Initially, antibiotic therapy must be broad-spectrum to cover multiple organisms and drug resistance
BY ANTHONY J. SCHAEFFER, MD
INFECTIONS ARE a serious complication and leading cause of death in debilitated patients, including those with cancer, immunosup-pression (e.g., transplantation or AIDS patients), diabetes, chronic renal failure, severe neurologic conditions such as Parkinsonism or spinal cord injury, and the elderly.1 For example, approximately 50% of patients dying from solid tumors who had a complete postmortem examination died from infection. Since debilitating factors frequently coexist, the impact is frequently compounded.1
Urinary tract infections are among the most common infections in the debilitated population in large part because many of the patients have urinary catheters. In fact, catheter-associated bacteriuria (CAB) occurs at a rate of 5% per day,2,3 and although it does not require treatment, conversion to symptomatic events with fever and upper tract disease is common. Since these infections are usually acquired in a health-care setting where antimicrobial use is pervasive, bacterial virulence and antimicrobial resistance is increased. Because these patients are usually on multiple medications, drug-drug interactions that reduce agent efficacy and increase associated side effects are common. Corticosteroids, for example, which are frequently used to treat these comorbidities, enhance the susceptibility to infection.1
Lastly, structural or functional abnormalities of the urinary tract are common in debilitated patients. Urinary obstruction and dehydration lead to renal failure and reduced ability of the antimicrobials to concentrate within the urinary tract, thus diminishing their efficacy. Therefore, careful assessment, diagnosis and management are essential to maximize efficacy and reduce morbidity in debilitated patients with urinary tract infections.
Pathogenesis
Uncomplicated UTIs, in patients who are non-debilitated, are usually ascending events caused by
bacteria that migrate through the urethra into the bladder; instrumentation is not associated in these instances. In debilitated patients, the urinary tract is frequently compromised due to aging and acquired effects of obstruction, for example, from stones or enlargement of the prostate gland or BPH. In addition, catheterization bypasses the normal defense systems, allowing easier bacterial access to the urinary tract. These catheters also provide a convenient nidus for bacteria that can be incorporated within the catheter's biofilms where they are protected from antimicrobials.4
Recent evidence suggests that bacteria also may be incorporated into intracellular pods within the bladder where they become surrounded by a biofilm.4 Urinary tract levels of antimicrobials effective against superficial bacteria may not as effectively treat these bacteria.4 When the upper tract is compromised by decreased renal function and/or other comorbidities such as severe diabetes, infections can become much more severe. Pyelonephritis can progress to intrarenal and perirenal abscesses with mortality rates in excess of 50%.5 These infections are frequently complex due to multiple bacteria and yeast. In addition, the bacteria frequently show multiple drug resistance because of the patients' exposure to antimicrobials and the fact that the bacteria are usually acquired within a hospital or nursing home setting.6
Multiple drug resistance is usually associated with extrachromosomal transfer of plasmids.7,8 These plasmids incorporate not only resistance to the drug the patient is receiving but also multiple agents that share this plasmid-mediated resistant capability. These include broad-spectrum and beta lactams, aminoglycosides, and sulfonamides. Only the quinolones are not associated with plasmid-mediated resistance.
Management
Many debilitated patients have bacteriuria associated with catheterization or aging. Whether debilitated patients have symptoms related to the urinary tract, and whether these symptoms are consistent with infection, is often difficult to evaluate as the patients may be unable to communicate discomfort.9 Symptoms such as malaise, anorexia, weakness, mental changes, and weight loss are commonly seen in debilitated patients without infection, which makes diagnosis difficult, particularly in advanced disease.10 Furthermore, debilitated patients may have difficulty mounting a response to infection; for example, fever, a common symptom of severe infection, has been noted to be present in only 50% of cancer patients with UTIs. In many cases, fever is not initially thought attributable to the UTI.11
The difficulty associated with diagnosing infections is magnified because of the substantial risk associated with either not treating an infection or treating a patient who does not have an infection. Most debilitated patients with asymptomatic bacteriuria should not be treated. However, if there is a possibility that the patient's symptoms, particularly fever, are associated with a UTI, then treatment should be initiated. Urine cultures must be obtained because of the possibility of multiple organisms with different antimicrobial profiles. The organisms causing UTIs most commonly are Escherichia coli, but other gram-negative organisms such as Klebsiella species and Pseudomonas are encountered frequently. In addition, gram-positives such as enterococci, staphylococci, and even yeast may be identified, the latter presenting particularly difficult co-infections. Since catheters indwelling for any length of time may incorporate bacteria within biofilms, they should be changed, if at all possible, prior to diagnosing the infection and initiating therapy.4
Given the complexity of the microbiologic flora and the overwhelming possibility of multiple drug resistance, a severe infection should be treated aggressively with broad-spectrum antimicrobials. If time permits, culture data should be used to select agents which are most likely to be effective. Duration of therapy is not well defined in this population, but systemic parenteral therapy should be continued until the patient's symptoms improve. The patient can then be converted to oral therapy based on susceptibility testing. At least 7-14 days or longer therapy may be required. Cultures should be obtained during and after therapy to identify efficacy and relapse, respectively.
Complicated UTI, defined as those associated with functional or structural abnormalities in the urinary tract, are very prevalent in debilitated populations. Therefore, early imaging of the urinary tract using CT or ultrasound should be performed. If at all possible, any obstruction must be relieved by either catheter drainage or removal of the obstructing focus. Other more significant findings, such as renal or perirenal abscess, must be drained, often percutaneously.
Concomitant with initiating therapy and maximizing the status of the urinary tract, efforts must be made to improve the status of the patient and reduce comorbidities. These steps should include appropriate hydration and review and adjustment of medications to enhance management of other comorbidities such as diabetes.
Because renal function has a key role in delivering appropriate concentrations of antimicrobials to the urinary tract, serum creatinine should be monitored regularly. Dehydrated elderly patients are more susceptible to the effects of antimicrobials, particularly those with potential nephrotox-icity such as aminoglycosides. Once-daily dosing with aminoglycosides is particularly attractive in this population for two reasons: first, because the high, initial dose takes advantage of the dose-dependent killing activity, and second, the low, sustained dose reduces toxicity.12,13 Once-daily dosing with aminoglycosides requires adherence to a simple formula; after administering the initial dose, for example, 7.5 mg/kg, a serum level should be obtained between 8-14 hours later. A nomogram is used to determine the time for subsequent doses, for example at 24 hours, then repeated at 12-hour intervals (36 hours, 48 hours, etc). It is imperative that periodic serum aminoglycoside and creatinine be monitored to ensure effective and safe dosing. Peaks and trough levels are not appropriate for monitoring once-daily aminoglycoside therapy.14, 15
Drug-drug interactions can be particularly problematic for several reasons. Efficacy of some drugs, such as the fluoroquinolones, can be diminished by antacids, which reduce absorption from the GI tract. Other drugs may not only reduce the activity of the agent but enhance side effects. Because of these possibilities, pharmaceutical guidance should be obtained when multiple drugs are used.
Several complicated UTIs can be particularly difficult to treat in debilitated patients. For example, infected hydronephrosis can lead to pyonephrosis and destruction of renal parenchyma. Xanthogranulomatous pyelonephritis is an acute necrotizing parenchymal and perirenal infec-
tion caused by gas forming uro-pathogens.16 It is usually associated with urinary calculi, obstruction, diabetes, and significant renal functional impairment—all characteristics of debilitated patients. The mortality rate for this condition can exceed 50%. Severe cases require prompt drainage or removal of the site of infection. Because of the risk of surgery in these patients, percutaneous or open drainage and aggressive antimicrobial therapy should be initially attempted if possible until the patient's condition can be stabilized or improved.
Summary
UTI in the debilitated patient occurs frequently and causes significant morbidity and mortality. Diagnosis must be based on a high index of suspicion and careful interpretation of symptoms. Although severe symptoms can occur, paradoxically debilitated patients may present with symptoms that are either thought to be associated with other conditions, and/or relatively asymptomatic. Conversely, the diagnostics of bacteriuria in asymptomatic debilitated patients can lead to false diagnosis of infection and unnecessary treatment. Diagnosis must be confirmed by urinalysis and culture. A chronic indwelling catheter should be changed before obtaining a specimen so the bacteria within the catheter's biofilm do not contaminate the bladder.
Initially, antimicrobial therapy must be broad-spectrum to cover multiple organisms and drug resistance. Once-daily aminoglycoside therapy is effective and reduces morbidity but must be carefully monitored. Oral therapy should be instituted when clinically indicated.
Efforts should be made to maximize response by improving the overall status of the patient and the urinary tract during and after the infection. Imaging must be employed to rule out obstruction and other structural or functional abnormalities. Response to therapy is the key indicator for duration of antimicrobial therapy and decisions regarding interventions are required. Relief of obstruction by percutaneous or by catheter drainage is imperative. Following resolution of the acute event, risk factors and comorbidities should be managed aggressively to maximize therapeutic outcomes and minimize relapse.
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