There is no question that the microbiology laboratory has a role to play in these new foci,3-6 but we would suggest that there are signs that the role of the microbiologist is changing from a less passive one to a more active, perhaps even interventional, one. As the benefits of rapid detection of infectious agents and appropriate antibiotic therapy contribute to better clinical and financial outcomes,7-9 the microbiology laboratory takes a more important seat at the table for clinical decision making.
What possibilities are there for a more integrated role for the microbiologist in the management of infectious diseases? We suggest that interventions can benefit both individual and public health in two ways: one as microbiologists design better and more novel pathways for specimen evaluation and also as they convey information to providers leading to more expeditious care. A recent case illustrates aspects of this process.
A 14-month-old female was seen in the emergency department for evaluation of a sore, swollen left knee and fever of 102^0F. Plain X-ray studies of the lower extremity as well as ultrasonography of the left hip were normal. Arthrocentesis of her left knee was performed which yielded joint fluid containing 200,000 WBC/mm3 and a negative Gram stain.
She was taken to surgery where a diagnosis of purulent arthritis was confirmed; the joint was irrigated, and a drain placed. Empiric therapy using clindamycin was started that night. The following morning, blood and chocolate agar plates and thioglycolate broth had no aerobic or anaerobic growth. Using primers to detect the mecA and nuc genes of Staphylococcus aureus and the cpn60 target on the chaperon gene of Kingella kingae, polymerase chain reaction (PCR) was performed using the purulent drainage obtained from the knee. The joint fluid was negative for S aureus and mecA but positive for K kingae. After review, the molecular microbiologist communicated the result directly to the attending physician. Within 21 hours of the surgical procedure, the clindamycin was stopped and appropriate therapy using cefazolin was initiated. The following morning the patient was improved, her drain was removed, a peripherally inserted central catheter was placed, and she was discharged home to complete therapy. After 96 hours, K kingae was identified from joint fluid following direct inoculation into BACTEC (BD, Sparks, MD) blood-culture medium.
A few years earlier, this case would have posed a diagnostic and therapeutic challenge. The management of a case of culture-negative arthritis would have required a trial period of empiric antibiotic therapy in the hospital to verify therapeutic benefit10 requiring two to four days to evaluate the impact of the surgery and associated side effects. There would have been clinical evaluation regarding the antibiotic selection. Most likely, a combination of agents would have been selected to treat the common causes of septic arthritis in children (i.e., methicillin susceptible and resistant S aureus [MSSA and MRSA, respectively] and K kingae)11 even though empiric combination therapy has been associated with increased morbidity12,13 and length of stay (LOS).10 Instead, both PCR and improved culture technology accelerated diagnosis and treatment.
Our case illustrates early evidence of a shift in the role of microbiology practitioners. To what extent is more interventional microbiology found in current and future practice?
A requirement for beneficial intervention is active communication
between the microbiologist and the clinician.
Reflex testing of predetermined specimens is not new. For years, the microbiologist has determined which tools should be used for certain clinical specimens. Evolving novel molecular methodologies in diagnostic testing call for some expansion and revision of our current guidelines. Some protocols that previously required physician orders are now being incorporated into the standard operating procedures (SOPs) for specimens. A team of infectious-disease specialists, pathologists, microbiologists, and administrators is necessary to determine appropriate testing and diagnostic pathways.14 Because the focus of our institution is children, we pre-determined our critical clinical need to be the rapid identification of pediatric pathogens in osteoarthritis: MSSA, MRSA, K kingae, and Streptococcus pneumoniae. Therefore, the SOP was that all joint specimens should have PCR testing for selected pathogens by age. The result drove the clinician’s decisions regarding antibiotics and discharge planning.
Point of care testing offers a more rapid way for the microbiological diagnosis to be made at the point of patient and clinician interface. The wide use of the rapid Group A streptococcus test most clearly illustrates this point. Although routine use is still in the future, advances in molecular techniques provide the potential for multiplex point-of-care diagnostic testing (i.e., direct specimen testing). Improvements in amplification and identification of multiple nucleic-acid sequences by using locked pentamer residues as universal primers provide amplification, hybridization, and identification in a single tube. This provides future opportunities for efficient multiplex platforms at the point of care.15 Multiplex molecular-detection platforms utilizing manual enzyme hybridization, automated electronic microarray, and reverse-line blot hybridization for detection of viral and bacterial pathogens most commonly causing community-acquired pneumonia and sepsis provide future opportunities for point-of-care diagnostics.16-17 Fluorescent beacon probes have been developed for use in identification of Plasmodium spp. in direct blood samples with a sensitivity of 0.004 parasites/uL blood in approximately two hours compared to limitation of 5 parasites/uL by microscopic evaluation.18 Hand-held devices have been developed for use in biodefense, such as Liat Analyzer (IQuum, Marlborough, MA) and other microarray technologies providing multiplex PCR of nucleic acids and protein targets on direct fluids within one hour using nanoliter volumes.19-21
Availability of molecular testing seven days a week can provide results within four hours to 24 hours with increased sensitivity in comparison to routine culture that often requires 48 hours to >=72 hours to obtain results22 or for some pathogens, acute and convalescent serologies. In addition to identification of the causal organism, newer molecular assays provide information on the organism’s susceptibility to specific antimicrobial agents (e.g., MRSA, mecA). Once identification of causative organism is determined, genes associated with invasiveness can be identified for prognostic purposes.23 These novel molecular techniques reduce decision times by clinicians by providing results on direct specimens from critical patients within hours of hospital arrival, improving quality of care and safety.
A requirement for beneficial intervention is active communication between the microbiologist and the clinician. In the past, most microbiological information has been communicated to the provider on request. In our case, the positive molecular finding of K kingae was actively called to the physician instead of sending a paper report. This enabled a change in the clinical care and a quicker discharge home. Receiving information quickly leads to decreased LOS and cost savings.9,24,25 The mode of communication, however, can affect accuracy and clinical impact. Historically, communication was face-to-face contact or by written reports; today, electronic systems enable immediate notification which increases accuracy and facilitates efficiency26,27 ; however, the systems must be effective, clinically relevant, and have the ability to evolve with emerging needs. Providers — in particular infectious-disease specialists, critical-care doctors, and pharmacists — are increasing their personal contact with the microbiology laboratory to enhance patient care; and microbiologists who have traditionally worked in a clinical-information vacuum are becoming better connected to the patients they serve. Advanced systems can now incorporate patient demographics, microbiology reports, and hospital-specific antibiogram data into a rules-based system for clinicians or infection-control professionals. These systems have been shown to decrease costs and provide appropriate antimicrobial therapy options.28
System-communication tools, which actively distribute information directly to a member of the healthcare team without the need for the physician to access the electronic record are a major interventional aspect of communication. Designing these to prevent excessive data flow to providers will be critical to the success of such systems. This can be theoretically permitted by provider-specific criteria linked to on-call information, personal schedules, service and unit specifics, or other information. Such systems can be programmed to contact clinicians by e-mail, text message, or other electronic media when critical information such as pathogen identification or susceptibility data become available.
Clinical and public-health impact
Rapid diagnosis coupled with communication provides opportunity to decrease morbidity and mortality. For example, interventional microbiology can affect emergency medicine by integrating rapid diagnostics on direct specimens and effective communication to emergency medicine physicians. This increases throughput and accelerates care in overtaxed emergency departments.
Another important potential of the rapid transmittal of information is improved antibiotic stewardship. By coupling rapid identification of organisms and their susceptibilities to the rapid dissemination of this information to decision makers, inappropriate antibiotics can be discontinued and appropriate therapy instituted. This reduces antimicrobial pressure by reducing overuse of antibiotics such as vancomycin. When information is disseminated to a member of an antimicrobial stewardship team, consultation can be made at the patient-care level with immediate re-assessment of several factors: the new laboratory results, pharmacokinetic/pharmacodynamic factors, and the clinical course. Optimal therapy can then be determined by the physician.
These analytic and communication tools can consolidate real-time data specific for a given patient population or antimicrobial-resistance problems per hospital unit to guide empiric-therapy choices. For instance, LOS for patients presenting with sepsis, pneumonia, and non-critical infections is directly related to timeliness and appropriateness of antibiotic therapy.2,24,29 Antibiogram algorithms linking patient-specific and region-specific data can guide empiric therapy using current data.
The hypothesis that a newer, less passive microbiology
(“interventional microbiology”) can improve care and
reduce costs deserves testing in several institutions.
In addition to clinical care, infection-control management is also improved through interventional microbiology. By determining the sensitivity of pathogens more quickly, infection-control guidelines can be more rapidly implemented or discontinued. Timely detection and notification of resistant organisms is correlated with a reduction in the spread of hospital-acquired infection and associated decreased costs.3,4 Software systems that patrol clinical data continuously can quickly identify outbreaks of pathogens in hospital units, presumably with more reproducibility and with better pattern recognition than can the infection-control officer or microbiologist.27 When linked to demographic information, such a system has the potential to recognize community outbreaks when cases of pathogens are linked to zip codes or to particular patient populations. In addition, regional or national systems can potentially identify bioterrorism-associated organisms earlier, a distinct advantage for homeland security.
Costs versus benefits
The costs of newer diagnostic programs such as a molecular program to an established microbiology laboratory can be substantial in terms of personnel and equipment. As described by Peterson and Noskin3 in 2001, a minimum $400,000 annually was needed to sustain such a molecular program. For now, such an innovation may be restricted to large, regional hospital laboratories. Only when the benefits of such programs are documented will smaller facilities more likely to be able to justify implementing these programs. As the technology becomes accessible to smaller clinical laboratories, cost analysis should include projections of decreased healthcare-associated infections and LOS.
An opportunity for economic benefit is in emergency medicine where crowding and inefficiency have led to delays in patient care and medical errors. Due to the large number of hospital admissions from the emergency departments for community-acquired pneumonia and relationship of morbidity to treatment delay, early antimicrobial therapy was targeted as a measure of quality of care by the Joint Commission.30 Increased patient volumes, acuity, and limitations of diagnostic testing (e.g., radiography and culture results), affect the ability to administer antimicrobials to patients within four hours of arrival.31-33 By incorporating interventions from a clinical pharmacist in antimicrobial-therapy decisions, over $1 million in cost avoidance of unnecessary use in a four-month period demonstrated economic utility.25
by integrating rapid diagnostics on direct
specimens and effective
communication to emergency medicine physicians.
The case presentation of K kingae osteoarthritis used here illustrates technological and procedural advances in microbiological diagnostics and communication. These activities are active in the sense that molecular developments are driving rapid diagnoses and that rapidly communicated results have the potential to drive better decision making and care. The hypothesis that a newer, less passive microbiology (“interventional microbiology”) can improve care and reduce costs deserves testing in several institutions. If confirmed, rapid implementation of diagnostic pathways into standard practice, point-of-care molecular diagnostics, enhancement of traditional culture methods, and effective communication in emergency departments and hospitals are warranted and should be a focus for quality improvement.
Toni Beavers, MPH, BSMT(ASCP)SM , was the technical chief of Microbiology at the Arkansas Children’s Hospital at the time of article submission, and is now an infection prevention consultant, Infectious Diseases, at BD Diagnostics. J. Gary Wheeler, MD, MPS, works within the University of Arkansas for Medical Sciences, Little Rock, AR.
- Bringing everyone to the table: White House health care stakeholders discussions. HealthReform.Gov. Available at http://www.healthreform.gov/forums/stakeholderdiscussions/index.html. Accessed July 30, 2009.
- Fraser VJ, Olsen MA. The business of health care epidemiology: creating a vision for service excellence. Am J Infect Control. 2002;30(2):77-85.
- Peterson LR, Noskin GA. New technology for detecting multidrug-resistant pathogens in the clinical microbiology laboratory. Emerg Infect Dis. 2001;7(2):306-311.
- Hacek DM, Suriano T, Noskin GA, Kruszynski J, Reisberg BE, Peterson LR. Medical and economic benefit of a comprehensive infection control program that includes routine determination of microbial clonality. Am J Clin Pathol. 1999;11:647-654.
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- Harbarth S, Masuet-Aumatell C, Schrenzel J, Francois P, Akakpo C, Renzi G, et al. Evaluation of rapid screening and pre-emptive contact isolation for detecting and controlling methicillin-resistant Staphylococcus aureus in critical care: An interventional cohort study. Crit Care. 2006;10(1):R25.
- Edelsberg J, Berger A, Weber D, Mallick R, Kuznik A, Oster G. Clinical and economic consequences of failure of initial antibiotic therapy for hospitalized patients with complicated skin and skin-structure infections. Infect Control Hosp Epidemiol. 2008;29(2):160-169.
- Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis. 2003;36(1):1418-1423.
- Beekmann SE, Diekema DJ, Chapin KC, Doern GV. Effects of rapid detection of bloodstream infections on length of hospitalization and hospital charges. J Clin Microbiol. 2003;41(7):3119-3125.
- Kocher MS, Lee B, Dolan M, Weinber J, Shulman ST. Pediatric orthopedic infections: Early detection and treatment. Pediatr Ann. 2006;35(2):112-122.
- Saphyakhajon P, Joshi AY, Huskins WC, Henry NK, Boyce TG. Empiric antibiotic therapy for acute osteoarticular infections with suspected methicillin-resistant Staphylococcus aureus or Kingella. Pediatr Infect Dis J. 2008;27(8):765-767.
- Yuan HC, Wu KG, Chen CJ, Tang RB, Hwang BT. Characteristics and outcome of septic arthritis in children. J Microbiol Immunol Infect. 2006;39(4):342-347.
- Boeck HD. Osteomyelitis and septic arthritis in children. Acta Orthop Belg. 2005;71(5):505-515.
- Jackson BR. Managing laboratory test use: Principles and tools. Clin Lab Med. 2007;27(4):733-748.
- Sun Z, Chen Z, Hou X, Li S, Zhu H, Qian J, et al. Locked nucleic acid pentamers as universal PCR primers for genomic DNA amplification. PloS One. 2008;3(11). E3701.
- Kumar S, Wang L, Fan J, Kraft A, Bose M, Tiwari S, et al. Detection of 11 common viral and bacterial pathogens causing community-acquired pneumonia or sepsis in asymptomatic patients by using a multiplex reverse transcription-PCR assay with manual (enzyme hybridization) or automated (electronic microarray) detection. J Clin Microbiol. 2008;46(9):3063-3072.
- Wang Y, Kong F, Yang Y, Gilbert G. A multiplex PCR-based reverse line blot hybridization (mPCR/RLB) assay for detection of bacterial respiratory pathogens in children with pneumonia. Pediatr Pulmonol. 2008;43(2):150-9.
- Elsayed S, Plewes K, Church D, Chow B, Zhang K. Use of molecular beacon probes for real-time PCR detection of Plasmodium falciparum and other Plasmodium spp. in peripheral blood specimens. J Clin Microbiol. 2006;44(2):622-624.
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- Dahl A, Sultan M, Jung A, Schwartz R, Lange M, Steinwand M, et al. Quantitative PCR based expression analysis on a nanoliter scale using polymer nano-well chips. Biomed Microdevices. 2007;9:307-314.
- Matsubara Y, Kerman K, Kobayashi M, Yamamura S, Morita Y, Tamiya E. Microchamber array based DNA quantification and specific sequence detection from a single copy via PCR in nanoliter volumes. Biosens Bioelectron. 2005;20:1482-490.
- Chometon S, Benito Y, Chaker M, Boisset S, Ploton C, Berard J, et al. Specific real-time polymerase chain reaction places Kingella kingae as the most common cause of osteoarticular infections in young children. Pediatr Infect Dis J. 2007; 26(5):377-381.
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