Clinically Relevant, Cost-Effective Clinical Microbiology ...

MICROBIOLOGY AND INFECTIOUS DISEASE Review Article

Clinically Relevant, Cost-Effective Clinical Microbiology

Strategies To Decrease Unnecessary Testing MICHAEL L. WILSON, MD

It has long been evident that laboratory tests are overused.Until recently, however, efforts to curb unnecessary laboratory testing were undermined by lack of incentives for change and because of inability to predictably modify physician test ordering patterns. Ongoing changes in health care financing have changed this. First, reimbursement for laboratory tests has decreased, particularly for capitated managed care systems. Second, some health care systems have implemented utilization reviews designed to limit inappropriate laboratory testing. Third, laboratory resources have decreased to the point where unnecessary testing has become an unaffordable excess. Last, governance changes in health care organizations have enabled some laboratories to control utilization in ways that were unthinkable a few years ago. Taken together, these changes provide an important opportunity to modify how laboratory tests are used.

As with any type of laboratory testing, the cost-effectiveness and clinical relevance of microbiology tests are affected by prelaboratory, laboratory, and post-laboratory variables. Prelaboratory variables include test ordering patterns, preanalytical test probabilities, and specimen collection, transport, storage, and processing. Laboratory variables include specimen processing, instrumentation, quality control, direct costs, test accuracy and precision, automation, assay time, and the level of expertise necessary to perform the test. Postlaboratory variables include test result reporting

From the Department of Pathology and Laboratory Services, Denver Health Medical Center, Denver, Colorado; and Department of Pathology, University of Colorado School of Medicine, Denver.

Manuscript received July 16,1996; revision accepted September 12,1996.

Address reprint requests to Dr Wilson: Medical Laboratories #0224, Denver Health Medical Center, 777 Bannock St, Denver, CO 80204-4507.

and interpretation. On the other hand, microbiology tests differ from other diagnostic tests. Issues unique to clinical microbiology include the need to propagate and work with live pathogenic microorganisms, the presence of contaminating indigenous or environmental flora, the time required to perform various tests to identify microorganisms, the need to test for antimicrobial susceptibility or resistance, and the need for special procedures and facilities to prevent laboratory-acquired infections. Each of these contributes to the cost of microbiologic tests and must be minimized or eliminated for tests to be cost-effective and clinically relevant.

Much has been written during the past 20 years about the issues of cost-effectiveness and clinical relevance in clinical microbiology. This article is written to review how microbiologists can reduce utilization of selected tests yet improve the clinical usefulness and cost-effectiveness of those tests. Strategies for implementing these changes are also reviewed.

GENERAL PRINCIPLES IN COST-EFFECTIVE, CLINICALLY RELEVANT

MICROBIOLOGIC TESTING

To be clinically relevant and cost-effective, diagnostic laboratory tests must have certain characteristics.

Clinical Relevance 1. Test results can be used to alter therapy. 2. Therapy can be altered based on test results. 3. Test results are available in a clinically relevant

time frame. 4. Tests are sufficiently sensitive and specific to pro

vide false-positive and false-negative results with frequency and consequences acceptable to users.

5. Test positive and negative predictive values are appropriate for the type of test and clinical setting.

6. Test results can be easily interpreted by users.

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Cost-Effectiveness 1. Test methodology is technically feasible, repro

ducible, reliable, and economical. 2. Test volume is sufficient to maintain performer

competence. 3. Test results are readily interpretable by laborato-

rians. 4. Test results are easily communicated. 5. Tests are sufficiently sensitive and specific to

provide false-positive and false-negative results with frequencies and consequences acceptable to users.

A point often overlooked is that tests are clinically relevant only when they are used correctly; overuti-lization, underutilization, and inappropriate use of tests all negate clinical usefulness. The same principle applies to cost-effectiveness. Thus the two concepts are not independent.

Several axiomatic principles guide clinically relevant, cost-effective microbiologic testing:

1. Only properly collected, transported, and labeled specimens are accepted for testing.

2. Appropriate specimens are tested; inappropriate specimens are rejected.

3. Only tests for which Food and Drug Administration (FDA) approval or clearance was granted are used.

4. Tests are performed and interpreted according to manufacturers' recommendations.

5. Only adequately trained and competent staff perform tests.

6. Tests are offered only if sufficient numbers are performed to ensure laboratory proficiency.

7. Test results are reported as soon as possible and by the most appropriate route. Whereas most test results can be transmitted by means of routine methods, certain test results (eg, cerebrospinal fluid [CSF] Gram's stain results) must be telephoned directly to the requesting physician.

Laboratories should accept only properly collected, transported, and labeled specimens, guidelines and recommendations for which are readily available from several sources1-3:

1. To minimize contamination, use strict asceptic technique when collecting specimens.

2. Collect specimens from anatomic sites most likely to yield pathogens and least likely to yield contaminants.

3. Tissue or fluid submitted for culture is always superior to material collected on swabs.

4. Submit adequate volumes of specimens. 5. Provide complete information on specimen requi

sition forms or during electronic order entry. 6. Notify the microbiology laboratory and surgical

pathology laboratory when both culture and histopathologic analysis are needed.

Laboratories should use explicit and unequivocal specimen rejection criteria, including the following3:

1. Unlabeled or improperly labeled specimens. 2. Specimens received in leaking, cracked, or broken

containers. 3. Specimens with visually apparent contamination. 4. Unpreserved specimens received more than 12

hours after collection. 5. Specimens not appropriate for a particular test.

Steps to make laboratory testing more clinically relevant and cost-effective can be taken during prelabo-ratory, laboratory, and postlaboratory phases of testing. Dur ing the p re labora to ry phase of test ing, laboratory consultation can be effective in improving laboratory utilization and in test selection, particularly in teaching hospitals. Effective laboratory consultation requires resources not available in many non-teaching hospitals. Physician education is largely ineffective as a means of limiting test utilization but can be used to in t roduce and gain s u p p o r t for changes. Optimizing specimen collection, transport, and storage helps ensure that only quality specimens are tested; these are crucial for good microbiologic testing. Last, it is generally accepted that utilization control strategies are the most effective means of controlling inappropriate testing. Developed in consultation with clinicians, these strategies consist of (1) defined tests (or test panels) that are offered routinely, with consultation only, or are not offered; (2) substitution of different tests from those ordered; and (3) use of alternative diagnostic methods. Laboratory information systems that accommodate expert pathways facilitate implementation of such strategies.

During the laboratory phase of testing, specimen rejection criteria must be rigorously enforced; it makes no sense to process specimens that do not meet these minimum criteria. Proper specimen storage is crucial, particularly for laboratories that are not staffed during all shifts. Programmatic test ordering, testing by specimen type and body site, and programmatic antimicrobial susceptibility testing should be standard practice

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in all laboratories. In programmatic test ordering, specimens are processed and tested according to type of specimen, how it was collected, and the body site from which it was taken. For example, requests for anaerobic bacterial cultures on CSF and voided urine generally should be ignored, whereas deep tissue specimens should be set up for anaerobic cultures even if not requested. As another example, antimicrobial susceptibility testing should be done according to algorithms; only rarely are requests for special susceptibility testing justified. Last, microbiologic-histopathologic correlation can help in ensuring proper specimen processing, interpretation of culture results, and rendering of preliminary diagnoses.

For the postlaboratory phase of testing, feedback to ordering physicians (laboratory utilization reviews) can be effective in reducing or modifying laboratory utilization, particularly when each physician's utilization pattern is presented in the context of those of a peer group. Laboratory consultation is also useful, particularly when test results are ambiguous, difficult to interpret, or the clinical relevance of a result is unclear. It is perhaps the best opportunity for teaching the correct use of laboratory medicine to house officers. Last, test result reporting must be prompt, easy to understand, and accompanied by necessary text explanations or verbal reports from the laboratory.

STRATEGIES FOR SPECIFIC TESTS

Inasmuch as the most effective method for improving clinical relevance and cost-effectiveness in clinical microbiology is to minimize unnecessary testing, laboratories need to develop specific strategies for different specimen types and tests. Herein are reviewed test utilization strategies for specific specimen types and tests, along with a review of one successful method for implementing these strategies. Other methods for improving the cost-effectiveness of clinical microbiology testing, although effective in some settings, are not reviewed.

Antimicrobial Susceptibility Testing

Antimicrobial susceptibility testing is among the more challenging tasks confronting modern clinical microbiology laboratories. Increasing antimicrobial resistance among common bacterial and fungal pathogens, a growing need for surveillance for emergence of resistant strains, emergence of new pathogens, introduction of new antimicrobial agents, new antimicrobial susceptibility test methods, and the need for more r ap id t u r n a r o u n d t ime have compl ica ted

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antimicrobial susceptibility testing and increased costs during an era when laboratory resources are stable or decreasing.

For common bacterial pathogens, clinical microbiology laboratories typically control antimicrobial susceptibility testing by (1) testing only certain antimicrobial agent-microorganism combinations; (2) selecting the method or methods to be used; and (3) reporting selective antimicrobial susceptibility test results. In other words, the decision of what to test, how to test it, and what to report is made by the laboratory and not by clinicians (except for consultation with the pharmacy, infectious diseases consultants, or other appropriate persons). In general, adherence to National Commit tee for Clinical Labora tory S tandards (NCCLS) guidelines ensures the most accurate, precise, and clinically relevant test results. This approach has obvious advantages and is a model for good laboratory practice. Performing tests by methods other than those approved by the NCCLS is strongly discouraged because the clinical relevance and accuracy of test results from such methods are unknown.

Antimicrobial susceptibility testing of other microbial pathogens is more problematic. For yeasts and molds, minimum inhibitory breakpoints have not been defined for antifungal agents, and the clinical relevance of antifungal suscept ibi l i ty test results is unclear.4 Although the NCCLS has a proposed method for susceptibility testing of yeasts,5 a commercial version has yet to be validated, and it is unlikely that standardized tests for yeasts will be widely used in the near future. A reliable method has not been developed for testing molds. Therefore, at this time laboratories should not routinely perform antifungal susceptibility tests or refer specimens to reference laboratories for testing. Such testing should be done only after consultation with the laboratory, because the clinical relevance of the test results, if any, is unknown.

The NCCLS, Centers for Disease Control and Prevention (CDC), Association of State and Territorial Public Health Laboratory Directors (ASTPHLD), and American Thoracic Society (ATS) have issued guidelines and recommendations for antimycobacterial susceptibility testing of mycobacteria.6-8 Antimicrobial susceptibility testing of Mycobacterium tuberculosis is standardized, and the performance characteristics of the various methods are well known, as is the need to test isolates from all pa t ients wi th tuberculosis . Because of the need for prompt isolation and identification of clinical isolates of M tuberculosis, laboratories receiving small numbers of specimens should refer all mycobacterial cultures to a reference laboratory.

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Laboratories receiving sufficient numbers of specimens to justify on-site testing should use a broth culture method such as the BACTEC 460 TB System (Becton Dickinson Microbiology Systems, Sparks, Md). Other new broth-based systems are now commercially available. The most rapid method for identifying isolates is nucleic acid probe hybridization (AccuProbe; GenProbe, San Diego, Calif). Although nucleic acid amplification techniques may become useful for detecting M tuberculosis in clinical specimens, recovery of isolates from cultures is still necessary for antimycobacterial susceptibility testing. As for isolating mycobacteria, antimycobacterial susceptibility testing is fastest when broth systems are used.

Routine antimycobacterial susceptibility testing of mycobacteria other than M tuberculosis is not recommended, because a standardized method has yet to be defined.6-8 In particular, testing Mycobacterium avium complex isolates is inappropriate, because "M avium complex (M avium or M intracellulare) isolates are resistant to all of the antituberculosis drugs routinely tested, and there are no convincing published data that demonstrate therapeutic success with these drugs even when in vitro tests indicate susceptibility to a specific drug. It therefore serves no useful purpose to pursue susceptibility against M avium complex."6 A possible exception to this is testing M avium complex isolates against the macrolide agents clarithromycin and azithromycin, although no method for testing M avium complex against macrolide agents has been approved by the NCCLS.

Special tests such as minimum bactericidal concentrations and serum bactericidal titers are not necessary for routine patient care. These tests often do not meet the criteria for clinical relevance because the results can be difficult to interpret, test results may or may not be useful in guiding patient care, and the methods are labor intensive and capricious.

Limitat ion of inappropr ia te test ut i l izat ion is accomplished by close interaction between the laboratory, pharmacy (or pharmacy and therapeutics committee), and appropriate staff physicians. Together, this group should determine which antimicrobial agent-microorganism combinations are to be tested and reported for isolates recovered from each type of specimen. In general, testing should be done in strict accordance with NCCLS, ASTPHLD, and CDC guidelines.6"10 Tables 1 and 1A from NCCLS documents M2-A5 and M7-A3 are the best and most current source of information for deciding which combinations to test and report. Similarly, limitation of laboratory workup is best achieved by adherence to NCCLS guidelines.

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Although data have been published that indicate that rapid reporting of antimicrobial susceptibility test results affects patient care,11 not all laboratories have the resources to do so. Moreover, as John Washington has written, "Microbiologists...need to recognize that having the technical capability to produce rapid results is not sufficient in and of itself to optimize therapy."12 To ensure that rapid antimicrobial susceptibility test results are both clinically relevant and cost-effective, microbiologists should test only isolates for which rapid test results are likely to affect patient care in a given setting. It would be inappropriate, for example, to perform rapid antimicrobial susceptibility tests on isolates recovered from outpatient urine specimens, because having the results in 4 to 6 hours rather than 24 hours is unlikely to affect patient care. On the other hand , rapid test ing for methicil l in resistance in Staphylococcus aureus blood isolates from patients in an intensive care unit could significantly affect both patient care and infection control measures.

Autopsy Cultures

The earliest reports of postmortem cultures are nearly a century old.13 Systematic analysis of the utility of these cultures was undertaken in the early part of this century and again in the 1960s and early 1970s. Since then, fewer than a dozen papers have been published on this topic. A critical review of this literature suggests that many tenets regarding postmortem microbiology are incorrect. For example, essentially no data have been published that validate the concepts of "postmortem transmigration" or "agonal invasion" of bacteria from the gut into surrounding tissues and to distant sites through the bloodstream; tissues that are not contiguous with a mucosal or cutaneous surface are sterile both during and after life; the duration of sterility has been documented as long as 30 days after death. The reason that a large proportion of postmortem cultures grow microorganisms is because they are contaminated during collection.

Despite this, routine collection of postmortem cultures persists. To reassess the clinical utility of postmortem blood cultures using modern blood culture techniques, Wilson et al14 undertook a retrospective review to determine whether postmortem blood cultures yield any information not known from ante-mortem blood cultures, the clinical setting, or autopsy findings. One hundred eleven autopsies with positive antemortem blood cultures were reviewed. Sixty (54%) had positive postmortem blood cultures despite a cause of death not related to infection. Fifty-four

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patients (49%) had antemortem blood cultures drawn in the 7 days before death, of which 34 (63%) were negative and 20 (37%) were positive. The 20 patients with true-positive antemortem blood cultures had the following postmortem blood culture results: 7 (35%) grew the same microorganism, 10 (50%) grew multiple microorganisms assessed to be contaminants, and 3 (15%) grew different microorganisms that were related to the patients ' illness but did not provide informat ion not a l ready known from clinical or autopsy findings. Ninety-one (63%) patients had no, negative, or contaminated antemortem blood cultures. Of these, 69 (76%) had postmortem blood cultures that grew contaminants and 22 (24%) had postmortem blood cultures that grew microorganisms that were of uncertain clinical importance. Taken together, these findings indicate that "postmortem blood cultures rarely, if ever, provide information that is not already known, can be interpreted, provide new insights into pathophysiology, or detect errors in therapy."14

Clinical microbiology laboratories should work closely with and educate pathologists regarding the limitations of autopsy microbiology, particularly postmortem blood cultures. Although published data are more limited for other specimen types, there is no a priori reason to expect lower contamination rates for specimens other than blood. Consequently, pathologists should limit the collection of specimens to those that are crucial to the autopsy. Cultures should be taken only if previously unsuspected or undocumented infection is found during prosection and if sterile specimens can be collected.

The laboratory should process postmortem specimens in the same way as contaminated antemortem specimens. Isolates are evaluated based on (1) the number of isolates recovered, (2) their relative quantities, (3) results of a direct Gram's stain, and (4) the source of the specimen. With rare exception, there is no point in testing for antimicrobial susceptibility or resistance, because the clinical relevance of postmortem isolates is usually unclear. If necessary, epidemiologic investigations are more reliably pursued using molecular techniques rather than by testing isolates to determine "antibiograms."

Bacterial Antigen Detection

A variety of products designed to detect minute quantities of bacterial antigens in CSF or urine have been developed and marketed. These bacterial antigen tests are intended to make the diagnosis of bacterial meningitis easier and faster. Initially done by counter-

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immune electrophoresis, commercial antigen detection methods typically use latex particle agglutination methods. During the last few years, published data have shown that these tests add little or nothing to what can be learned from CSF chemistry tests, cell counts, and Gram's stains for the diagnosis of bacterial meningitis.

The most comprehensive study of the clinical utility of bacterial antigen tests was by Perkins et al,15

performed at Duke University Medical Center and the Cook/Fort Worth Children's Medical Center. A total of 5,169 specimens were tested, including 2,236 tests on CSF, 2,907 tests on urine, and 26 tests on other body fluids. Fifty-seven (1.1%) tests were positive, of which 31 (54%) were false-positive, 22 (38%) were true-positive, and 4 (7%) were indeterminate. For the 7 (0.3%) positive CSF tests, 5 were true-positive and 2 were false-positive. For the 49 (1.7%) positive urine tests, 16 were true-positive, 29 were false-positive, and 4 were indeterminate. For the 22 total true-positive tests, chart review revealed that in no instance was clinical management changed on the basis of the test result. For all 7 patients who had true-positive CSF test results, Gram' stain of CSF was positive. For all 15 infants with positive urine bacterial antigen tests for group B streptococcus, group B streptococcal sepsis was suspected clinically and cultures of blood or amniotic fluid were positive. Although bacterial antigen tests are often ordered for patients who have received antimicrobial therapy, in this study no positive bacterial antigen test results were from patients whose cultures were negative because of antimicrobial therapy. Overall, 54% of test results were erroneous and 7% were of uncertain clinical importance. The authors noted that "the clinical impact of false-positive results, in contrast to true-positives, was substantial. These results led to subspecialty consultation, to lengthened hospital stay, to prolonged courses of antibiotic therapy, and in some cases to important clinical complications."15

As recommended by Perkins et al,15 laboratories should consider the criteria listed below: (1) not offering bacterial antigen testing, and referring specimens that meet these criteria to a reference laboratory; (2) performing bacterial antigen tests only with consultative approval; and (3) if tests are offered and performed, using sequential test ordering so that other clinically important tests are performed first (CSF Gram's stain, glucose, protein, and cell count). Most important, if Gram's stain of CSF reveals microorganisms likely to be the cause of meningitis, bacterial antigen testing is unlikely to provide any useful information. If bacterial antigen testing is performed, (1) bag collections of urine

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should not be accepted for testing; (2) the tests should not be offered as a panel; (3) tests should not be performed on CSF unless the cell count is abnormal, the Gram stain is negative, and CSF and blood cultures remain negat ive at 48 hours ; and (4) tests for Haemophilus influenzae type B (HiB) should not be requested or done for HiB-vaccinated children, because false-positive results can occur when specimens collected from vaccinated patients are tested for the presence of H influenzae antigens.15

Routine Blood Cultures

Most septic ep isodes are caused by common microbial pathogens such as S aureus, coagulase-negative staphylococci, streptococci, enterococci, members of the family Enterobacteriaceae, nonfer-mentative gram-negative bacilli, and yeasts. Septic episodes caused by fastidious bacteria and fungi are less common. Inasmuch as most of these pathogenic microorganisms can be recovered from commercial blood culture bottles, there is no reason to use more specialized blood culture methods for routine patient care. The most important variables in recovering microorganisms from blood and for interpret ing blood culture results apply irrespective of which blood culture method is used.

Number of Blood Cultures.—As shown by Washington16 and Weinstein et al,17 nearly all episodes of bacteremia or fungemia in adult patients can be detected with two or three cultures. This observation holds true even for patients with infective endocarditis, because one of the hallmarks of infective endocarditis is continuous bacteremia.17 Except in cases of suspected infective endocarditis, no more than two or three blood cultures should be submitted per septic episode. Practically speaking, this means that patients with suspected bacteremia or fungemia should have two or three blood cultures drawn initially, with additional blood drawn for culture if (1) the initial set of blood cultures is negative but the clinical setting continues to suggest sepsis; (2) infective endocarditis is suspected, in which case as many as four or five cultures may be necessary to rule out the possibility of contamination with common skin flora18; or (3) blood cultures for fastidious pathogens are determined to be appropriate. In the case of negative blood cultures in a clinical setting consistent with sepsis, the laboratory should be consulted regarding the use of special blood culture methods. Drawing excess blood cultures is expensive, increases laboratory work, increases the number of contaminant blood cultures, and contributes to nosocomial anemia.

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Blood Culture Contamination Rate.—Even with optimal disinfection and collection technique, 2% to 3% of blood cultures collected from peripheral veins are contaminated by skin flora. In settings in which many different persons are collecting blood cultures (eg, large hospitals, teaching hospitals, busy outpatient clinics), contamination rates can be much higher. Because only 8% to 10% of blood cultures are true-positive, higher contamination rates complicate interpretation of blood culture results. Blood culture contaminants also add to health care costs.19 Therefore, blood cultures should be collected from peripheral veins using recommended techniques. Whenever possible, blood cultures should not be drawn from indwelling vascular catheters, because these are more likely to grow contaminants.20,21

Blood culture contamination rates should be monitored as part of the clinical microbiology laboratory quality assurance program.

Volume of Blood Cultured.—The volume of blood cultured is the most important variable in the recovery of microorganisms from the blood of adult patients with sepsis.22-28 Whenever possible, 20 to 30 mL of blood should be collected per culture (ie, per venipuncture). Laboratories should monitor the volume of blood inoculated into each blood culture bottle as part of the clinical microbiology laboratory quality assurance program. Receipt of single or inadequately filled blood culture bottles should result in notification of the ordering physician that two or three adequately filled blood culture bottles should be drawn to evaluate each septic episode.29

Anaerobic Blood Cultures.—There is now a significant database regarding the issue of anaerobic blood cultures.30,31 Since the 1970s, when antimicrobial surgical prophylaxis became more refined, the incidence of anaerobic bac te remia has decl ined steadily. Consequently, for most routine blood cultures it may be better to inoculate the entire blood volume into two aerobic blood culture bottles, reserving use of anaerobic bottles for selected patients. Although this approach probably would increase microbial recovery, there are no published data regarding which, if any, patient groups would benefit from anaerobic blood cultures. Until such data are published, most laboratories will continue to perform both aerobic and anaerobic blood cultures for all patients.

Incubation and Testing.—For instrumented blood culture systems, the routine incubation and testing period can be limited to 5 days.32 For manual blood culture systems, a 7-day testing period probably is necessary for optimal microbial recovery, although incubating cultures beyond that period does not increase microbial

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recovery, even of fastidious bacteria.33 Neither blind nor terminal subcultures are necessary for bottles processed on most instrumented blood culture systems. For manual blood culture systems, either blind or terminal subcultures should be performed for optimal microbial recovery. The exception to this is with "biphasic" bottles, where a solid medium is incorporated into the bottle and provides a subculture as each bottle is processed.

Fungal Blood Cultures

In general, most aerobic blood culture bottles are adequate for recovering common yeasts such as Candida albicans. Anaerobic blood culture bottles will not reliably recover strictly aerobic microorganisms such as fungi (or Pseudomonas aeruginosa). Because of the growing incidence of and high mortality associated with fungemia, several manufacturers have developed commercial products designed to improve recovery of fungi from blood. Perhaps the best known is the lysis-centrifugation system (Isolator; Wampole Laboratories, Cranbury, NJ). This is a reliable method for routine fungal blood cultures and is the method of choice for recovering Histoplasma capsulatum. An alternative method is the BACTEC High-Blood-Volume Fungal Medium (HBV-FM; Becton Dickinson), which is superior to other methods for recovering fungi (although this medium will not reliably recover H capsulatum using routine test schedules).34 Blood culture bottles containing "resins" or similar products are another acceptable alternative for recovering common pathogenic yeasts.34

It is of interest that even for patients likely to have fungemia, approximately 75% of clinically important isolates are bacteria, not fungi.34 Consequently, in patients with suspected fungemia, blood for both fungal and routine bacterial blood cultures should be drawn.

A common practice on transplant units is to perform "surveillance" blood cultures, particularly for the p u r p o s e of de tec t ing fungemia caused by Aspergillus species. It cannot be overemphasized that, even in the most profoundly immunocompromised hosts (eg, bone marrow transplant recipients), laboratory detection of aspergilli in CSF, blood, or bone marrow is extremely rare. Moreover, interpreting cultures that do contain aspergilli is difficult because these fungi are among the most common environmental contaminants of microbiologic cultures.

Mycobacterial Blood Cultures

The clinical practice of performing two or three b lood cu l tu res per sept ic ep i sode is commonly

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applied to mycobacterial blood cultures, particularly to detect M avium complex bacteremia. As documented in two studies, however, most episodes of M avium complex bacteremia can be detected with a single blood culture.35'36 In both studies, the incremental increase in microbial recovery was 85% to 90% for one culture to 100% with two cultures. The second blood culture is generally not necessary, however, because (1) the clinical course of M avium complex bacteremia is more indolent than that of bacteremia caused by other bacteria or fungi, and (2) a second blood culture is not needed to interpret mycobacterial blood cultures (ie, mycobacteria are virtually never contaminants). Based on these principles, it is now our practice to draw single mycobacterial blood cultures and await the results before drawing additional blood specimens for culture.35

In a recent study, Wilson et al37 compared recovery rates from 7 H l l / 7 H l l - s e l e c t i v e biplates and Lowenstein-Jensen slants used in conjunction with BACTEC 12B vials processed on the BACTEC 460 TB System. A total of 5,399 specimens (all specimen types were included) were evaluated. For 578 specimens in which all three media were inoculated, 580 mycobacteria were isolated, including 277 (48%) M avium complex isolates, 230 (40%) M tuberculosis isolates, and 73 (12%) other mycobacterial isolates. The relative recovery rates for each medium are shown in Table 1. Given that mycobacterial growth can be detected earlier on plates, colonial morphologic features are much easier to see on plates, and because of the difference in recovery and contamination rates, we no longer use Lowenstein-Jensen slants as an adjunct to BACTEC vials.

In another study, Wilson et al38 (Table 2) determined the proportion, if any, of mycobacterial blood or bone marrow isolates recovered beyond the fifth or sixth weeks of incubation. Positive blood or bone marrow cultures processed during a 17-month period when BACTEC vials were incubated and tested for 6 weeks were reviewed retrospectively; the incubation period was then prolonged to 8 weeks during the subsequent 6 months to determine whether any additional isolates could be recovered during the seventh and eighth weeks of incubation. None were. Therefore, if the BACTEC 460 TB System is used to process 12B vials, mycobacterial blood cultures can be limited to 6 (or possibly 5) weeks of incubation and testing.

Cerebrospinal Fluid

Given the importance of prompt and accurate diagnosis of bacterial meningitis, CSF specimens should

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TABLE 1. RELATIVE RECOVERY RATES FROM MYCOBACTERIAL MEDIA

Test Result for 578 Cultures

Positive Negative Contaminated

Medium n % n % n %

12B vials 506 87 45 8 29 5 Biplates 469 81 95 16 16 3 L-J* slant cultures 230 40 111 19 239 41

Modifed from Wilson ML, Stone BL, Hildred MV, Reves RR. Comparison of recovery rates for mycobacteria from BACTEC 12B vials, Middlebrook 7Hll-selective 7H11 biplates, and Lowenstein-Jensen slants in a public health mycobacteriology laboratory. / Clin Microbiol. 1995;33:2516-2518.

*L-J = Lowenstein-Jensen.

TABLE 2. BLOOD AND BONE MARROW CULTURES: DAYS TO DETECTION OF GROWTH OF

MYCOBACTERIUM AVIUM COMPLEX

No. of

Specimens

Retrospective data 127 Prospective data 50

Mean

00

00

No. of Days

Median Mode

7 7 7 7

Range

1-34 3-22

Modified from Wilson ML, Stone BL, Hildred MV, Reves RR. Prolonged incubation of blood and bone marrow cultures in 12B bottles processed on the BACTEC TB System does not increase microbial recovery. Diagn Microbiol Infect Dis. 1996;25:113-115.

be treated with special care throughout all stages of specimen collection, transport, and processing. Care must be taken in collecting specimens to prevent contamination (and accidental inoculation of microorganisms into the spinal canal); specimens should be transported immediately to the laboratory; and processing should be done without delay. CSF should not be refrigerated except for aliquots to be used for viral cultures. Chemistry tests, cell counts, and Gram's stains should be performed and reported within 30 minutes of receipt. For Cryptococcus neoformans meningitis in patients with acquired immunodeficiency syndrome (AIDS), antigen testing is recommended for rapid diagnosis. For fungal and mycobacterial cultures, larger CSF volumes (up to 20 mL) are necessary to optimize microbial recovery.

Because central nervous system (CNS) tuberculosis is rare, mechanisms to screen out inappropriate test requests are necessary. The approach described by Albright et al,39 whereby CSF is held until screening tests are performed and the results indicate cultures are appropriate, is effective in reducing unnecessary

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tests.39 A similar approach, based on the same principle, is effective in reducing CSF-VDRL tests, most of which are inappropriate.40 As with any type of tiered testing system, the mechanism described by Albright and coworkers can be facilitated by use of computer expert pathways.

General Considerations for Processing Tissue and Fluid Specimens

Media.—Three issues regarding media warrant comment. First, microbiologists should restrict the number and type of media to those that are appropriate for the type of specimen and the pathogen or pathogens being sought by culture. Guides for media selection are available in most standard microbiology textbooks. Second, microbiologists should use the best media available. Although making media in-house is largely a luxury of the past, commercial media approach the same quality if they are fresh. Careful attention should be paid to out-dates and quality control. Third, some longstanding approaches to culture need to be abandoned. For example, routine use of a thioglycolate b ro th m e d i u m as an adjunct to other media is unwarranted for most specimen types. As reported by Morris et al,41 microorganisms recovered only from this medium are usually contaminants, and for those isolates categorized as true (not contaminants), only 11% resulted in a change in therapy or other pat ient management . Furthermore, some patients whose isolates were categorized as contaminants received inappropriate therapy for the contaminants. Because some specimen types were r ep re sen ted by small n u m b e r s , the authors of that study recommended that broth "backup" cultures be abandoned for all specimens with the exception of tissue specimens, CSF specimens from patients with CNS shunts, and continuous ambulatory peritoneal dialysis specimens.

Incubation.—Specimens should be incubated at the most appropriate temperature and for the length of time needed to recover the pathogen or pathogens being sought. In general, prolonging incubation times does not increase recovery of pathogens but does increase recovery of contaminants. The best example of this phenomenon is that of blood cultures, in which almost all clinically relevant isolates are recovered during the first 5 days of testing and almost all isolates recovered after that time are contaminants . Recently, Morris et al42 demonstrated a similar phenomenon with fungal cultures: routine incubation of fungal cultures beyond 2 weeks produces only small

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incremental increases in yield. In their study, 98% of yeasts were detected within the first 7 days of incubation, and 99% within 14 days; for molds, 81% were recovered within the first 7 days of incubation, and more than 96% within 14 days. For both yeasts and molds, none of the isolates recovered after the second week of incubation were considered clinically relevant . The only except ion to this is the the rma l dimorphs, which grow more slowly. In areas endemic for one of these fungi or for laboratories serving large numbers of immunocompromised patients, especially those with AIDS, certain specimens need to be held longer. As a general rule, however, fungal cultures can be discarded after 14 days of incubation.

Identification.—Many microbiologists use simple test schemes to identify microbial isolates. For example, with outpatient urine cultures, lactose-fermenting gram-negative bacilli that are spot indole-positive are almost certainly Escherichia coli. As another example, mixed bacterial flora isolated from an intraabdominal abscess may not need any identification other than what is seen on a Gram's stain of the smear; the results of the Gram's stain, coupled with clinical (eg, foul odor) and other laboratory data, are usually sufficient to guide therapy. The extent of identification for isolates recovered from each body site should be tailored to what is most clinically relevant.

Rapid Diagnostic Tests

Perhaps the most widely used commercial rapid diagnostic tests are designed to detect group A streptococcal antigens from patients with streptococcal pharyngitis. The multiplicity of commercial products, varying technologies used, differing clinical and laboratory settings in which they are used, and lack of clinical correlation make it difficult to interpret the published literature. In general, these products have test sensitivities in the range of 50% to 95%43 and test specificities approaching 100%. Because many of these products are expensive, routine throat cultures would have to be eliminated to make the rapid diagnostic test cost-effective. Since these tests have sensitivities too low to eliminate cultures, however, the only way that rapid diagnostic tests can be cost-effective is if the shortened turnaround time offsets the cost by means of other savings. This depends on the health care setting, the current prevalence of streptococcal pharyngitis in the patient population being served, the ease with which the product can be used and the results interpreted, and the ability of the user to generate reproducible test results.

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Rapid diagnostic tests have also been marketed for de tec t ion of g r o u p B s t rep tococca l an t igen in neonates with bacteremia. In a recent clinical trial,44

four commercial antigen detection assays were compared for their ability to detect antigen in concentrated and unconcentrated urine specimens. As with rapid diagnostic tests for detecting group A streptococcal antigens, these products were found to be highly specific but insensitive (sensitivities were much higher when concentrated urine specimens were used). Thus the same issues apply to these rapid diagnostic tests as for those used to detect streptococcal pharyngi t is , especially the issue of whether the products are sufficiently sensitive and specific to justify eliminating cultures. If cultures must be continued, these products are unlikely to be cost-effective in many settings.

In summary, many of the guidelines suggested for bacterial antigen tests apply to rapid diagnostic tests. Specifically, laboratories should consider offering them only after carefully evaluating (1) whether there is a clinical need for the test; (2) any published performance characteristics; (3) how easily the test can be used in a given setting; (4) the cost of using each test; and (5) the clinical impact, if any, of test results.

Sputum Cultures

Bartlett45 (Table 3) and Murray and Washington46

(Table 4) showed that the relative proportions of neutrophils and squamous epithelial cells present in sputum specimens can be used to determine whether specimens are contaminated with saliva and oral flora. This screening allows specimens to be processed or rejected based on results of a Gram's stain, which also provides information regarding the type of bacteria or fungi present in the specimen. It is difficult to imagine a more straightforward and simple test that is more useful. Screening sputum specimens by this method has become the s tandard of practice and should be used in every laboratory.

Flournoy et al47 evaluated the utility of using the re la t ive n u m b e r s of n e u t r o p h i l s vs a lveolar macrophages for assessing the quality of specimens submitted for bacterial culture. Their data suggest that absence of alveolar macrophages "is not a good criterion for ruling out...lower respiratory tract materials in expectorated specimens."47 Consequently, the criteria used for one test (assessing mater ia l for cytopathologic examination) do not necessarily apply when the same specimen is submitted for a different test (bacterial culture).

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TABLE 3. SPECIMEN REJECTION CRITERIA FOR EXPECTORATED SPUTUM (BARTLETT)

Grade

Neutrophils per low-power (10X) field <10 0 10-25 +1 >25 +2 Presence of mucus +1

Squamous epithelial cells per low-power field 10-25 - 1 >25 - 2

Total*

From Wilson ML. General principles in specimen collection and transport. Clin Infect Dis. 1996;22:766-777. Used with permission.

'Numbers of neutrophils and squamous epithelial cells are averaged based on examination of 20 to 30 separate low-power fields, and the total is calculated. Final scores of <0 suggest contamination with saliva or lack of acute inflammation.

TABLE 4. SPECIMEN REJECTION CRITERIA FOR EXPECTORATED SPUTUM (MURRAY AND WASHINGTON)

No. of Cells per Low-Power Field

Squamous Epithelial Cells

25 25 25

10-25 <10

Neutrophils

10 10-25

25 25 25

Perforin Culture

No No No No Yes

From Wilson ML. General principles in specimen collection and transport. Clin Infect Dis. 1996;22:766-777. Used with permission.

Havlik and Woods48 studied whether the rejection criteria used to screen sputum specimens submitted for bacterial cultures could be used to screen sputum specimens submitted for mycobacterial cultures. Of 391 specimens evaluated, 173 (44%) would have been rejected using standard criteria. A mycobacterium was isolated from 42 (24%) of these specimens and from 66 (30%) specimens that wou ld have been accepted for culture. The authors concluded that their policy "for rejection of sputum specimens submitted for routine bacterial culture should not be applied to those [sputum specimens] submitted for mycobacterial culture, unless it is possible to timely collect a subsequent sample from patients whose initial specimen is found to be contaminated with saliva."48 McCarter and Robinson49 arrived at the same conclusion but found that the presence or absence of neutrophils was

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"an effective method to evaluate the acceptability of sputum for mycobacterial smear and culture."

Among the most problematic of respiratory specimens are endotracheal suction aspirates. Even though expectorated sputum specimens have been screened for bacterial contamination for many years, similar criteria were not used for endotracheal suction aspirates until 1993, when Morris et al50 published results of an evaluation of 504 consecutive endotracheal suction aspirates using Gram's stain. Of the 504 specimens, 201 (40%) were Gram-negative. For the cultures of these 201 specimens, 40% were sterile, 48% grew normal flora, 5% grew 1+ normal flora plus 1+ gram-negative bacilli, and 7% grew <1+ gram-negative bacilli alone or in mixed culture. For the 303 of 504 (60%) specimens that were Gram-positive, 74 (14.7%) had more than 10 squamous epithelial cells per low-power (100 X) field, of which 54% grew normal flora, 29% grew rare to 4+ normal flora plus 1+ gram-negative bacilli, 9% grew 1 to 4+ normal flora plus 2+ gram-negative bacilli, and 8% grew 1 to 4+ normal flora plus 3 to 4+ gram-negative bacilli. The number of segmented neutrophils per low-power field did not predict the mean number of flora recovered. The authors concluded that endotracheal suction aspirate specimens should be rejected if no bacteria are seen on Gram stain or if more than 10 squamous epithelial cells per low-power field are seen. In a subsequent period, application of these criteria resulted in 847 of 2,068 (41%) specimens being rejected.

Because it is a clinical decision to submit sputum specimens for culture, prelaboratory steps to maximize cost-effectiveness include scrupulous collection technique and limiting the number of specimens submitted in a given period. Most laboratories accept at most one sputum specimen per 24 hours; some limit the number of specimens accepted to one per 48 hours . Once received in the laboratory, expectorated sputum specimens and endotracheal suction aspirates should be screened for bacterial contamination. It is of no benefit to patients to culture specimens that should be rejected. It is less clear whether sputum specimens submitted for mycobacterial culture should be screened. For outpatients, this is probably not practical. If specimens can be easily collected, screening expectorated sputum specimens may be appropriate.

Stool Cultures and Examination for Ova and Parasites

In 1990, Siegel et al51 reported on the diagnostic yield of performing stool cultures and examinations for ova and parasites from specimens collected from patients in hospital. Their observation that the yield

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from these tests is minimal if performed on specimens collected after the third day of hospitalization has been verified many times.52-60 Although some published data suggest that processing specimens up to the fourth day of hospitalization may be important, all of the published data indicate that processing specimens after that time does not result in a meaningful incremental increase in detection of pathogens. Based on these data, it is now standard process for hospital laboratories to reject stool specimens collected after the third or fourth day of hospitalization. Diarrhea that develops in hospitalized patients after this time should be tested for Clostridium difficile.

Data have also been published indicating that the traditional practice of routinely submitting three stool specimens for culture and examination for ova and parasites does not result in a meaningful incremental increase in detection of pathogens.53'57'59-62 Unlike the issue of testing hospitalized patients, however, conflicting data have also been published.63,64 Because most published data support submitting one or two specimens, laboratories should consider this standard practice except for pathogens that are shed intermittently (eg, Entamoeba histolytica). For pathogens that can be difficult to detect, use of specialized methods (eg, coprocul ture for Strongyloides stercoralis or enzyme immunoassays for Giardia lamblia) may be more cost-effective than routine microscopic examinations for ova and parasites.65

A cost-effective approach to examination of stool spec imens for C difficile has been pub l i shed by Manabe et al.66 In that study, both clinical and laboratory data were useful in predicting which specimens were likely to contain C difficile toxin. These included a hospital stay longer than 15 days, onset of diarrhea more than 6 days after the initiation of antimicrobial therapy, use of a cephalosporin, semiformed (not watery) stools, and the presence of fecal leukocytes (by microscopy or lactoferrin assay). Toxin can be detected by several methods, of which cytotoxin assay is the most accurate. Cultures for C difficile combined with a toxin assay is the gold standard but, because of the added expense and the delays in diagnosis, is not cost-effective.

Urine Cultures

For most microbiology laboratories, urine is the specimen most often received for culture. In some ways, it is also the most difficult specimen to analyze, because contamination with perineal flora occurs read i ly and confounds cu l tu re in te rp re ta t ion .

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Overcoming the problem of contamination, in large part, guides how urine specimens are collected and processed and how culture results are interpreted.

Several axiomatic principles guide the collection, transport, and processing of urine cultures. Specimens should be collected by the means most appropriate for the patient and the clinical setting. Acceptable techniques for collecting specimens include clean catch, catheterization, or suprapubic aspiration; specimens should never be collected from indwelling urinary catheters or urine collection bags. To minimize contamination, urine specimens must be collected carefully and transported and processed immediately (or refrigerated) to minimize growth of contaminants. The usefulness and cost-effectiveness of collection and transportation systems remains controversial. Once received in the laboratory, specimens (other than those collected by suprapubic aspiration) should be screened for leukocyte esterase or nitrate reduction to determine whether culture is appropriate (although urine screening also remains controversial). A Gram's stain of urine is useful, although many laboratories have insufficient staff to perform this test routinely. Specimens should be plated so that semiquantitative colony counts are possible. Antimicrobial susceptibility testing should be modified from that used for other body sites.

Interpretation of urine culture results is difficult because it is affected by the age and gender of the patient, whether the patient was hospitalized or was an outpatient, the presence or absence and type of symptoms, other clinical and laboratory information, how the specimen was collected, and the types and numbers of isolates recovered. The most commonly applied criterion for distinguishing between clinically important isolates and contaminants is a colony count of >105 colony-forming units (CFU)/mL. While this criterion is useful for interpreting clean-catch urine cultures collected from asymptomatic women, a significant proportion of these patients have colony counts <105 CFU/mL. Furthermore, the criterion is useful only when a member of the family Enterobacteriaceae is isolated; cultures yielding other gram-negative bacteria, gram-positive bacteria, or fungi typically have lower colony counts. Symptomatic women also often have lower colony counts, and in men as few as 103

CFU/mL may indicate infection. The criterion of >105

CFU/mL is inappropriate for pediatric patients. Last, recovery of multiple isolates from a given culture makes interpretation difficult; even when one or more isolates is present in quantities >105 CFU/mL, the culture is likely contaminated. In general, cultures should

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be repeated if there is any uncertainty as to the clinical relevance of the results.

STRATEGIES FOR LIMITING TEST USE

McLaughlin67 has published a 10-point plan for the "implementation of cost-effective, clinically relevant diagnostic microbiology policies"; the following is a modified version.

1. Base proposed changes on "data and opinions and ideas published in well-known, refereed journals or newsletters, or by respected experts."

2. Whenever possible, supplement this with in-house data.

3. Have the support of the infectious disease service. 4. Discuss proposed changes in advance with the

"most influential physicians in the groups that will be affected" [by the changes].

5. Educate potential users who will be affected by the changes.

6. Announce proposed changes via newsletters, memoranda, or other forms likely to be read.

7. Educate technologists who will implement the changes.

8. Revise laboratory procedure manuals accordingly.

9. Provide physicians with an "override" mechanism. Although this almost never is clinically useful, it provides an important public relations function.

10. Be prepared to provide explanations and follow-up to users who were unaware of the proposed changes or who disagree with them.

In my experience, this is the best published plan for implementing many of the changes discussed in this review. Implementation of these changes can be difficult, and requires sustained and focused effort over time, as well as collaborative effort between laboratory staff and clinicians. Such changes require strong administrative support from both the laboratory and hospital (or other health care setting) administration. Such support is particularly important when changes are unpopular or affect long-standing policy and practice (tradition). All institutions carry diagnostic baggage that is often perceived as crucial for patient care but in reality could be shed.

One important issue that needs to be addressed by all laboratories is test turnaround time. Valenstein68

has recently reviewed this subject. Improving test turnaround time is crucial for successful implementation of test utilization strategies, particularly because

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the perceived effect of changes on patient care and clinical practice are weighted heavily toward timely result reporting.

CONCLUSION

Ongoing changes in health care, however challenging, have provided laboratorians with a rare opportunity to make important changes in how laboratories are used and how they operate. It is now known that, for many tests, laboratory test utilization can be decreased substantially without adversely affecting patient care. In fact, decreased utilization of some tests improves pat ient care, decreases costs, and lessens the complexity of laboratory operations. The information presented in this article is limited to a few tests; for many other tests there is either no data or the data are equivocal. As the United States grapples with the problem of funding health care, research on cost-effective laboratory practice (in all areas of laboratory medicine) should receive high priority.

Acknowledgment: 1 thank Dr Paul Valenstein, codirector of an ASCP workshop on cost-effective clinical microbiology. Many of the ideas used in this review are derived from that workshop.

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68. Valenstein P. Laboratory turnaround time. Am J Clin Pathol. 1996;105:676-688.

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