host defences. Thus the organisms are likely to cause recurrence of infection and become more resistant to antimicrobials after each course of treatment. If possible, urinary catheters should be removed and a condom catheter or another form of drainage system be used instead. The use of physician reminders to remove unnecessary urinary catheters may help.2 If the patient still requires a catheter, a new one should be inserted either when collecting the specimen of urine in a patient with symptoms of a cUTI or soon after starting treatment for a symptomatic infection, so symptoms will settle in a shorter time and increase the interval before the next relapse.11

Where a urinary tract abnormality is not apparent a diagnostic investigation should be carried out to look for other complicating factors such as an abscess. Options include diagnostic imaging, which may include pelvic and renal ultrasound, intravenous pyelogram, CT or magnetic resonance imaging. Renal investigations such as cystoscopy, retrograde pyelogram or urodynamic studies may be required depending on the history given.7,11

How long should a patient receive antibiotics for?

The optimal length of treatment for symptomatic cUTI has not been extensively studied. As there are many different causes of underlying abnormality, a simple recommendation cannot be made. Most clinical trials have evaluated 7–14 days of treatment, but a recent randomized multicentre study demonstrated that levofloxacin for 5 days was non-inferior to ciprofloxacin for 10 days in cUTI and acute pyelonephritis.31 Ten to fourteen days of antibiotics are usually recommended for patients with bacteraemia, hypotension and other signs of severe sepsis, whereas a 7 day regimen should suffice for those with a lower UTI.3 A 3 day course is usually not sufficient and is thus not recommended for cUTI.32 Clinical improvement should occur within 24–48 h after starting treatment. If the patient has not responded, the choice of antibiotic should be reviewed in the light of the culture results. They may need an urgent investigation to exclude an abscess that needs drainage. A patient can be switched to an oral agent when they are clinically improved providing they can tolerate it and the organism is susceptible.

What preventative strategies can be used?

These have been well-reviewed in the Canadian Guidelines for the management of cUTI in adults.1 Extended courses of antibiotics should only be used in specific situations such as for men with a relapsing infection from a prostatic source when 6–12 weeks of therapy have been given.33 They are not recommended as long-term prophylaxis for the prevention of infection in, for example patients with spinal cord lesions undergoing intermittent catheterization, as prophylaxis will select for antibiotic-resistant organisms.32 Rarely, a long-term course of antimicrobials has been given as suppressive therapy to prevent enlargement of stones that cannot be removed.34 In this situation the benefit of giving the antibiotic must be weighed against the likely side effects and the risk of selecting for antibiotic-resistant organisms.

Sexually active women with recurrent UTI are recommended to take prophylactic antibiotics at the time of intercourse and to not use a spermicide-containing contraceptive. Results of studies on the use of oral or vaginal oestrogen by post-menopausal women with recurrent UTIs have been inconsistent and thus the routine use of these agents has not been recommended.5 The use of oral lactulose however, to reduce constipation in elderly patients, may be helpful and some studies have shown that cranberry products (juice, tablets or capsules) may reduce the frequency of recurrent UTI in women.5,8,33,35 In the future other preventative strategies may include the development of vaccines. The use of intentional colonization with benign organisms that are also susceptible to a wider range of antibiotics may need to be considered.33

There is an urgent need for research into the effectiveness of combinations of oral antibiotics in the treatment of complicated UTI in ambulatory care and the impact on the epidemiology of resistance. There is also an immediate requirement for increased availability of fosfomycin in the UK.

Transparency declarations

This article is part of a Supplement sponsored by the BSAC.

A. P. has received funds for speaking at symposia and attending advisory boards organized on behalf of Novartis, Wyeth/Pfizer and AstraZeneca. K. H. has received funds for speaking at symposia and attending advisory boards organized on behalf of Novartis, Wyeth/Pfizer and Astellas.

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