Current Issues in the Treatment of Resistant Bloodstream Infections

Introduction

Many hospitals and cancer treatment centers in the United States and Europe are now routinely reporting an increase in the proportion of bloodstream infections caused by gram-positive bacteria.[1-4] Gram-negative pathogens were previously the most frequently isolated organisms causing infections among cancer patients, but in recent years there has been a progressive increase in the isolation of gram-positive species. Gram-negative species, although less frequently isolated, remain a significant source of infection.

The shift to a gram-positive pathogen dominance is in part the result of changes in treatment practices and in the patient populations. For example, the practice of using quinolones prophylactically has been noted to increase the occurrence of infections due to gram-positive pathogens.[5] The use of indwelling central venous catheters for drug delivery is also associated with an increased incidence of gram-positive infection among immunocompromised patients.

Antimicrobial Resistance Continues to Rise

Centers across the United States now routinely report increasing antimicrobial resistance among many pathogens, including those most often implicated in bloodstream infections of immunocompromised patients. Geographic variation in resistance levels and patterns do exist, but the overall trend confirms the increasing ability of bacteria to evolve new resistant species. Antimicrobial resistance is a local phenomenon and also a class of treatment phenomenon. Several strains are now partially or fully resistant to standard, broad-spectrum antibiotics, and to newer drugs in the same classes. Resistance is also emerging to relatively new drugs representing novel structural classes, such as the streptogramin combination, quinupristin/dalfopristin (Synercid).

In the United States, methicillin resistance among Staphylococcus aureus was reported to average 29% nationwide in 1999, and almost 80% for coagulase-negative species of staphylococci.[3] Whereas vancomycin(Drug information on vancomycin) was able to control staphylococcal, streptococcal, and enterococcal infections a decade ago, the average nosocomial resistance among enterococcal species in the United States in 1999 has risen to 18% and is higher (30%) among hematology/oncology patients.

 Enterococcal infections in immunocompromised patients are of especially grave concern because these species are relatively poorly controlled by other drugs that are currently available. Antimicrobial resistance rates in Europe are generally lower than the rates of resistance reported for hospitalized patients in several studies from the United States.[6] In contrast, colonization of nonhospitalized, healthy individuals in Europe with glycopeptide-resistant enterococci has been reported to range from 2% to 12%, compared to a virtual absence of such resistance in the community sector in the United States.[6]

The likelihood that attempts to combat bacteria have inadvertently become the source of selection for resistance mechanisms emphasizes the fact that drug choice and therapeutic regimen design must be made with a knowledge of antibiotic resistance patterns, and that efforts to minimize unnecessary antibiotic exposure must be redoubled.

Standard Empiric Therapy and Individualized Treatment

Patients with neutropenia and presumed or documented infection require immediate antimicrobial treatment. Empiric antibiotics remain the standard of practice, and will continue to be until identification and characterization of bloodstream isolates become readily available. Ideally, the choice of antibiotics would be pathogen-specific; empiric choices must be based on knowledge of current, institution-specific patterns of microbial prevalence and resistance and the pathogens most likely to cause infection.

Many institutions provide care for patients from a wide geographic area and are less able to rely on nosocomial patterns alone to predict antimicrobial susceptibility patterns of the possible causative pathogens in a given individual. Antibiotic pressures from communities also contribute to the resistance pattern.

Each patient presents his or her own unique history of previous antibiotic exposures, co-morbidities, pathogen colonizations, risk factors, and medication intolerances. The design of a regimen should take into account as many of these variables as possible. For example, glycopeptides (ie, vancomycin) generally are not used as initial treatment for a febrile episode. Beta-lactams are the preferred agents, unless the patient has a history of methicillin-resistant S aureus (MRSA), is known to be colonized by antibiotic-resistant streptococci or enterococci, is receiving high-dose mucositis-inducing chemotherapy, or has a clinically significant catheter-site infection.

The Trend Toward Outpatient Treatment

Traditionally, patients with fever and neutropenia have been hospitalized to receive intravenous antibiotics and then discharged at the completion of a successful treatment course. Patients remained hospitalized even when their fever had quickly resolved (within a few days). It is now considered possible to discharge patients who experience rapid defervescence, especially those with resolving neutropenia, to continue their antibiotic regimen on an outpatient basis. Studies that have evaluated an outpatient treatment approach find this a safe and effective alternative for low-risk patients.[7-9] “Low-risk” patients are usually those who are clinically stable, have no major co-morbidities and have responding cancer. When such “low-risk” patients have received ambulatory treatment, the risk of infection-associated complications and deaths has been low.[7-9]

The success of ambulatory therapy depends on being able to accurately identify low-risk patients and having an effective ambulatory infrastructure to care for patients 24 hours per day, 7 days a week. Also important is the ability of the patients to get to the emergency center easily and quickly, should their clinical condition change. Thus, while this practice is theoretically appealing and is supported by a small number of clinical trials, successful implementation at most institutions will require development of the appropriate infrastructure for emergency outreach and management. Treatment centers or clinics that currently provide such highly accessible outpatient services appear to be very successful and patient satisfaction seems high.

Cost-Effectiveness

The perceived cost-effectiveness of ambulatory treatment of fever and neutropenia has yet to be demonstrated in practice. A single week-long hospital stay may turn out to be less expensive than outpatient care if the latter requires emergency room visits for poorly controlled infection. Finally, the availability of orally active antibiotics with good gram-positive and gram-negative pathogen coverage is important for the success of ambulatory antibiotic therapy in the febrile hematologic/oncologic patient.

Although patients may be discharged on parenteral antibiotics, the benefits of orally active agents are obvious. In this regard, linezolid(Drug information on linezolid) (Zyvox) appears to be the first option of an antibiotic that is active following both parenteral and oral administration, and has excellent activity against gram-positive infections. The bioavailability of linezolid in the setting of mucosal disruption caused by chemotherapy-induced mucositis must still be investigated.

A Need for New Antibacterial Drugs

Empiric antibiotic treatment for most patients with fever and neutropenia is with high-dose, broad-spectrum monotherapy or antibiotic combinations.[10] Individual practitioners’ preferences as to specific drug choice vary widely. Three recommended approaches are: monotherapy with either a carbapenem or an extended-spectrum antipseudomonal cephalosporin; combination therapy using an aminoglycoside and an antipseudomonal penicillin or cephalosporin, or a combination of ciprofloxacin(Drug information on ciprofloxacin) (Cipro) with piperacillin(Drug information on piperacillin) (Pipracil). Any of the preceding regimens may be combined with intravenous vancomycin in select clinical situations.[10]

In many cases, such treatment adequately manages febrile episodes, even in cases in which in vitro resistance of a strain would indicate a lack of drug efficacy. If fever does not resolve early (within about 48 hours), changes in the initial regimen may be effective.

Antimicrobial resistance is of concern and limits the efficacy of antibiotics that have been used in the past. For example, the growing resistance to glycopeptides (ie, vancomycin) among enterococcal strains, and the potential fatality associated with such resistant infections, has alerted most clinicians to the need to use care in prescribing this class of antibiotics. Fortunately, new drugs are being developed that have excellent activity among many gram-positive pathogens, with minimal or no inherent resistance.

The streptogramin drug combination quinupristin/dalfopristin still has relatively high activity in most bacterial species, although resistance is emerging, and its activity against Enterococci faecalis is poor.[11] Glycylcycline derivatives (tetracycline class), and new drugs in the macrolide/ketolide and carbapenem classes, are being tested as possible additions to the antibiotic armamentarium.

Another new class of drugs, the oxazolidinones, which includes linezolid, has shown excellent early activity, including activity among multidrug-resistant gram-positive species.[12, 13, 14] The fact that the oxazolidinones are synthetic agents unrelated to any known class of available antibiotics suggests that the development of resistance may be retarded. Linezolid has been found to be active against clinically significant gram-positive species, including methicillin-resistant S aureus, vancomycin-resistant enterococci, and even penicillin-resistant Streptococcus pneumoniae, with no evidence of in vitro resistance or cross-resistance with other antibiotic classes.[15]

Reducing Antimicrobial Drug Use

It now is clear that antibiotic usage can exacerbate resistance among bacteria. Greater exposure to antibiotics, particularly among hospitalized populations, is associated with the emergence of resistance to specific antibiotics and to other agents in the same antibiotic class. The practice of prophylactic antibiotic use also may alter pathogen species mix and influence the emergence of resistant strains. While prophylactic treatment is important in some cases (eg, transplant recipients), it should be administered with a recognition of the risk of resistance.

Balancing the need for adequate antibiotic use, control of bloodstream infections, the prevention of antibiotic overuse, and associated facilitation of resistance is an ongoing struggle. One way to reduce the incidence of resistance is to reduce the use of specific antibiotics, particularly glycopeptides. This can be accomplished with an awareness of the problem and determination within the institution and practitioners to limit these drugs for only those cases in which they are specifically indicated.

Recent trials have shown that using drug combinations that include piperacillin/tazobactam (Zosyn) as empiric therapy can reduce the need for glycopeptides and decrease glycopeptide resistance. [16] A switch in treatment away from glycopeptides or cephalosporins can also reduce the incidence of resistant strains.[17,18] The use of alternate new antibiotics, such as quinupristin/dalfopristin (a streptogramin antibiotic), linezolid (an oxazolidinone), and glycylcyclines (new derivatives of tetracycline(Drug information on tetracycline)), may be other clinically important options.

Standard infection control measures are other strategies that must not be overlooked, and include careful hand-washing by all staff who come into contact with patients, meticulous catheter insertion and maintenance care, and isolation techniques (for example, through the food chain) for patients known to harbor antibiotic-resistant pathogens (ie, MRSA, VRE, etc.).

Conclusions

Because empiric therapy is still the mainstay for treatment of fever and neutropenia in immunocompromised cancer patients, knowledge of pathogen prevalence and resistance patterns will continue to be essential. The accumulation of antimicrobial resistance via multiple mechanisms will require the implementation of consistent infection control measures, appropriate antibiotic usage, plus the continued development of novel antibiotics. In the foreseeable future, this avenue of treatment will be the only reliable protection against fatal infection for high-risk, neutropenic patients. Careful risk assessment and, when possible, patient-specific and pathogen-specific treatment can reduce excessive antimicrobial use and inhibit the development of resistance.

Although most patients with fever and neutropenia will continue to receive empiric antibiotics in a hospital setting, there is a trend, particularly in the United States, to treat “low-risk” patients who are expected to have a low incidence of complications in an outpatient setting. Once-daily dosing, the availability of antibiotics with long biological half-lives, and antibiotics with both oral and parenteral formulations facilitate both inpatient and outpatient therapy. The desire of many patients to return to a home setting as soon as possible is one factor that is fueling the shift to ambulatory care for low-risk patients. However, there are a number of considerations before ambulatory antibiotic therapy can become a successful strategy in the management of such patients, including an infrastructure to provide 24-hour emergency treatment as needed, and the ability of ambulatory patients to reach such centers quickly.

In the future, our attention must continue to be focused on minimizing inappropriate antibiotic use, while maintaining (and improving) our awareness of pathogen prevalence and resistance patterns. The value of standard infection control measures cannot be underestimated as a very effective means to reduce the need for treatment and transmission of resistant strains (Table 1).