The Case

A 41-year-old woman presented to the hospital with acute renal failure, which came to be diagnosed as a first presentation of systemic lupus erythematosus (SLE). During the hospitalization, she developed additional complications of SLE including cerebritis, hemolytic anemia, and thrombocytopenia.

After 2 weeks in the hospital, the patient was given vancomycin and piperacillin/tazobactam for altered mental status and leukocytosis of 19,000. A few days later, antibiotics were changed to vancomycin and levofloxacin for persistent leukocytosis and low-grade fevers. Multiple cultures from urine, blood, and sputum yielded no organisms, but the patient was kept on antibiotics due to fevers. Although no clear source of infection was identified, antibiotics were continued for 3 weeks, at which point her fevers spiked to 38.5°C. At that time, a single blood culture grew vancomycin-resistant Enterococcus faecium (VRE), as did a central line catheter tip. Furthermore, urine cultures grew more than 100,000 colonies of Candida glabrata.

The patient received a consultation from an infectious disease (ID) specialist, who recommended that all antibiotics be discontinued. Within 24 hours, the patient defervesced. She remained hemodynamically stable and underwent further treatment for her SLE.

Additional information: Although the ID consultants would have preferred to treat the VRE with linezolid, the patient’s severe thrombocytopenia and anemia prohibited its use. Thus, she was given doxycycline, a second-line agent for this organism, and had her central venous catheter discontinued. A repeat blood culture grew VRE, which necessitated removal and re-placement of yet another central venous catheter. In an attempt to clear colonization of C glabrata, multiple Foley catheters were changed, and the organism eventually was eliminated. Initiating immunosuppressive treatment for the patient’s SLE had to await eradication of the resistant organisms.

The Commentary

Nosocomial infections and antibiotic-resistant organisms are two common problems among hospitalized patients. This case clearly illustrates how the confluence of these two problems—nosocomial infections caused by antibiotic-resistant organisms—makes management challenging.

Of the more than 2 million nosocomial infections each year in the United States, 50%-60% are caused by antibiotic-resistant organisms.(1) This high rate of resistance has been identified as an urgent national problem; it increases the morbidity, mortality, and costs associated with nosocomial infections. Among gram-positive bacteria, the most important resistant pathogens are vancomycin-resistant Enterococcus, beta-lactam resistant and multi-drug resistant streptococci, and methicillin-resistant Staphylococcus aureus. From 1990 to 1997, the prevalence of vancomycin-resistant Enterococcus increased from 1)

Multiple factors may contribute to increasing antibiotic resistance, including increased severity of illness; more severe immunosuppression; newer invasive devices and procedures; increasing levels of antibiotic resistance in the community; suboptimal use of isolation and barrier precautions leading to cross-transmission and outbreaks; increased use of prophylactic and empiric antibiotics; and higher overall antibiotic use per area, per unit time.(2) Prolonged length of hospital stay also seems to predispose patients to infection with antibiotic-resistant bacteria, possibly due to the greater likelihood over time of becoming colonized with resistant bacteria, either from horizontal nosocomial transmission or endogenous emergence of resistance.(3)

In this case, antibiotic initiation was prompted by low-grade fever and leukocytosis, both common reasons for antimicrobial treatment. However, fever should not be seen as an automatic indication for antibiotics. Fever can have many causes in hospitalized patients, including non-infectious etiologies such as drug fever, thromboemboli, atelectasis, or an underlying illness. Some infectious causes, like viral and fungal infections, will not benefit from treatment with antibiotics. In febrile patients, evidence of a bacterial infection should be sought diligently with blood and urine cultures, urinalysis, a chest x-ray, and a careful physical exam with special attention to the skin for soft tissue infections, infections associated with venous catheters, or evidence of cutaneous emboli. Continued fever following the initiation of antibiotics may indicate a non-infectious etiology, or an infectious cause not covered by antibiotics.

In this patient, fever, leukocytosis, and mental status changes could all be attributed to her SLE. However, the distinction between fever from infection and fever from other sources can be difficult to make prospectively. This patient is also at increased risk for infection due to her underlying disease and its likely treatment with corticosteroids. Starting antibiotics in these circumstances is not necessarily an error, but continuing them for 3 weeks without clear evidence of a bacterial infection is.

In severely ill patients, the desire to start antibiotic treatment early and with broad-spectrum agents is understandable, especially given recent data showing an association between inadequate initial antimicrobial therapy and increased mortality among intensive care unit patients.(4,5) However, not all patients require immediate antibiotic treatment. Broad-spectrum empiric coverage benefits patients in intensive care units who are critically ill with hemodynamic instability or severely immunocompromised patients. Patients who are clinically stable without any clear focus of infection usually are not harmed by waiting until culture results are available before starting antibiotics. When the choice is made to begin empiric antibiotic coverage, if no evidence of bacterial infection is found, all antibiotics should be stopped, even in the face of persistent fevers. In hemodynamically unstable patients or patients with significant immunosuppression, if clinical suspicion for a bacterial infection is high, antibiotics may be continued even if cultures are negative. In these cases, a reasonable course of therapy (7-10 days) should be administered and then antibiotics should be stopped. This is also true if a patient was pre-treated with antibiotics, which may render the culture results unreliable. After antibiotics are stopped, the patient can be monitored clinically and recultured to evaluate any new symptoms or signs of infection. If a bacterial infection is identified, the culture and susceptibility data should be used to narrow the antibiotic coverage as soon as possible.(6) Physicians should evaluate the patient’s response to treatment daily and re-evaluate the continued need for antibiotics.

In this case, although initial empiric broad-spectrum antibiotic coverage was considered necessary, stopping therapy on the basis of negative cultures was imperative. Why? Because prolonged exposure to broad-spectrum antibiotics increases the risk of colonization with resistant organisms and subsequent infection with resistant bacteria--not just at a population level but also in an individual patient. Prolonged exposure to broad-spectrum antibiotics predictably increases the risk of overgrowth of Clostridium difficile and of subsequent colitis, the risk of overgrowth of vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus, and the risk of fungal infections. Many physicians find it hard to limit antibiotic use when they think that broad-spectrum antibiotic coverage is in the patient’s best interest, despite possible societal consequences such as increasing antibiotic resistance in the hospital. This case illustrates very well how societal needs and the needs of individual patients are not in conflict: they are generally the same.

Colonization is often a precursor to infection. This patient’s urine cultures with C glabrata were recognized as colonization and managed appropriately, by changing the catheter (removing it if possible) and minimizing the use of broad-spectrum antibiotics. A urinary tract infection (not just colonization) might be signaled by persistently positive cultures, consistent symptoms such as dysuria, pyuria, or evidence of upper tract disease. In those cases, antifungal therapy would be indicated. Colonization of central lines can likewise herald infection. When blood cultures drawn from a catheter are positive (even in the absence of positive peripheral blood cultures), the line and/or the catheter hub can be considered colonized and the line should be removed.

How can overuse of antibiotics be prevented? Strategies to improve antibiotic stewardship and reduce antibiotic resistance have recently been summarized.(3) Educational programs for all physicians, including personal interactions, detailed information on local susceptibility patterns, and feedback on prescribing practices, can change behavior.(7) Hospitals can also develop guidelines for antibiotic use. In some settings, these guidelines are maintained on a Web site for easy access by working physicians. These guidelines can be supplemented with informatics support including prescribing reminders, formulary restrictions, and automatic stop alerts. Involvement of infectious disease specialists increases the likelihood that patients receive adequate empiric antibiotic therapy and is also associated with less use of unnecessary broad-spectrum antibiotics, more rapid shift to oral agents, and reductions in infections with resistant organisms.(3) Perhaps most effective of all, some hospitals have developed robust computerized decision support to help guide physicians to better choices about antibiotic usage. These programs, which can constantly integrate updated information on pathogen prevalence and local resistance patterns, have led to marked improvements in the appropriateness of antibiotic use, the costs of care, and the frequency of antibiotic resistance.(8,9)

Effective infection control programs are also crucial.(10,11) Studies have shown that rates of catheter-related bloodstream infection can be decreased with proper catheter insertion technique and care. Educational interventions addressing these issues should target practicing physicians and trainees.(12,13) Additionally, infection control programs are instrumental in setting, enforcing, and educating staff about the importance of isolation and barrier precautions as well as hand hygiene for the prevention of cross-transmission of resistant organisms.

Take-Home Points

• Consider non-infectious causes of fever.
• Obtain appropriate cultures and use susceptibility results to guide antibiotic therapy.
• Antibiotics should be stopped when there is no evidence of bacterial infection. If antibiotics are continued in immunocompromised or unstable patients with negative cultures, a defined course of therapy (7-10 days) should be administered and then discontinued.
• Broad-spectrum empiric antibiotics should be changed to narrow-spectrum agents when susceptibility results are available.
• Antibiotic use should be evaluated frequently in each patient to determine the response to therapy and its duration.(14)
• Well-supported infection control programs can offer important mechanisms (contact isolation, surveillance, and guidelines) for preventing the spread of antibiotic-resistant organisms.(15-19) The integration of infection control and informatics yields considerable promise for improving the quality of care in this area.
• Use of invasive devices, and the duration of their use, should be minimized. Adherence to standards for insertion and care can decrease the risk of infection.(12)

Hilary M. Babcock, MD Instructor of Medicine Infectious Disease Division Washington University School of Medicine

Victoria J. Fraser, MD Professor of Medicine Infectious Disease Division Washington University School of Medicine

References

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