OUTPATIENT PARENTERAL ANTIBIOTIC THERAPY FOR FEVER AND NEUTROPENIA

Neutropenia is a clear predisposing factor to serious and complex infections. Although it may occur for a variety of reasons, it is most commonly due to the use of chemotherapeutic medications for malignancy. The polymorphonuclear (PMN) or granulocyte series of white blood cells are the mainstay of host defense against life-threatening bacterial infections. Fever is a useful indicator of infection and may be the first sign. Although there are many moderating factors and exceptions or variations in definitions, the concept of fever and neutropenia has emerged as a useful clinical concept, especially in the specialties of oncology and infectious diseases. The focus here shall be on patients with malignancies who have received chemotherapy, although the lessons may apply to other diseases and causes of neutropenia as well. Early in the study of chemotherapy it was recognized that granulocytopenic patients with signs or symptoms of infection could not wait until cultures were positive before treatment with antibiotic therapy. Mortality rates for gram-negative infections, without empiric antibiotic therapy, were reported as high as 80%. 47 For that reason, empiric intravenous antibiotic therapy has been advocated for patients with fever and neutropenia. 12,21 A variety of antimicrobial regimens have been tried and compared in empiric treatment. It is clear that coverage of most gram-negative bacteria and Staphylococcus aureus must be included in the initial regimen. The consequences may not be as dire if fungi, viruses, coagulase-negative staphylococci, and even Pseudomonas aeruginosa are not treated empirically. 10,14,42 With increasing effectiveness, chemotherapy for cancers has been more widely used. With the potential for cure, regimens have become more aggressive and often more marrow toxic. This has been outweighed in part by the use of granulocyte colony-stimulating factors, but the risk of life-threatening infection remains high. The need to deal effectively with infections during neutropenia remains one of the greatest challenges in medicine. There have been changes in the organisms causing infections and the use of antimicrobial agents to treat them with. The incidence of gram-negative organisms appears to have declined over the last 30 years, whereas that of gram-positive organisms has increased. 10 The problems with complex viral, fungal, protozoal, and multidrug-resistant pathogens have increased as we have pushed back the frontiers of immune deficiency. There is also considerable variation in the infecting microbes with respect to geographic location, whether the patient was hospitalized or not, and even within the same institution. 13,22,39 With the high mortality and morbidity owing to infections complicating neutropenia, attempts have been made to characterize risk factors and identify useful indicators in order to develop the most effective methods possible to prevent and treat the infections. The role of granulocytopenia in relation to outcomes can be stratified by the number of PMNs and the duration or even the anticipated duration of low numbers. 5,9,37 The usual categories consider less than 1000 PMNs/mm 3 a clear risk for infection and less than 500 PMNs/mm 3 a higher risk for infection. 5,11,21 Fever is usually defined as a single oral temperature over 38.3°C (101°F) or over 38°C (100.4°F) for at least an hour. 21 Studies at the Dana Farber Cancer Center elucidated additional risk factors for infection and poor outcome. These included progressive cancer, complicating medical cofactors, and inpatient status. 49 Whether hospitalization is an independent risk factor or simply a correlate of multiple medical cofactors is unclear, but both are possible. The type of malignancy also appears to be related to outcome, with solid tumors having fewer serious infections than hematologic malignancies. 29 A variety of indicators have been used to judge the value of interventions. Although death rates are useful, they are not very sensitive. Other indicators that have been used include days of fever, days of hospitalization, and occurrence of serious medical complications, including signs of sepsis, transfer to the intensive care unit, neurologic change, cardiac failure, and serious bleeding. 49 The number of changes in antibiotics has even been found to be a useful indicator. 11 These outcome indicators and correlates have been useful in categorizing patients as at high or low risk for infection and complications of infection. Talcott was able to break down 444 cancer patients at the Dana Farber Cancer Center into 4 groups—one of which was considered "low risk." This group had a granulocyte count of less than 500 PMNs/mm 3 and a temperature of over 100.5°F but no comorbid conditions. There were no deaths and a less than 2% complication rate in this group compared to the other higher risk groups, who had a 17% mortality rate and a more than 30% medical complication rate. 49 With the discovery and characterization of a low-risk group of oncology patients, the stage was set for methods to improve care and lessen cost. Antimicrobial therapy has also been under review. There are numerous studies documenting the value of most intravenous regimens. 61 It appears that the choices need to be based on the local pathogens, the individual patient, and a variety of other factors. Any empiric therapy should be altered when a pathogen is recovered. Recent guidelines from the Infectious Disease Society of America (IDSA) suggest that the use of antibiotics to prevent infections in neutropenic patients may not be reasonable given their potential toxicity and selection of resistant pathogens. 21 They also consider a variety of regimens acceptable for empiric therapy—from monotherapy to duotherapy, with or without vancomycin. 21 There has also been interest in using oral antibiotics for empiric and switch therapy. 11,28