The judicious use of antibiotics to conserve efficacy is difficult…

Oct. 1, 2011

A baby girl born in 1900 had a life expectancy of fewer than 40 years. Today, a baby girl can expect to live beyond the age of 80. A major reason for this doubling of life expectancy was the development of antibiotics. When penicillin was introduced, it was a wonder drug, saving lives and dramatically improving patient outcomes. Mass production of penicillin and subsequent antibiotics resulted in ready access to relatively safe and inexpensive therapy, which in turn changed the perspective of doctors and patients about infectious diseases. Patients came to expect antibiotics, a trend that has proven hard to reverse. For physicians, it was often easier to write a prescription than to educate patients about antibiotics’ lack of efficacy in viral diseases and the dangers of over-prescribing antibiotics.

As common pathogens such as Escherichia coli and Staphylococcus aureus developed resistance, new antibiotics were developed to treat them, and doctors changed their prescribing patterns accordingly. These newer antibiotics were typically active against a broader spectrum of bacteria. Use of broad spectrum antibiotics allowed treatment of resistant strains, but it also contributed to the development of even more resistance. As multi-drug resistant strains emerged and treatment success became less assured, healthcare professionals began to understand that inappropriate use of antibiotics (too little, too much, too often, wrong spectrum) drives emergence of resistant organisms. Physicians know that many infections are of viral origin and that antibiotics are unnecessary. They recognize that overuse of antibiotics leads to the emergence of resistance and the potential for antibiotic side effects. They know that unnecessary antibiotic prescriptions add cost to the healthcare system. They have read the guidelines on appropriate treatment of infections. They want to do what is best for their patients. Yet they continue to prescribe antibiotics for the majority of patients with presumed infections, because of uncertainty and the pressure of time. When physicians first evaluate a patient, they have access to only a few diagnostic tools. Usually, they do not know for sure that the patient has an infection–much less the causative agent. They cannot delay treatment, as time to receipt of appropriate antibiotics is a major factor in successful outcomes. So physicians establish a probable diagnosis and empirically select the most appropriate therapy, which is often broad spectrum. In order to appropriately limit the prescription of antibiotics, physicians need better tools to assist them in making the diagnosis of infections sooner, preferably at the initial patient contact.

Diagnostic microbiology has come a long way in the years since penicillin was introduced. Today, identification and antibiotic susceptibility testing (ID/AST) is automated, miniaturized and very fast. Isolation of routine pathogens can be completed in hours as opposed to the days and even weeks that were previously required. Blood cultures are automated, significantly increasing both speed and accuracy. Today’s manual methods are faster, easier and highly accurate. However, most diagnostic microbiology is growth-based, and all growth-based microbiology takes time. Thus the results are most commonly used to confirm, rather than to make, the initial diagnosis.

Rapid diagnostic testing has been developed for a few specific pathogens (e.g., Streptococcus pyogenes, Legionella pneumophila, Streptococcus pneumoniae, influenza) and has the potential to shorten the time to diagnosis in some cases. Rapid panels for viral meningitis have enhanced treatment decisions, especially in children. Molecular testing for MRSA and multiplex virology testing are also available. Molecular identification directly from blood samples for a limited panel of organisms has been developed, although it is not currently FDA cleared. However, the advances in molecular and genetic technology that have revolutionized the research laboratory have been slow to substantively impact the clinical laboratory. Most of the tests that have been commercialized are moderately expensive and many require investment in new instrument platforms. Even if pathogens can be identified rapidly, antibiotic susceptibility testing still requires isolation of the organism.

For most of these rapid tests, positive impact on physician prescribing behavior has not been demonstrated, in large part because there remains substantial uncertainty. For example, it is possible to establish the presence of a respiratory virus by commercially available PCR, but not all possible respiratory viruses are on the menu and the tests are not 100 percent sensitive. So a negative test does not rule out a viral infection. Conversely, the presence of a respiratory virus does not exclude the possibility of a secondary or co-existing bacterial infection. The presence of one bacterial pathogen from a limited molecular menu does not rule out the presence of a second one that is not on the menu, as mixed infections do occur. Some bacteria (e.g., S pneumoniae) can cause serious disease but can also colonize the upper airway. In the absence of a very extensive menu and some indication of pathogenicity, the physician remains uncertain and often opts to treat with empiric broad-spectrum antibiotics.

There is still the promise of new diagnostic technologies, but in the meantime, pathogens are developing resistance and few new antibiotics are on the horizon to treat them. There are things that laboratories can do now to help prevent and even decrease resistance. They involve adequate staffing, reasonable proximity, maximizing the use of currently available tests, and judicious use of new tests and technology.

Make full use of the technology currently in the laboratory.

Some ID/AST instruments allow for automated reporting of results. Judicious use of this feature can decrease time to results for a large number of cultures.

Provide adequate staffing 24/7 to process positive blood cultures immediately and perform, interpret, and report gram stains on newly received specimens.

Optimize the timing of reporting so that results are available to physicians when prescribing decisions are made.

A properly executed gram stain of a properly collected sputum sample can provide significant guidance to physicians evaluating a patient with respiratory tract symptoms, but only if the results are available in a reasonable timeframe.

Most physicians do not want to be alerted after hours for a routine ID/AST result on a hospitalized patient who is doing well. However, those results reported after hours will be available for early morning rounds and are much more likely to impact treatment decisions than results available just a few hours later.

At the time a positive blood culture is reported, the physician often makes a decision to alter antibiotic therapy based on gram stain morphology. Utilizing new technology such as MALDI-TOF, laboratories will soon have the ability to report the actual identity of the organism. Combined with access to the current institutional antibiogram, early identification facilitates selection of more narrow spectrum agents.

Make judicious use of newly available technology and tests.

Fungal infections are on the increase. Antifungal susceptibility testing is now standardized (CLSI and EUCAST) for many common species and tests for yeast are commercially available. Physicians can now choose from several antifungal drugs in three different classes. Routine reporting of antifungal susceptibility test results can improve outcomes and prevent emergence of resistance.

Biomarker tests such as procalcitonin may assist physicians in assessing the probability of bacterial infection and the risk of progression to severe sepsis. To maximize utility, the result must be available in a reasonable time frame 24/7.

MALDI-TOF is expected to provide accurate rapid identification of at least 85 percent of organisms isolated in clinical laboratories. Commercial instruments in development are currently undergoing the FDA clearance process.

Present the results in a way that maximizes understanding of them.

Many laboratories report only S/I/R susceptibility results. The information contained in the actual MIC is lost. Combining a visual presentation of the MIC result with relative proximity to the susceptible and resistant break points can help knowledgeable physicians make more effective antibiotic choices.

If using technology such as MALDI-TOF to report identification results substantially sooner than susceptibility results, provide ready access to the institutional antibiogram for that organism to facilitate antibiotic selection.

Educate the medical staff about the expected time to results, use of the results, and the impact of new tests.

Many physicians assume culture results will take 4 to 6 days and only actively seek them earlier if their patient is not adequately responding to empiric therapy. If the laboratory commits to staffing and technology that allows more rapid reporting, physicians can expect to use the results in treatment decisions earlier in the course of therapy.

Discovery and widespread availability of highly effective antimicrobial drugs stands as a major accomplishments of the 20th century. However, we can no longer count on the imminent development of ever more potent antibiotics. To maintain the effectiveness of these wonder drugs, we must use them judiciously.

Cynthia L. Fowler, MD, is senior medical director. global medical affairs, bioMerieux, Inc.