John W. Warren

Guidelines for Antimicrobial Treatment of Uncomplicated Acute Bacterial Cystitis and Acute Pyelonephritis in Women

This is part of the series of practice guidelines commissioned by the Infectious Diseases Society of America (IDSA) through its Practice Guidelines Committee. The purpose of this guideline is to provide assistance to clinicians in the diagnosis and treatment of two specific types of urinary tract infections (UTIs): uncomplicated, acute, symptomatic bacterial cystitis and acute pyelonephritis in women. The guideline does not contain recommendations for asymptomatic bacteriuria, complicated UTIs, Foley catheter-associated infections, UTIs in men or children, or prostatitis. The targeted providers are internists and family practitioners. The targeted groups are immunocompetent women. Criteria are specified for determining whether the inpatient or outpatient setting is appropriate for treatment. Differences from other guidelines written on this topic include use of laboratory criteria for diagnosis and approach to antimicrobial therapy. Panel members represented experts in adult infectious diseases and urology. The guidelines are evidence-based. A standard ranking system is used for the strength of the recommendation and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council, the sponsor and supporter of the guideline. The American Urologic Association and the European Society of Clinical Microbiology and Infectious Diseases have endorsed it. An executive summary and tables highlight the major recommendations. Performance measures are described to aid in monitoring compliance with the guideline. The guideline will be listed on the IDSA home page at http://www.idsociety.org It will be evaluated for updating in 2 years.

CATHETER-ASSOCIATED URINARY TRACT INFECTIONS

Nosocomial urinary tract infection (UTI) is the most common infection acquired in both hospitals and nursing homes and is usually associated with catheterization. This infection would be even more common but for the use of the closed catheter system. Most modifications have not improved on the closed catheter itself. Even with meticulous care, this system will not prevent bacteriuria. After bacteriuria develops, the ability to limit its complications is minimal. Once a catheter is put in place, the clinician must keep two concepts in mind: keep the catheter system closed in order to postpone the onset of bacteriuria, and remove the catheter as soon as possible. If the catheter can be removed before bacteriuria develops, postponement becomes prevention.

Catheter-associated urinary tract infections

The two most common indications for long-term catheterization are recalcitrant urinary incontinence and urinary obstruction that is not corrected by surgery. For incontinent patients, if behavioral changes, nursing care, special clothes, special bed clothes, and medications have not been successful, then a device to collect urine must be considered. For men such a device is a condom catheter; for women an analogous external collection device would be very useful. Suprapubic catheterization may offer an alternative but has been inadequately studied in this patient population. Long-term urinary catheterization has salutary effects for selected patients including patient comfort, family satisfaction, and nursing efficiency and effectiveness. To the patient for whom any physical movement is uncomfortable or painful, and indwelling catheter may be preferable to frequent changes of clothes. Similarly, the family of of severely impaired patients may want to accept the risks of urethral catheterization in order to keep the patient dry. Further, to the extent that the indwelling catheter is effective in decubitus ulcer prevention and/or management, long-term catheterization may diminish the risk of bacteremia or death from soft tissue infection. These benefits of long-term urethral catheterization, in addition to its risks, should be examined in future studies. Once a urethral catheter is in place, even with good catheter hygiene, bacterial entry can be postponed only temporarily; eventually all patients become bacteriuric. Indeed, as the catheter remains in place, organisms continue to enter, others leave or die, and the bacteriuria becomes complex, polymicrobial, and dynamic. Some organisms, particularly recognized uropathogens such as E. coli and K. pneumoniae, appear to reside in the urinary tract itself. Others, such as P. mirabilis, P. stuartii, and M. morganii, probably establish a niche within the urinary catheter, thus increasing their ability to cause subsequent bladder bacteriuria. The complications of long-term urinary catheterization include fevers, acute pyelonephritis, and bacteremias (such as seen in short-term catheterized patients), as well as catheter obstructions, urinary stones, chronic renal inflammation, local periurinary infections, vasicoureteral reflux, renal failure, and, for very long-term catheterized patients, bladder cancer. The thrust of catheter care for the long-term catheterized patient is to prevent complications of the omnipresent bacteriuria. Unfortunately, clinical opportunities for preventing complications are limited.(ABSTRACT TRUNCATED AT 400 WORDS)

Diagnosis of interstitial cystitis

We reviewed clinical and histological findings in 55 patients with interstitial cystitis and 21 with voiding dysfunction secondary to other pathological conditions. Of our interstitial cystitis patients 36% would fail to meet the research definition proposed at a recent National Institutes of Health workshop. Detrusor mastocytosis was present in 64% of our interstitial cystitis patients compared to 80% of the noninterstitial cystitis group. There was no statistically significant difference in mean detrusor mast cell counts between interstitial cystitis and noninterstitial cystitis patients. Biopsies of 12 patients who did meet the proposed National Institutes of Health research definition were evaluated by immunohistochemical techniques. Early results are inconclusive. These studies indicate that interstitial cystitis is a complex disease whose diagnosis presently still must be made from a symptom complex rather than from objective histological criteria, including mastocytosis or the presence of any specific immunoreactive cell.

Isogenic P‐fimbrial deletion mutants of pyelonephritogenic Escherichia coli: the role of α Gal(1–4)β Gal binding in virulence of a wild‐type strain

Escherichia coli strains causing acute pyelonephritis often express multiple fimbrial types and haemolysin, which may contribute to their ability to adhere to, and interact with, kidney epithelial cells. Strain CFT073, a pap+, sfa+, pil+, hly+ pyelonephritis strain, previously established as virulent in the CBA mouse model of ascending urinary tract infection and cytotoxic for cultured human renal epithelial cells, was selected for construction of isogenic strains. From a gene bank of this strain, two distinct copies of the pap operon were isolated. The two P‐fimbrial determinants were sub‐cloned into pCVD442, a positive selection suicide vector containing the sacB gene of Bacillus subtilis. Deletion mutations were introduced into each of the two constructs, within papEFG of one operon and papDEFG of the other. Suicide vectors carrying pap deletions were mobilized from E. coli SM10 lambda pir into CFT073 (NalR) and cointegrates were passaged on non‐selective medium. The first pap mutation was identified by screening a Southern blot of DNA from sucrose‐resistant colonies using a papEFG probe. This mutant retained the MRHA+ phenotype since a second functional copy of pap was still present. A double pap‐deletion mutant, UPEC76, confirmed by Southern blotting, was unable to agglutinate human type O erythrocytes or α Gal(1–4)β Gal‐coated latex beads.

Incidence and characteristics of antibiotic use in aged nursing home patients

Objective. To measure the prevalence, incidence, types, and certain characteristics of antibiotics prescribed in nursing homes.

Urinary tract infection in adults: research priorities and strategies

Waning interest in urinary tract infection (UTI) research has limited clinical advances during the past two decades. Although care has improved for some specific UTI syndromes, there is limited evidence for most of the decisions made each day in the management of these infections. Additional clinical research is necessary to improve UTI prevention and care strategies.

Antecedent Nonbladder Syndromes in Case-Control Study of Interstitial Cystitis/Painful Bladder Syndrome

OBJECTIVES Probing for clues to the pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS), we sought antecedent nonbladder syndromes that distinguished incident IC/PBS cases from matched controls. METHODS Female incident IC/PBS cases were recruited nationally, and their IC/PBS onset date (index date) was established. The controls were recruited by national random digit dialing and matched to the cases by sex, age, region, and interval between the (assigned) index date and interview. The prevalence of 24 nonbladder syndromes before the index date was assessed, 7 by multiple methods. RESULTS The cases with IC/PBS had greater antecedent prevalence of 11 syndromes, and 243 of 313 cases (78%) vs 145 of 313 controls (45%) had multiple syndromes (P < .001). Fibromyalgia-chronic widespread pain (FM-CWP), chronic fatigue syndrome, sicca syndrome, and irritable bowel syndrome were associated with each other by pairwise and factor analyses using numerous assumptions. Cases with FM-CWP, chronic fatigue syndrome, sicca syndrome, and/or irritable bowel syndrome (n = 141, 45%) were more likely to have other syndromes (ie, migraine, chronic pelvic pain, depression, and allergy). Three other syndrome clusters were identified; each was associated with this FM-CWP cluster. CONCLUSIONS Eleven antecedent syndromes were more often diagnosed in those with IC/PBS, and most syndromes appeared in clusters. The most prominent cluster comprised FM-CWP, chronic fatigue syndrome, sicca syndrome, and irritable bowel syndrome; most of the other syndromes and identified clusters were associated with it. Among the hypotheses generated was that some patients with IC/PBS have a systemic syndrome and not one confined to the bladder.

Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor–like growth factor, and epidermal growth factor as urine markers for interstitial cystitis ☆

We previously determined that the urine of interstitial cystitis (IC) patients specifically contains a factor (antiproliferative factor [APF]) that inhibits primary bladder epithelial cell proliferation, and that it has significantly decreased levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and increased levels of epidermal growth factor (EGF) compared with urine from asymptomatic controls and patients with bacterial cystitis. We sought to confirm the specificity of these findings for IC using a larger patient population, including control patients with a variety of urogenital disorders. Clean catch urine specimens were collected from 219 symptomatic IC patients, 113 asymptomatic controls without bladder disease, and 211 patients with various urogenital diseases including acute bacterial cystitis, vulvovaginitis, chronic nonbacterial prostatitis, overactive bladder, hematuria, stress incontinence, neurogenic bladder, benign prostatic hyperplasia, bladder or pelvic pain without voiding symptoms, bladder cancer, prostate cancer, or miscellaneous diagnoses including anatomic disorders. APF activity was determined by (3)H-thymidine incorporation into primary normal adult human bladder epithelial cells. HB-EGF and EGF levels were determined by enzyme-linked immunosorbent assay. APF activity was present significantly more often in IC than control urine specimens (P <0.005 for IC vs any control group; sensitivity = 94%, specificity = 95%, P <10(-82) for IC vs all controls). HB-EGF levels were also significantly lower and EGF levels significantly higher in IC urine than in specimens from controls (P <10(-84) and P <10(-36), respectively). These findings confirm the utility of APF, HB-EGF, and EGF as markers for IC. Understanding the reasons for altered levels of these markers may lead to understanding the pathogenesis of this disorder.

BLADDER EPITHELIAL CELLS FROM PATIENTS WITH INTERSTITIAL CYSTITIS PRODUCE AN INHIBITOR OF HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH FACTOR PRODUCTION

PURPOSE The etiology of interstitial cystitis is unknown. We previously identified an interstitial cystitis urine factor, antiproliferative factor, that inhibits proliferation of bladder epithelial cells in vitro and complex changes in epithelial growth factor levels, including profound decreases in heparin-binding epidermal growth factor-like growth factor (HB-EGF). Bladder and renal pelvic catheterization of patients with interstitial cystitis indicated that the antiproliferative factor is made and/or activated in the distal ureter or bladder. Therefore, we determined whether bladder epithelial cells from interstitial cystitis cases produced the antiproliferative factor and whether purified antiproliferative factor could alter production of growth factors known to be abnormal in interstitial cystitis. MATERIALS AND METHODS Antiproliferative factor activity was determined by 3H-thymidine incorporation into primary bladder epithelial cells. The antiproliferative factor was purified by size fractionation followed by sequential chromatography involving ion exchange, hydrophobic interaction and high performance liquid chromatography. HB-EGF, epidermal growth factor, insulin-like growth factor and insulin-like growth factor binding protein 3 levels were determined by enzyme-linked immunosorbent assay. RESULTS Bladder epithelial cells from patients with interstitial cystitis produced a single antiproliferative factor with the same purification profile as that purified from interstitial cystitis urine. Purified antiproliferative factor specifically inhibited HB-EGF production by bladder epithelial cells in vitro, and the effect of interstitial cystitis urine or purified antiproliferative factor on bladder cell proliferation was inhibited by recombinant human HB-EGF in a dose dependent manner. Similar to urine HB-EGF, serum HB-EGF was also significantly lower in interstitial cystitis cases than in controls. CONCLUSIONS Bladder epithelial abnormalities in interstitial cystitis may be caused by a negative autocrine growth factor that inhibits cell proliferation by down-regulating HB-EGF production. Furthermore, decreased levels of urine and serum HB-EGF indicate that interstitial cystitis may be a urinary tract manifestation of a systemic disorder.