Pyelonephritis (acute) in non-pregnant women Search date November 2013 Ignacio Neumann and Philippa Moore ABSTRACT INTRODUCTION: Pyelonephritis is usually caused by ascent of bacteria (most often Escherichia coli) from the bladder, and is more likely in people with structural or functional urinary tract abnormalities. The prognosis is good if pyelonephritis is treated appropriately, but complications include renal abscess, renal impairment, and septic shock. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of antibiotic treatments for acute pyelonephritis in non-pregnant women with uncomplicated infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found four studies that met our inclusion criteria. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (intravenous), antibiotics (oral), and antibiotics (switch therapy).
QUESTIONS What are the effects of antibiotic treatments for acute pyelonephritis in non-pregnant women with uncomplicated infection?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 INTERVENTIONS ANTIBIOTIC TREATMENTS
Antibiotics (intravenous) versus each other . . . . . . . 5
Likely to be beneficial Antibiotics (oral or intravenous) versus placebo* . . . 3 Unknown effectiveness
Covered elsewhere in Clinical Evidence Recurrent cystitis Footnote
Antibiotics (oral) versus each other . . . . . . . . . . . . . 3
*Categorisation is based on consensus
Oral antibiotics versus switch therapy (intravenous antibiotics followed by oral antibiotics) . . . . . . . . . . . . . 4 Key points • Pyelonephritis is usually caused by ascent of bacteria from the bladder, most often Escherichia coli, and is more likely in people with structural or functional urinary tract abnormalities. The prognosis of acute uncomplicated pyelonephritis is good if pyelonephritis is treated appropriately, but complications include renal abscess, renal impairment, and septic shock. • We found no direct information from RCTs about whether oral or intravenous antibiotics are better than no active treatment. However, consensus holds that these drugs are effective. We don't know which is the most effective oral antibiotic regimen, or the optimum duration of treatment, although it may be sensible to continue treatment for at least 10 days. We don't know how switch regimens (intravenous antibiotics followed by oral antibiotics) compare with oral antibiotic regimens. We don’t know which is the most effective intravenous antibiotic regimen, or the optimum duration of intravenous treatment. Clinical context DEFINITION
Acute pyelonephritis, or upper urinary tract infection, is an infection of the kidney characterised by pain when passing urine, fever, chills, flank pain, nausea, and vomiting. White blood cells are almost always present in the urine. White blood cell casts are occasionally seen on urine microscopy. There is no consensus on the definitions for grades of severity. However, in practice, people with acute pyelonephritis may be divided into people who are able to take oral antibiotics and those who require intravenous antibiotics. Management may be ambulatory or in hospital. Some consider the absolute indications for hospital admission to be persistent vomiting, progression of uncompli[1] cated urinary tract infection, suspected sepsis, or urinary tract obstruction. Pyelonephritis is considered uncomplicated if caused by a typical pathogen in an immunocompetent person who [2] has normal renal anatomy and renal function. There is little difference in the treatment of men and non-pregnant women. Diagnosis: People presenting with fever and back pain suggest a [3] possible diagnosis of acute pyelonephritis. Urinalysis and urine culture should be performed to confirm the diagnosis. Significant pyuria (defined as >20 WBCs per high-power field [hpf] on a specimen spun at 2000 rpm for 5 minutes) is present in almost all patients and can be detected
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rapidly with leukocyte esterase test (sensitivity: 74%–96% and specificity: 94%–98%) or the nitrite [1] 4 5 test (sensitivity: 35%–85% and specificity: 92%–100%). Bacterial growth of 10 to 10 colony[4] forming units on urine culture of a mid-stream specimen will confirm bacteriological diagnosis. INCIDENCE/ PREVALENCE
[5]
The estimated annual incidence per 10,000 people is 27.6 cases in the US and 35.7 cases in [6] South Korea. Worldwide prevalence and incidence are unknown. The highest incidence of [3] pyelonephritis occurs during the summer months. Women are approximately five times more [1] likely than men to be hospitalised with acute pyelonephritis.
AETIOLOGY/ Pyelonephritis is most commonly caused when bacteria in the bladder ascend the ureters and invade RISK FACTORS the kidneys. In some cases, this may result in bacteria entering and multiplying in the bloodstream. The most frequently isolated organism is Escherichia coli (56%–85%); others include Enterococcus [5] [7] [8] faecalis, Klebsiella pneumoniae, and Proteus mirabilis. In older people, E coli is less common (60%), whereas people with diabetes mellitus may also have infections caused by Kleb[1] siella, Enterobacter, Clostridium, or Candida. People with structural or functional urinary tract abnormalities are more prone to pyelonephritis that is refractory to oral therapy or complicated by bacteraemia. Risk factors associated with pyelonephritis in healthy women are sexual intercourse, use of spermicide, urinary tract infection in the previous 12 months, a mother with a history of urinary [5] tract infection, diabetes, and urinary incontinence. The most important risk factor for complicated [9] urinary tract infection is obstruction of the urinary tract. The incidence of drug-resistant microorganisms varies in different geographical areas. Recent hospital admission, recent use of antibiotics, immunosuppression, recurrent pyelonephritis, and nephrolithiasis increase the risk of drug resistance. [7]
PROGNOSIS
Prognosis is good if uncomplicated pyelonephritis is treated appropriately. Complications include renal abscess, septic shock, and renal impairment, including acute renal failure. Short-term independent risk factors for mortality include age above 65 years, septic shock, being bedridden, and [7] immunosuppression. Conditions such as underlying renal disease, diabetes mellitus, and immunosuppression may worsen prognosis, but we found no good long-term evidence about rates of sepsis or death among people with such conditions.
AIMS OF To reduce the duration and severity of symptoms; to prevent or minimise potential complications, INTERVENTION with minimum adverse effects. OUTCOMES
Cure rates: clinical cure (remission of signs and symptoms), bacteriological cure (negative urine culture after treatment); Rates of complications of infection; and Adverse effects.
METHODS
Clinical Evidence search and appraisal November 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to November 2013, Embase 1980 to November 2013, and The Cochrane Database of Systematic Reviews 2013, Issue 10 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews of RCTs in the English language, at least single-blinded, containing at least 20 individuals (at least 10 per arm), of whom more than 80% were followed up.There was no minimum length of follow-up. We excluded all studies described as ‘open’, ‘open label’, or not blinded unless blinding was impossible. We excluded studies with greater than 25% men, pregnant women, or people with complicated pyelonephritis. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 7 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included,
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in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com). QUESTION
What are the effects of antibiotic treatments for acute pyelonephritis in non-pregnant women with uncomplicated infection?
OPTION
ANTIBIOTICS (ORAL OR INTRAVENOUS) VERSUS PLACEBO. . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Pyelonephritis (acute) in non-pregnant women, see table, p 7 .
•
We found no direct information from RCTs about whether antibiotics (oral or intravenous) are better than no active treatment in non-pregnant women with acute pyelonephritis. However, consensus holds that these drugs are effective. Benefits and harms
Antibiotics (oral or intravenous) versus placebo: We found no systematic review or RCTs (see Comment below). Comment:
OPTION
The lack of placebo-controlled RCTs may reflect that experimental trials would be considered unethical. However, consensus holds that these drugs are effective. ANTIBIOTICS (ORAL) VERSUS EACH OTHER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Pyelonephritis (acute) in non-pregnant women, see table, p 7 .
•
We don’t know which is the most effective oral antibiotic regimen or the optimum duration of oral treatment for non-pregnant women with acute pyelonephritis, although it may be sensible to continue treatment for at least 10 days. Benefits and harms
Antibiotics (oral) versus each other: [4] [10] We found two systematic reviews, which identified RCTs comparing different oral antibiotics versus each other in acute pyelonephritis. Neither review performed a meta-analysis. The first systematic review (search date [10] 1991, 9 RCTs) did not include any RCTs that met the Clinical Evidence inclusion criteria. The second systematic [4] review (search date 2004) identified eight RCTs in adults comparing oral antibiotics versus each other. However, none of these eight RCTs fulfilled Clinical Evidence inclusion criteria. We found one subsequent RCT (284 people, [11] 129 with acute pyelonephritis) fulfilling Clinical Evidence criteria, which compared antofloxacin with levofloxacin. Cure rates Antibiotics (oral) versus each other We don’t know whether antofloxacin and levofloxacin differ in effectiveness at increasing clinical cure or bacterial cure in people with acute pyelonephritis (very low-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Cure rates [11]
RCT
[11]
RCT
129 patients with Clinical cure , 7 days after the P = 0.19 acute pyelonephri- end of treatment tis (109 [84%] 56/64 (87.5%) with antofloxacin women) 51/65 (78.5%) with levofloxacin See Further information on studies Per-protocol results also reported
Not significant
129 patients with Bacteriological eradication , at Significance not assessed acute pyelonephri- the end of treatment tis (109 [84%] 52/54 (96.3%) with antofloxacin women) 51/57 (89.5%) with levofloxacin
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Ref (type)
Population
Outcome, Interventions
See Further information on studies
Per-protocol results also reported
Results and statistical analysis
Effect size
Favours
Results and statistical analysis
Effect size
Favours
Adverse effects Ref (type)
Population
Outcome, Interventions
Adverse effects [11]
254 people with acute bacterial infection (129 [51%] with acute pyelonephritis)
RCT
Serious adverse effects 0/126 (0%) with antofloxacin 0/128 (0%) with levofloxacin
See Further information on studies
Different durations of antbiotics (oral) versus each other: We found no RCTs comparing the same oral antibiotics for two different time periods. Further information on studies [11]
The RCT included people with acute pyelonephritis and acute exacerbation of chronic bronchitis and was conducted in hospitals in China. Results were reported separately on people with acute pyelonephritis for clinical cure, but this included men as well as women. However, it did not report separately on the subgroup of women with acute pyelonephritis. Pregnant women were excluded from the study. Clinical cure was defined as disappearance of clinical symptoms and signs related to infection. Adverse effects were reported for total study population only.
Comment:
Clinical guide: We found no evidence from RCTs to support the use of any specific oral antibiotic compared with any other oral antibiotic. Therefore, local resistance rates should always be considered when deciding which antibiotic to use. There is consensus that when antibiotic sensitivity is not known, the choice of antibiotics should take into account the setting, the patient’s medical history, Gram stain of the urine, previous infecting organisms, and local antibiotic sensitivities. There is no good evidence regarding duration of treatment; however, treatment should probably not be given for less than 10 days.
OPTION
ORAL ANTIBIOTICS VERSUS SWITCH THERAPY (INTRAVENOUS ANTIBIOTICS FOLLOWED BY ORAL ANTIBIOTICS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Pyelonephritis (acute) in non-pregnant women, see table, p 7 .
•
We found no direct information from RCTs about oral antibiotics compared with intravenous antibiotics followed by oral antibiotics (switch therapy) in non-pregnant women with uncomplicated acute pyelonephritis.
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Benefits and harms Oral antibiotics versus switch therapy (intravenous antibiotics followed by oral antibiotics): [10] [4] We found two systematic reviews (search date 1991; and 2004 ), which included one RCT each comparing oral antibiotics with switch therapy, neither of which fulfilled Clinical Evidence inclusion criteria. Comment:
OPTION
We found no RCTs of sufficient quality comparing oral therapy with switch therapy in women with pyelonephritis. More research is needed as this is a common dilemma for clinicians. ANTIBIOTICS (INTRAVENOUS) VERSUS EACH OTHER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Pyelonephritis (acute) in non-pregnant women, see table, p 7 .
•
We found no direct information from RCTs comparing intravenous antibiotics with each other in non-pregnant women with acute pyelonephritis. Benefits and harms
Antibiotics (intravenous) versus each other: [4] [12] [13] [14] We found one systematic review (search date 2004, 3 RCTs) and three subsequent RCTs comparing intravenous antibiotics with each other in people with acute pyelonephritis; however, none of these RCTs fulfilled Clinical Evidence inclusion criteria. Different durations of antibiotic (intravenous) treatments versus each other: We found no RCTs comparing the same intravenous antibiotic for two different time periods. Comment:
Clinical guide: We found no evidence from RCTs to support the use of any specific intravenous antibiotic compared with any other intravenous antibiotic. Therefore, local resistance rates should always be considered when deciding which antibiotic to use. There is consensus that when antibiotic sensitivity is not known, the choice of antibiotics should take into account the setting, the patient’s medical history, Gram stain of the urine, previous infecting organisms, and local antibiotic sensitivities.
GLOSSARY Very low-quality evidence Any estimate of effect is very uncertain.
SUBSTANTIVE CHANGES Antibiotics (oral) versus each other Existing evidence re-evaluated. One new RCT added. unchanged (unknown effectiveness).
[11]
Antibiotics (intravenous) versus each other Existing evidence re-evaluated. One RCT added. unchanged (unknown effectiveness).
Categorisation [14]
Categorisation
REFERENCES 1.
Ramakrishnan K, Scheid DC. Diagnosis and management of acute pyelonephritis in adults. Am Fam Physician 2005;71:933–942.[PubMed]
5.
Bergeron MG. Treatment of pyelonephritis in adults. Med Clin North Am 1995;79:619–649.[PubMed]
Scholes D, Hooton TM, Roberts PL, et al. Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med 2005;142:20–27. [Summary for patients in: Ann Intern Med 2005;142:I34][PubMed]
2.
6.
3.
Czaja CA, Hooton TM. Update on acute uncomplicated urinary tract infection in women. Postgrad Med 2006;119:39–45.[PubMed]
Ki M, Park T, Choi B, et al. The epidemiology of acute pyelonephritis in South Korea, 1997–1999. Am J Epidemiol 2004;160:985–993.[PubMed]
7.
4.
Piccoli GB, Consiglio V, Colla L, et al. Antibiotic treatment for acute 'uncomplicated' or 'primary' pyelonephritis: a systematic, 'semantic revision'. Int J Antimicrob Agents 2006;28(suppl 1):S49–S63.[PubMed]
Efstathiou SP, Pefanis AV, Tsioulos DI, et al. Acute pyelonephritis in adults: prediction of mortality and failure of treatment. Arch Intern Med 2003;163:1206–1212.[PubMed]
8.
Farrell DJ, Morrissey I, De Rubeis D, et al. A UK multicentre study of the antimicrobial susceptibility of bacterial pathogens causing urinary tract infection. J Infect 2003;46:94–100.[PubMed]
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9.
David RD, DeBlieux PM, Press R. Rational antibiotic treatment of outpatient genitourinary infections in a changing environment. Am J Med 2005;118(suppl 7A):7S–13S.[PubMed]
12.
Peng F-YJ, Wang S. A multicenter, randomized controlled, double-blind clinical trial of piperacillin/tazobactam(4:1) in the treatment of bacterial infections. Chin J Antibiot 2008;33:114–120.
10.
Pinson AG, Philbrick JT, Lindbeck GH, et al. Oral antibiotic therapy for acute pyelonephritis: a methodologic review of the literature. J Gen Intern Med 1992;7:544–553. Search date 1991.[PubMed]
13.
Liu Y-B, Lu X, Huang L. A multicenter, double-blind, randomized clinical trial of parenteral cefepime in the treatment of acute bacterial infections. Chin J Antibiot 2007;32:367–370,376.
11.
Wang J, Xiao Y, Huang W, et al. A phase II study of antofloxacin hydrochloride, a novel fluoroquinolone, for the treatment of acute bacterial infections. Chemotherapy 2010;56:378–385.[PubMed]
14.
Ebrahimzadeh A, Saadatjoo SA, Tabrizi AA. Comparing ceftriaxone and cefazolin for treatment of adult acute pyelonephritis; a clinical trial. Ir J Clin Infect Dis 2010;5:75–79.
Ignacio Neumann Pontificia Universidad Católica de Chile Santiago Chile Philippa Moore Pontificia Universidad Católica de Chile Santiago Chile Competing interests: IN and PM declare that they have no competing interests. IN and PM would like to acknowledge the previous contributor, M. Fernanda Rojas.
Disclaimer The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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GRADE
Evaluation of interventions for Pyelonephritis (acute) in non-pregnant women.
Important outcomes Studies (Participants)
Cure rates Outcome
Comparison
Type of evidence
Quality
Consistency
Directness
Effect size
GRADE
Comment
–1
0
Very low
Quality points deducted for sparse data, inclusion of men in the analysis; directness point deducted for no statistical analysis between groups for one outcome
What are the effects of antibiotic treatments for acute pyelonephritis in non-pregnant women with uncomplicated infection? 1 (129)
[11]
Cure rates
Antibiotics (oral) versus each other
4
–2
0
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasirandomisation, sparse data [
QUESTIONS What are the effects of antibiotic treatments for acute pyelonephritis in non-pregnant women with uncomplicated infection?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 INTERVENTIONS ANTIBIOTIC TREATMENTS
Antibiotics (intravenous) versus each other . . . . . . . 5
Likely to be beneficial Antibiotics (oral or intravenous) versus placebo* . . . 3 Unknown effectiveness
Covered elsewhere in Clinical Evidence Recurrent cystitis Footnote
Antibiotics (oral) versus each other . . . . . . . . . . . . . 3
*Categorisation is based on consensus
Oral antibiotics versus switch therapy (intravenous antibiotics followed by oral antibiotics) . . . . . . . . . . . . . 4 Key points • Pyelonephritis is usually caused by ascent of bacteria from the bladder, most often Escherichia coli, and is more likely in people with structural or functional urinary tract abnormalities. The prognosis of acute uncomplicated pyelonephritis is good if pyelonephritis is treated appropriately, but complications include renal abscess, renal impairment, and septic shock. • We found no direct information from RCTs about whether oral or intravenous antibiotics are better than no active treatment. However, consensus holds that these drugs are effective. We don't know which is the most effective oral antibiotic regimen, or the optimum duration of treatment, although it may be sensible to continue treatment for at least 10 days. We don't know how switch regimens (intravenous antibiotics followed by oral antibiotics) compare with oral antibiotic regimens. We don’t know which is the most effective intravenous antibiotic regimen, or the optimum duration of intravenous treatment. Clinical context DEFINITION
Acute pyelonephritis, or upper urinary tract infection, is an infection of the kidney characterised by pain when passing urine, fever, chills, flank pain, nausea, and vomiting. White blood cells are almost always present in the urine. White blood cell casts are occasionally seen on urine microscopy. There is no consensus on the definitions for grades of severity. However, in practice, people with acute pyelonephritis may be divided into people who are able to take oral antibiotics and those who require intravenous antibiotics. Management may be ambulatory or in hospital. Some consider the absolute indications for hospital admission to be persistent vomiting, progression of uncompli[1] cated urinary tract infection, suspected sepsis, or urinary tract obstruction. Pyelonephritis is considered uncomplicated if caused by a typical pathogen in an immunocompetent person who [2] has normal renal anatomy and renal function. There is little difference in the treatment of men and non-pregnant women. Diagnosis: People presenting with fever and back pain suggest a [3] possible diagnosis of acute pyelonephritis. Urinalysis and urine culture should be performed to confirm the diagnosis. Significant pyuria (defined as >20 WBCs per high-power field [hpf] on a specimen spun at 2000 rpm for 5 minutes) is present in almost all patients and can be detected
© BMJ Publishing Group Ltd 2014. All rights reserved.
..................... 1 .....................
Clinical Evidence 2014;11:807
Women's health
..................................................
rapidly with leukocyte esterase test (sensitivity: 74%–96% and specificity: 94%–98%) or the nitrite [1] 4 5 test (sensitivity: 35%–85% and specificity: 92%–100%). Bacterial growth of 10 to 10 colony[4] forming units on urine culture of a mid-stream specimen will confirm bacteriological diagnosis. INCIDENCE/ PREVALENCE
[5]
The estimated annual incidence per 10,000 people is 27.6 cases in the US and 35.7 cases in [6] South Korea. Worldwide prevalence and incidence are unknown. The highest incidence of [3] pyelonephritis occurs during the summer months. Women are approximately five times more [1] likely than men to be hospitalised with acute pyelonephritis.
AETIOLOGY/ Pyelonephritis is most commonly caused when bacteria in the bladder ascend the ureters and invade RISK FACTORS the kidneys. In some cases, this may result in bacteria entering and multiplying in the bloodstream. The most frequently isolated organism is Escherichia coli (56%–85%); others include Enterococcus [5] [7] [8] faecalis, Klebsiella pneumoniae, and Proteus mirabilis. In older people, E coli is less common (60%), whereas people with diabetes mellitus may also have infections caused by Kleb[1] siella, Enterobacter, Clostridium, or Candida. People with structural or functional urinary tract abnormalities are more prone to pyelonephritis that is refractory to oral therapy or complicated by bacteraemia. Risk factors associated with pyelonephritis in healthy women are sexual intercourse, use of spermicide, urinary tract infection in the previous 12 months, a mother with a history of urinary [5] tract infection, diabetes, and urinary incontinence. The most important risk factor for complicated [9] urinary tract infection is obstruction of the urinary tract. The incidence of drug-resistant microorganisms varies in different geographical areas. Recent hospital admission, recent use of antibiotics, immunosuppression, recurrent pyelonephritis, and nephrolithiasis increase the risk of drug resistance. [7]
PROGNOSIS
Prognosis is good if uncomplicated pyelonephritis is treated appropriately. Complications include renal abscess, septic shock, and renal impairment, including acute renal failure. Short-term independent risk factors for mortality include age above 65 years, septic shock, being bedridden, and [7] immunosuppression. Conditions such as underlying renal disease, diabetes mellitus, and immunosuppression may worsen prognosis, but we found no good long-term evidence about rates of sepsis or death among people with such conditions.
AIMS OF To reduce the duration and severity of symptoms; to prevent or minimise potential complications, INTERVENTION with minimum adverse effects. OUTCOMES
Cure rates: clinical cure (remission of signs and symptoms), bacteriological cure (negative urine culture after treatment); Rates of complications of infection; and Adverse effects.
METHODS
Clinical Evidence search and appraisal November 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to November 2013, Embase 1980 to November 2013, and The Cochrane Database of Systematic Reviews 2013, Issue 10 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews of RCTs in the English language, at least single-blinded, containing at least 20 individuals (at least 10 per arm), of whom more than 80% were followed up.There was no minimum length of follow-up. We excluded all studies described as ‘open’, ‘open label’, or not blinded unless blinding was impossible. We excluded studies with greater than 25% men, pregnant women, or people with complicated pyelonephritis. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 7 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included,
© BMJ Publishing Group Ltd 2014. All rights reserved.
........................................................... 2
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Pyelonephritis (acute) in non-pregnant women
in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com). QUESTION
What are the effects of antibiotic treatments for acute pyelonephritis in non-pregnant women with uncomplicated infection?
OPTION
ANTIBIOTICS (ORAL OR INTRAVENOUS) VERSUS PLACEBO. . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Pyelonephritis (acute) in non-pregnant women, see table, p 7 .
•
We found no direct information from RCTs about whether antibiotics (oral or intravenous) are better than no active treatment in non-pregnant women with acute pyelonephritis. However, consensus holds that these drugs are effective. Benefits and harms
Antibiotics (oral or intravenous) versus placebo: We found no systematic review or RCTs (see Comment below). Comment:
OPTION
The lack of placebo-controlled RCTs may reflect that experimental trials would be considered unethical. However, consensus holds that these drugs are effective. ANTIBIOTICS (ORAL) VERSUS EACH OTHER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Pyelonephritis (acute) in non-pregnant women, see table, p 7 .
•
We don’t know which is the most effective oral antibiotic regimen or the optimum duration of oral treatment for non-pregnant women with acute pyelonephritis, although it may be sensible to continue treatment for at least 10 days. Benefits and harms
Antibiotics (oral) versus each other: [4] [10] We found two systematic reviews, which identified RCTs comparing different oral antibiotics versus each other in acute pyelonephritis. Neither review performed a meta-analysis. The first systematic review (search date [10] 1991, 9 RCTs) did not include any RCTs that met the Clinical Evidence inclusion criteria. The second systematic [4] review (search date 2004) identified eight RCTs in adults comparing oral antibiotics versus each other. However, none of these eight RCTs fulfilled Clinical Evidence inclusion criteria. We found one subsequent RCT (284 people, [11] 129 with acute pyelonephritis) fulfilling Clinical Evidence criteria, which compared antofloxacin with levofloxacin. Cure rates Antibiotics (oral) versus each other We don’t know whether antofloxacin and levofloxacin differ in effectiveness at increasing clinical cure or bacterial cure in people with acute pyelonephritis (very low-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Cure rates [11]
RCT
[11]
RCT
129 patients with Clinical cure , 7 days after the P = 0.19 acute pyelonephri- end of treatment tis (109 [84%] 56/64 (87.5%) with antofloxacin women) 51/65 (78.5%) with levofloxacin See Further information on studies Per-protocol results also reported
Not significant
129 patients with Bacteriological eradication , at Significance not assessed acute pyelonephri- the end of treatment tis (109 [84%] 52/54 (96.3%) with antofloxacin women) 51/57 (89.5%) with levofloxacin
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Women's health
Pyelonephritis (acute) in non-pregnant women
Ref (type)
Population
Outcome, Interventions
See Further information on studies
Per-protocol results also reported
Results and statistical analysis
Effect size
Favours
Results and statistical analysis
Effect size
Favours
Adverse effects Ref (type)
Population
Outcome, Interventions
Adverse effects [11]
254 people with acute bacterial infection (129 [51%] with acute pyelonephritis)
RCT
Serious adverse effects 0/126 (0%) with antofloxacin 0/128 (0%) with levofloxacin
See Further information on studies
Different durations of antbiotics (oral) versus each other: We found no RCTs comparing the same oral antibiotics for two different time periods. Further information on studies [11]
The RCT included people with acute pyelonephritis and acute exacerbation of chronic bronchitis and was conducted in hospitals in China. Results were reported separately on people with acute pyelonephritis for clinical cure, but this included men as well as women. However, it did not report separately on the subgroup of women with acute pyelonephritis. Pregnant women were excluded from the study. Clinical cure was defined as disappearance of clinical symptoms and signs related to infection. Adverse effects were reported for total study population only.
Comment:
Clinical guide: We found no evidence from RCTs to support the use of any specific oral antibiotic compared with any other oral antibiotic. Therefore, local resistance rates should always be considered when deciding which antibiotic to use. There is consensus that when antibiotic sensitivity is not known, the choice of antibiotics should take into account the setting, the patient’s medical history, Gram stain of the urine, previous infecting organisms, and local antibiotic sensitivities. There is no good evidence regarding duration of treatment; however, treatment should probably not be given for less than 10 days.
OPTION
ORAL ANTIBIOTICS VERSUS SWITCH THERAPY (INTRAVENOUS ANTIBIOTICS FOLLOWED BY ORAL ANTIBIOTICS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Pyelonephritis (acute) in non-pregnant women, see table, p 7 .
•
We found no direct information from RCTs about oral antibiotics compared with intravenous antibiotics followed by oral antibiotics (switch therapy) in non-pregnant women with uncomplicated acute pyelonephritis.
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Women's health
Pyelonephritis (acute) in non-pregnant women
Benefits and harms Oral antibiotics versus switch therapy (intravenous antibiotics followed by oral antibiotics): [10] [4] We found two systematic reviews (search date 1991; and 2004 ), which included one RCT each comparing oral antibiotics with switch therapy, neither of which fulfilled Clinical Evidence inclusion criteria. Comment:
OPTION
We found no RCTs of sufficient quality comparing oral therapy with switch therapy in women with pyelonephritis. More research is needed as this is a common dilemma for clinicians. ANTIBIOTICS (INTRAVENOUS) VERSUS EACH OTHER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Pyelonephritis (acute) in non-pregnant women, see table, p 7 .
•
We found no direct information from RCTs comparing intravenous antibiotics with each other in non-pregnant women with acute pyelonephritis. Benefits and harms
Antibiotics (intravenous) versus each other: [4] [12] [13] [14] We found one systematic review (search date 2004, 3 RCTs) and three subsequent RCTs comparing intravenous antibiotics with each other in people with acute pyelonephritis; however, none of these RCTs fulfilled Clinical Evidence inclusion criteria. Different durations of antibiotic (intravenous) treatments versus each other: We found no RCTs comparing the same intravenous antibiotic for two different time periods. Comment:
Clinical guide: We found no evidence from RCTs to support the use of any specific intravenous antibiotic compared with any other intravenous antibiotic. Therefore, local resistance rates should always be considered when deciding which antibiotic to use. There is consensus that when antibiotic sensitivity is not known, the choice of antibiotics should take into account the setting, the patient’s medical history, Gram stain of the urine, previous infecting organisms, and local antibiotic sensitivities.
GLOSSARY Very low-quality evidence Any estimate of effect is very uncertain.
SUBSTANTIVE CHANGES Antibiotics (oral) versus each other Existing evidence re-evaluated. One new RCT added. unchanged (unknown effectiveness).
[11]
Antibiotics (intravenous) versus each other Existing evidence re-evaluated. One RCT added. unchanged (unknown effectiveness).
Categorisation [14]
Categorisation
REFERENCES 1.
Ramakrishnan K, Scheid DC. Diagnosis and management of acute pyelonephritis in adults. Am Fam Physician 2005;71:933–942.[PubMed]
5.
Bergeron MG. Treatment of pyelonephritis in adults. Med Clin North Am 1995;79:619–649.[PubMed]
Scholes D, Hooton TM, Roberts PL, et al. Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med 2005;142:20–27. [Summary for patients in: Ann Intern Med 2005;142:I34][PubMed]
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Czaja CA, Hooton TM. Update on acute uncomplicated urinary tract infection in women. Postgrad Med 2006;119:39–45.[PubMed]
Ki M, Park T, Choi B, et al. The epidemiology of acute pyelonephritis in South Korea, 1997–1999. Am J Epidemiol 2004;160:985–993.[PubMed]
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4.
Piccoli GB, Consiglio V, Colla L, et al. Antibiotic treatment for acute 'uncomplicated' or 'primary' pyelonephritis: a systematic, 'semantic revision'. Int J Antimicrob Agents 2006;28(suppl 1):S49–S63.[PubMed]
Efstathiou SP, Pefanis AV, Tsioulos DI, et al. Acute pyelonephritis in adults: prediction of mortality and failure of treatment. Arch Intern Med 2003;163:1206–1212.[PubMed]
8.
Farrell DJ, Morrissey I, De Rubeis D, et al. A UK multicentre study of the antimicrobial susceptibility of bacterial pathogens causing urinary tract infection. J Infect 2003;46:94–100.[PubMed]
© BMJ Publishing Group Ltd 2014. All rights reserved.
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9.
David RD, DeBlieux PM, Press R. Rational antibiotic treatment of outpatient genitourinary infections in a changing environment. Am J Med 2005;118(suppl 7A):7S–13S.[PubMed]
12.
Peng F-YJ, Wang S. A multicenter, randomized controlled, double-blind clinical trial of piperacillin/tazobactam(4:1) in the treatment of bacterial infections. Chin J Antibiot 2008;33:114–120.
10.
Pinson AG, Philbrick JT, Lindbeck GH, et al. Oral antibiotic therapy for acute pyelonephritis: a methodologic review of the literature. J Gen Intern Med 1992;7:544–553. Search date 1991.[PubMed]
13.
Liu Y-B, Lu X, Huang L. A multicenter, double-blind, randomized clinical trial of parenteral cefepime in the treatment of acute bacterial infections. Chin J Antibiot 2007;32:367–370,376.
11.
Wang J, Xiao Y, Huang W, et al. A phase II study of antofloxacin hydrochloride, a novel fluoroquinolone, for the treatment of acute bacterial infections. Chemotherapy 2010;56:378–385.[PubMed]
14.
Ebrahimzadeh A, Saadatjoo SA, Tabrizi AA. Comparing ceftriaxone and cefazolin for treatment of adult acute pyelonephritis; a clinical trial. Ir J Clin Infect Dis 2010;5:75–79.
Ignacio Neumann Pontificia Universidad Católica de Chile Santiago Chile Philippa Moore Pontificia Universidad Católica de Chile Santiago Chile Competing interests: IN and PM declare that they have no competing interests. IN and PM would like to acknowledge the previous contributor, M. Fernanda Rojas.
Disclaimer The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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Women's health
Pyelonephritis (acute) in non-pregnant women
GRADE
Evaluation of interventions for Pyelonephritis (acute) in non-pregnant women.
Important outcomes Studies (Participants)
Cure rates Outcome
Comparison
Type of evidence
Quality
Consistency
Directness
Effect size
GRADE
Comment
–1
0
Very low
Quality points deducted for sparse data, inclusion of men in the analysis; directness point deducted for no statistical analysis between groups for one outcome
What are the effects of antibiotic treatments for acute pyelonephritis in non-pregnant women with uncomplicated infection? 1 (129)
[11]
Cure rates
Antibiotics (oral) versus each other
4
–2
0
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasirandomisation, sparse data [
