Current Treatment of Infection in the Neutropenic Patient

Predominant Bacterial Pathogens and Changing EpidemiologyInitial ManagementOther Therapeutic ModalitiesPrevention of InfectionSummaryReferences

Neutropenia was recognized almost 3 decades ago as a major predisposing factor for the development of infection in patients with cancer [1]. The risk begins to increase when the neutrophil count drops below 1,000/mm³ and is greatest at counts of 100/mm³ or lower. At this level, approximately 20% of febrile episodes are caused by a bacteremic process [2].

The increasing use of more intensive chemotherapeutic regimens to achieve maximal antitumor activity has produced severe and prolonged neutropenia in many patients. Some regimens used for remission induction in acute leukemia (eg, high-dose cytarabine) are associated with severe oropharyngeal mucositis and gastrointestinal toxicity, resulting in infection caused by enteric organisms and by organisms colonizing the oropharynx (eg, streptococci). The skin, which is often breached by vascular access devices and invasive procedures, serves as a portal of entry. The paranasal sinuses also have been recognized as important sites of infection in neutropenic patients.

Predominant Bacterial Pathogens and Changing Epidemiology

Neutropenic patients are presumed to have developed an infection when they become febrile. However, it is not always possible to document an infection in these patients. Currently at The University of Texas M.D. Anderson Cancer Center, an infection can be documented in approximately 47% of patients with fever and neutropenia, whereas 53% are considered to have fever of undetermined origin [3]. The frequency of microbiologically documented infections differs from institution to institution and is influenced by factors such as the usage of prophylactic antibiotics in high-risk patients: Institutions that routinely use prophylactic antibiotics will probably have a lower incidence of microbiologically documented infections.

There have been several epidemiologic shifts in the types of microorganisms causing infection in neutropenic patients. Coagulase-negative staphylococci, Staphylococcus aureus, the enterococci, and the streptococci (particularly alpha-hemolytic [viridans] streptococci) are currently the most common gram-positive pathogens [4]. Most staphylococcal infections are cutaneous in origin, and most enterococcal infections arise in the gastrointestinal tract. However, some infections caused by Staphylococcusepidermidis are gastrointestinal in origin [5]. Corynebacterium jeikeium and Bacillus species are isolated less often but are capable of causing serious infections.

Although Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa are still frequently isolated, heavy antibiotic use in neutropenic patients has led to the emergence of other, often resistant, gram-negative organisms in these patients (Table 1). While many institutions have reported a decreased incidence of P aeruginosa infections in recent years, it remains an important pathogen at some centers and is currently the third most frequently isolated gram-negative pathogen at M.D. Anderson [3].

Staphylococcus aureus
Coagulase-positive staphylococci

Enterococcus species
Streptococcus species

Corynebacterium jeikeium
Bacillus species
Streptococcus species-Group G
Streptococcus pneumoniae

Escherichia coli
Klebsiella species
Pseudomonas aeruginosa
Enterobacter species
Citrobacter species
Xanthomonas maltophilia
Acinetobacter species

Serratia marcescens
Flavobacterium meningosepticum
Alcaligenes species
Flavimonas oryzihabitans
Aeromonas hydrophilia

Gram-negative bacilli that have emerged as pathogens in recent times include Acinetobacter calcoaceticus; Citrobacter, Enterobacter, and Serratia species; and Xanthomonas maltophilia [6–8]. Other uncommon but significant gram-negative pathogens include Alcaligenes species, Aeromonas hydrophila, Flavobacterium meningosepticum, and Flavimonas oryzihabitans [9-11].

Initial Management

Febrile neutropenic patients are often difficult to evaluate. Fever, which is occasionally low-grade (< 38ºC), may be the only manifestation of a serious infection. As a result of an impaired inflammatory response, clinical signs of infection may be undetectable even on a thorough physical examination. Absence of evidence of infection on physical examination does not, however, exclude the possibility of infection [12].

All appropriate sites (eg, blood, urine, stools) should be cultured prior to the administration of antibiotics. These procedures should be done as expeditiously as possible and should not cause a delay of more than 30 to 40 minutes in the administration of antibiotic therapy. Infections often develop and progress rapidly in neutropenic patients and can cause death if antibiotics are not administered promptly. A recent review of P aeruginosa infections from M.D. Anderson clearly demonstrated the efficacy of prompt antibiotic therapy. The response rate was 74% when antipseudomonal therapy was given during the first 24 hours but fell to 46% if there was a delay of more than 24 to 48 hours [13]. Prompt, empiric, broad-spectrum antimicrobial therapy has, therefore, become standard.

Initial Antibiotic Regimens

Other properties of antibiotics that should be taken into consideration when selecting empiric regimens are listed in Table 2. A number of combination regimens have been proposed for the treatment of febrile episodes in neutropenic patients [14]. These regimens have been used successfully for many years and are modified to account for the availability of improved antibiotics that are less toxic, more potent, or more favorable pharmacokinetically.

Aminoglycoside-Containing Combinations: The combination of an antipseudomonal carboxypenicillin (ticarcillin [Ticar]) or ureidopenicillin (mezlocillin [Mezlin], piperacillin [Pipracil], azlocillin) with an aminoglycoside (gentamicin, tobramycin, amikacin) has for many years been considered standard initial therapy for the febrile neutropenic patient and has been widely used. More recently, aminoglycosides have been successfully employed in combination with extended-spectrum cephalosporins such as cefoperazone (Cefobid) and ceftazidime (Table 3) [15-17]. These regimens produce response rates ranging from 71% to 76%.

The advantages of such combination regimens include a broad antimicrobial spectrum, minimal emergence of resistance during therapy, and the potential for synergistic activity against some gram-negative bacilli. Disadvantages include the toxicity generally associated with aminoglycosides (nephrotoxicity, ototoxicity) and lack of activity against many gram-positive organisms. Cancer patients are often elderly and are thus more susceptible to aminoglycoside toxicity. Many are already receiving other ototoxic and nephrotoxic drugs (amphotericin B [Fungizone], cisplatin [Platinol], cyclosporine [Sandimmune]), and administering aminoglycosides to these patients increases the risk of toxicity.

Double Beta-Lactam Combinations: Since beta-lactam antibiotics were found to have more consistent activity than aminoglycosides in neutropenic patients, regimens combining two beta-lactams were devised in an attempt to retain the advantages of combination therapy while avoiding aminoglycoside toxicity. Using a cephalosporin in combination with a carboxypenicillin (carbenicillin [Geocillin], ticarcillin) provided a broad-spectrum regimen with activity against organisms such as Klebsiella species, which were resistant to the carboxypenicillins. These broad-spectrum regimens were shown to be as effective as aminoglycoside-based regimens [18].

With the availability of the ureidopenicillins (which are active against Klebsiella species) and the extended-spectrum cephalosporins (some of which can be used as single agents in neutropenic patients), the rationale for double beta-lactam combinations may need to be reexamined. Nevertheless, a large number of double beta-lactam combinations, including cefoperazone plus mezlocillin, cefoperazone plus piperacillin, ceftazidime plus piperacillin, ceftazidime plus ticarcillin/clavulanate (Timentin), and cefoperazone plus aztreonam (Azactam), have been found to be highly effective and well tolerated by patients [19-21].

The limitations of double beta-lactam combinations include their relatively high cost, the rare possibility of antagonism, and the occasional emergence of resistant organisms such as Enterobacter and Citrobacter species. These combinations are also less than optimal against some currently prevalent gram-positive organisms (coagulase-negative staphylococci, methicillin-resistant staphylococci, and some viridans streptococci), but current evidence indicates that the addition of specific therapy (vancomycin) when such organisms are isolated or strongly suspected is almost always successful against the infections.

Vancomycin-Containing Combinations: Due to the resurgence of resistant gram-positive organisms in most cancer treatment centers, beta-lactam agents such as ceftazidime and aztreonam (with or without an aminoglycoside) have been evaluated in combination with vancomycin [22-24]. Although these regimens are effective, there are conflicting opinions regarding the initial use of vancomycin. Including vancomycin in the initial regimen may provide effective treatment for many gram-positive infections earlier in the course of a febrile episode, thus avoiding the need to wait for culture results or a clinical response. Vancomycin-containing regimens have been associated with shorter duration of fever (9 days vs 14 days) and quicker defervescence (61% within 24 hours vs 21% within 24 hours) in patients with gram-positive infections [25]. However, as a result, many patients receive vancomycin without a clear indication.

Another approach is to add vancomycin to the regimen only if gram-positive bacteria have been isolated and no clinical response has occurred after a few days of therapy. Several studies have shown that this approach is not associated with increased mortality and that its advantages include limiting the cost of therapy, avoiding vancomycin toxicity, and possibly reducing the potential for vancomycin resistance.

It is prudent to use vancomycin initially if an infection with methicillin-resistant staphylococci is strongly suspected or if these staphylococci are frequently isolated in the institution. There is also some evidence that infections caused by alpha-hemolytic (viridans) streptococci might respond better if treated initially with vancomycin. Otherwise, the addition of vancomycin to regimens is usually adequate if gram-positive organisms are isolated and the patient is not responding to existing therapy.

Monotherapy: The availability of broad-spectrum cephalosporins and carbapenems has made it possible to evaluate initial therapy with a single agent. Several recent studies have shown that single-agent therapy is safe and at least as effective as aminoglycoside-containing regimens or double beta-lactam combinations [15,17,26]. Winston and colleagues compared cefoperazone and ceftazidime, each combined with piperacillin, with imipenem alone in febrile neutropenic patients. The two double beta-lactam regimens were associated with response rates of 74% and 75%, respectively, while the response rate with imipenem alone was 82% [19]. Imipenem was also shown to be as effective as two aminoglycoside-containing combinations, ceftazidime plus amikacin and imipenem plus amikacin, in a study from M.D. Anderson [17]. This study also demonstrated that monotherapy with imipenem was superior to that with ceftazidime (72% vs 59% response rate).

The role of the extended-spectrum cephalosporins for single-agent therapy needs to be reexamined since they are only moderately active against many gram-positive organisms, and there are increasing reports of the emergence of resistance to these drugs among gram-negative bacilli such as Enterobacter and Klebsiella species. Patients on monotherapy need close monitoring for lack of response, emergence of resistance, or development of superinfections.

Other Approaches: The availability of newer broad-spectrum quinolones, such as ciprofloxacin (Cipro) and ofloxacin (Floxin) has made it possible to evaluate combinations of these agents with other antibiotics for febrile episodes in neutropenic patients. Ciprofloxacin has been combined with aminoglycosides, beta-lactam agents, and vancomycin and has also been used as a single agent [27-31]. Initial results with quinolone-containing combinations are promising, but further clinical experience will be necessary before they can be considered standard therapy. Currently available quinolones should not be used as single agents, because many staphylococci are now resistant to them and because they have limited activity against streptococci. The therapeutic use of quinolones also is limited by their widespread administration for prophylaxis against infection.

One approach to achieving maximal initial therapeutic effect and reducing toxicity is to initiate therapy with an aminoglycoside-containing combination and to discontinue the aminoglycoside after 72 to 96 hours. However, one study conducted by the European Organization for Research and Treatment of Cancer (EORTC) showed reduced efficacy in patients who were treated with a short-course combination regimen [16]. This approach needs further evaluation and should not be abandoned before a definitive study evaluating its role has been conducted.

Another approach is once-daily administration of the aminoglycoside rather than conventional (three-times-a-day) administration. This approach needs fuller evaluation in neutropenic patients.

Not all neutropenic patients have the same risk for developing infections or infection-related complications. Recently, investigators from the Dana-Farber Cancer Institute have developed a clinical model for predicting the medical risk of cancer patients with fever and neutropenia [32,33]. Using this model, four risk groups were identified. Patients in the highest risk group were those who had already been hospitalized when they developed fever. The incidence of serious complications in these patients was 34% and the mortality rate was 23%. At somewhat lower risk were outpatients with concurrent comorbidity (eg, hypotension, bleeding, altered mental status, hypercalcemia) or uncontrolled cancer. However, approximately 40% of febrile neutropenic patients were considered “low-risk.” These were outpatients without comorbidity and with cancers that were responsive to antineoplastic therapy. Only 2% of these patients developed complications, and none died.

At M.D. Anderson, we have treated low-risk neutropenic patients with either an intravenous regimen (aztreonam plus clindamycin) or an oral regimen (ciprofloxacin plus clindamycin) without hospital admission [34]. Patients with significant infections and the elderly were not excluded, and in our initial trial 39% had microbiologically documented infections. The overall response rates were 88% for the oral regimen and 95% for the intravenous regimen, producing a combined response rate of 92% for outpatient antibiotic therapy. No patients developed hypotension or septic shock, and there were no infection-related deaths. Three patients on the oral regimen developed reversible acute renal failure.

In an ongoing follow-up trial of outpatient/home antibiotic therapy, a response rate of 90% was achieved using the same intravenous regimen or a slightly different oral regimen (ciprofloxacin plus amoxicillin/potassium clavulanate [Augmentin]). No serious complications and no infection-related deaths have occurred in this trial to date [35].

Our experience indicates that with careful patient selection, appropriate antibiotic therapy, and close patient follow-up, low-risk febrile neutropenic patients can be treated safely without admission to the hospital. Although this approach is currently not considered standard practice and needs to be more thoroughly evaluated, it results in a considerable reduction in the cost of therapy, better utilization of resources, improved quality of life for patients and families, and the potential for reducing nosocomial superinfections caused by resistant bacteria and fungi.

Duration Of Therapy

The optimal duration of antibiotic therapy for febrile neutropenic patients continues to be debated. Some experts recommend continuation of therapy until the resolution of neutropenia, even if a prompt response renders the patient afebrile [36]. This approach requires prolonged administration of broad-spectrum antibiotics and probably increases the potential for the development of superinfections caused by resistant bacteria or fungi. It may also increase drug toxicity and the overall cost of therapy due to prolonged hospitalization.

Another approach is to discontinue antibiotic therapy in patients who have been treated for a minimum of 7 to 9 days, are clinically stable, have no evidence of active infection, and have been afebrile for 4 to 5 days but have persistent neutropenia. At M.D. Anderson, antibiotic therapy has been discontinued in stable, afebrile but neutropenic patients for the past 20 years, with resulting favorable response rates and low levels of superinfection and relapse [3].

Other Therapeutic Modalities

About 15% to 20% of infections in neutropenic patients fail to respond to antimicrobial therapy. In most cases, profound neutropenia persists, and patients remain febrile despite adjustments in antibacterial therapy and the addition of an antifungal agent. The role of granulocyte transfusions in such patients has been evaluated, with conflicting results. This approach has largely been abandoned due to technical problems, the incidence of reactions, failure to demonstrate a clear therapeutic benefit, and the potential for transmitting infections such as cytomegalovirus from the donor to the recipient.

The hematopoietic growth factors and other cytokines may yet play a significant role in the prevention and treatment of infections in neutropenic patients. These agents produce both quantitative and qualitative effects that could be beneficial. Granuloctye-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) promotes the production of neutrophils and mononuclear cells. Granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) and macrophage colony-stimulating factor (M-CSF) are narrower in their spectrum of activity, promoting the production of neutrophils or of mononuclear cells (ie, monocytes and macrophages) alone. The hematopoietic growth factors and other cytokines may act independently or in concert to improve the phagocytic functions of neutrophils and mononuclear cells against specific bacterial and fungal pathogens [37].

A number of studies with GM-CSF and G-CSF in patients with solid tumors, leukemia, and autologous bone marrow transplantation following cytotoxic chemotherapy have shown that patients receiving these agents have a reduced period of neutropenia, decreased number of days with fever, and fewer defined infections [38-44]. These agents should not be used routinely in patients who are neutropenic for less than 10 days, since the risk of infection in such patients is smaller and the response to conventional antibiotic therapy greater than in patients with more prolonged neutropenia [45].

Prevention of Infection

The high frequency of infection in cancer patients with myelosuppression has led to the development of programs for preventing infection. The two main strategies used are directed toward suppressing the endogenous microflora (from which up to 80% of infections in neutropenic patients arise) and preventing the acquisition of new organisms from environmental sources (Table 4). The former objective is usually achieved by administering prophylactic antibiotic regimens during periods of myelosuppression. The potential adverse effects of antimicrobial prophylaxis must be measured against its benefits. Many experts believe that the use of prophylactic antimicrobial regimens tilts the balance toward more resistant components of the bacterial and fungal flora, and these regimens generally have not been associated with a reduction in mortality.

The acquisition of new organisms from environmental sources can to some extent be prevented or reduced by various techniques, including strict hand-washing precautions, the use of well-cooked diets (which reduce contamination with gram-negative bacteria), and various isolation techniques or protected environments. In some instances, appropriate and effective prophylaxis against infection can obviate empiric therapy [46,47].

Summary

Infection continues to be a serious problem in patients with profound neutropenia. Advances in antibacterial therapy have enabled us to treat most common bacterial infections successfully. However, the spectrum of bacterial infection in these patients continues to change, requiring continued vigilance and the development of new strategies for infection prevention and therapy. The emergence of multidrug-resistant organisms will continue to challenge us for years to come. Generally, we need to focus more on infection prevention, as opposed to the treatment of established infections.

References:

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