The Clinical Relevance of Antimicrobial Susceptibility Testing : Ramblings of a Very Old Clinical Microbiologist Gary V. Doern, Professor Emeritus University of Iowa College of Medicine
What is the defining paradigm in medicine today? Dennis G. Maki, M.D. Professor Emeritus Department of Medicine University of Wisconsin School of Medicine Advances in cancer care? The technology of medicine? The business of medicine? Evidenced-based clinical practice! Medical Grand Rounds, University of Iowa College of Medicine (February, 2012)
I don t see much sense in that said Rabbit. No, said Pooh humbly, there isn t. But there was going to be when I began it. It s just that something happened to it along the way. (A.A. Milne, Winnie-the-Pooh, 1926) In the absence of unbiased empirical data derived from systematic, objective investigations, the practice of clinical microbiology is little more than an expensive crap shoot (G.V. Doern, J Clin Microbiol, 2014)
I guess I need to be careful here Trump administration prohibits CDC from using the following words in all communications: - entitlement - evidence-based - diversity - fetus - science-based - transgender - vulnerable (J. Eilperin, Washington Post, Dec. 15, 2017)
It s deja vue, all over again! (Yogi Berra, 1978) (George Orwell, 1949)
Not the first time S#$@, F*&%, P@&% C#%&, M%#@!&F%@&%, T$#@ and C%$&#@$^&
Survey CM laboratory directors 10 academic medical centers 5 acute care hospitals 5 state public health laboratories Parameters: - analytical precision - cost - laboratory impact - clinical impact Evidence scale: 1-3 (inadequate) (1-10) 4-7 (moderate) 8-10 (adequate)
Survey Results Method Automated BC systems Automated mycobacteriology Automated ID/AST Analytical precision Cost Laboratory impact Clinical impact 8 7 6 1 6 8 6 0 8 7 6 4 MALDI-TOF MS 5 6 3 0 NG sequencing 2 4 2 0 Multiplex PCR 3 4 4 1 POC molecular 2 3 3 1 Evidence scale: 1-3 = inadequate 4-7 = some evidence 8-10 = adequate
Heaven, forbid some data! Survey of 15 clinical microbiology laboratory directors (2014) Identify the most important concepts, activities and/or procedures in current laboratory practice 71 different functions identified - CM blood culture incubation for 5 days - 10 4 CFU/ml = significant bacteriuria - No C. diff determinations on formed stool - AFB smears only on concentrated sputa - WB definitive diagnostic method for Lyme - Sputum GS directs w/u of sputum cultures - AST essential in directing antimicrobial Rx
So how are we doing? Survey of 15 clinical microbiology laboratory directors (2014) Identify the most important concepts, activities and/or procedures in current laboratory practice 71 different functions identified - 46 functions accessed - 16 functions (35%) evaluable data - 7/16 (44%) data supports practice - 54% - data contradicts practice
But the question before us is: What do the results of in vitro susceptibility tests mean from the perspective of patients with infection? Stated another way: What is the clinical predictive value of AST results?
Manual AST Systems
Automated Antimicrobial Susceptibility Testing Systems
Results of In Vitro Susceptibility Testing Quantitative procedures: Minimum inhibitory concentrations Qualitative procedures: Susceptible (S) Intermediate (I) Resistant (R)
Good things come in threes!
Interpretive Categories The Big Three: Susceptible Favorable outcome Intermediate Don t know Resistant Unfavorable outcome
How is Resistance Defined? MIC determinations represent the most refined means of measuring in vitro antibacterial activity The units of an MIC are: ug/ml MIC breakpoints (interpretive criteria) Susceptible (S) Intermediate (I) Resistant (R)
AST Results Interpretive Criteria Australian Clinical Diagnosis Society British Society for Antimicrobial Chemotherapy Clinical and Laboratory Standards Institute Deutches Institut fur Normung European Committee on Antimicrobial Susceptibility testing Societe Francaise de Microbiologie Swedish Reference Group for Antibiotics Werkgroep Richtijnen Gevoeligheidsbepaligen
The Clinical and Laboratory Standards Institute (CLSI) * AST method standards Quality control criteria Drug selection Interpretive criteria 1972 - present *Formerly the National Committee for Clinical Laboratory Standards (NCCLS)
Establishing Interpretive Categories Four approaches: MIC frequency distribution analysis Correlation with known mechanisms of resistance Clinical correlation Pharmacodynamics
Establishing Interpretive Categories Four approaches: MIC frequency distribution analysis Correlation with known mechanisms of resistance Clinical correlation Pharmacodynamics
Number of isolates Penicillin MIC Frequency Distribution for S. pneumoniae 1925 isolates, 45 U.S. medical centers, 2001-02 600 500 Susc. Intermediate Resistant 400 300 200 100 0 0 0.01 0.02 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 MIC (µg/ml)
Establishing Interpretive Categories Four approaches: MIC frequency distribution analysis Correlation with known mechanisms of resistance Clinical correlation Pharmacodynamics
Resistance Mechanisms That Drive Treatment Failure Certain β-lactamases: - staphylococcal penase - TEM-1, TEM-2, SHV-1 - derepressed ampc - Rob-1, CTX-M - metallo-β-lactamases meca-derived PBP 2a erm-derived ribosomal alterations Aminoglycoside modifying enzymes van A and van B-altered CW pentapeptides parc + gyra mutations
Establishing Interpretive Categories Four approaches: MIC frequency distribution analysis Correlation with known mechanisms of resistance Pharmacodynamics Clinical correlation
Antibiotic Effect in Patients Potency a product of: antibacterial effect (MIC) drug delivery (PK) drug-bug interaction PHARMACODYNAMICS
PK/PD Analysis as a Means for Establishing MIC Breakpoints Advantages: Based on accessible data Arithmetic (ie. simple) Concepts based on empiric investigation Disadvantages: A broad averaging technique Merits dose specific breakpoints
Establishing Interpretive Categories Four approaches: MIC frequency distribution analysis Correlation with known mechanisms of resistance Pharmacodynamics Clinical correlation
Clinical Predictive Value? Focus: Single agents used parenterally to manage monomicrobic infections in non-immunocompromised hosts in which standard doses of agent reliably achieve typical concentrations at the site of infection
Correlation of Cefotaxime MICs and Disease Outcome Cefotaxime Percentage Percentage MIC (no.) cured or improved eradication 4 (1003) 94% 91% S 8 (273) 90% 86% 16 (151) 77% 75% I 32 (70) 84% 71% 64 (19) R 64% 50% [1506 patients total]
Correlation of Meropenem MICs and Disease Outcome Meropenem Percentage Percentage MIC (n) cured or improved eradication 2 (301) 94% 92% S 4 (89) 93% 92% 8 (29) I 86% 82% 16 (11) 65% 61% 32 (5) R 60% 60% [n = 435 patients total]
Clinical Correlation in Pneumococcal Pneumonia MIC No. of No. (%) who (µg/ml) patients failed therapy: Penicillin 0.06 (S) 126 24 (19) 0.12 1 (I) 24 5 (21) 2 (R) 10 2 (20) Cefotaxime 0.5 (S) 145 29 (20) 1 (I) 4 1 (15) 2 (R) 1 0 (0) 21% 20% [Pallares et al, N Engl J Med, 1995]
Clinical Correlation in Gonococcal Genital Tract Infections Men and women with urethritis or cervicitis [Jaffe et al, N Engl J Med, 1976] Penicillin no. Failure MIC rate 0.06 424 2% 0.12 183 3% 0.25 191 4% 0.5 128 6% 1.0 52 13% 4.8 mu PCN + 1 g proben
Clinical Predictive Value Monomicrobic infections in immunocompetent patients treated with a single parenteral antibiotic Susceptible 90% 95% response Intermediate 65% 90% response Resistant 60% 65% response 23/100 patients
Clinical Predictive Value Monomicrobic infections in immunocompetent patients treated with a single parenteral antibiotic The higher the MIC, the worse the outcome The lower the MIC, the better the outcome
Everybody Else. Infections treated with oral or topical antibiotics, or combination agents Polymicrobial infections Infections in sites with diminished penetration or concentration of drug at the site Infections in immunocompromised patients
Oral Antimicrobials and Respiratory Tract Infections Haemophilus influenzae infections AOME (n=262), AS (n=237), AECB (n =270) Agent Resp # No. of isolates with each MIC (µg/ml): 0.25 0.5 1 2 4 8 16 32 Loracarbef C/I 186 4 7 52 74 28 8 7 6 R/F 10 1 8 1 Amox/clav C/I 137 7 53 42 25 7 3 R/F 11 7 4 Doern et al, Am J Med, 1992
Multiple Antibiotics 143 of 200 patients with Pseudomonas aeruginosa bacteremia received combination therapy parenterally MICs of antimicrobial agents determined versus patient s infecting strains and correlated with outcome No Correlation! Hilf et al, Am J Med, 1989
Urinary Tract Infection 136 out-patient women with acute uncomplicated cystitis (DUF + PMNs) Positive urine cultures No previous antibiotics (6 months) Two TMP/SMX treatment groups: 2 g PO once vs. 500 mg q12h for 10 d Assess relationship between TMX MICs and outcome (ie. failure, relapse, recurrence) No Correlation! Schultz et al, Mayo Clin Proc, 1984
Urinary Tract Infection 618 women with DUF + pyuria 544 (88%) with positive urine cultures ALL treated with TMX 500 mg qd 5 d Period: No. responding/no. treated TMX S TMX R 1 week* 288/353 (86%) 64/151 (42%) 4 weeks* 265/285 (93%) 53/76 (70%) * P < 0.001 Raz et al, Clin Infect Dis, 34:1165, 2002
Closed Space Anaerobic Infections 19 patients with intraabdominal infections ALL treated with cefoxitin (2 g q 8 h for 10 d) Medium (method): G.M. Cefoxitin MIC: Cured a Failed b Wilkins Chalgren (AD) 18.2 24.7 Wilkins Chalgren (BMD) 14.1 20.8 Commercial media (BMD) 14.1 24.7 Brain heart infusion (BMD) 5.1 4.4 a. n = 11 patients; b. n = 8 patients Snydman et al, Antimicrob Agents Chemother, 1992
Everybody Else. Infections treated with oral or topical antibiotics, or combination agents Polymicrobial infections Infections in sites with diminished penetration or concentration of drug at the site Infections in immunocompromised patients
The Predictive Value of In vitro Susceptibility Testing Response Rate 100 80 60 ACTUAL 40 20 0 IDEAL Susceptible Intermediate Resistant
Clinical Predictive Value 51 years of in vitro susceptibility testing 1966 1972 2017
Clinical Correlation In vitro anti-tumor susceptibility test VS. Outcome in patients with hematologic malignancies DiSCA MTCS Number (%) MTCS Response 22 (18.5) > 55% 0% 31 (26.1) 31 55% 9% 36 (30.3) 5 30% 54% 30 (25.2) < 5% 79% (Bosanquet et al, Lancet, 1997)
Confounding Variables Fixed non-varying inoculum Constant ph; no protein binding Optimum growth conditions Fixed non-varying concentration of antimicrobial Host factors not considered
The Clinical Continuum AST results reporting Processing of information Exposure Incubation period Disease manefestations Performance of AST Specimen processing Specimen transport Intervention! Seek care Clinical evaluation Care plan Specimen collection Specimen ordering Implementation
What do these have in common?
Health Care Costs
We need to better. The distance between the clinical microbiology laboratory and the patient with infection is only as long as we choose to make it Linkage of AST results to: Patient parameters known to be associated with infection outcome: - age, gender, race, ethnicity - ± underlying disease - patient genotype - cytokine profiles - T-cell genotypes
For us you see my friends, it is not merely to endure, but rather to prevail Wm. Faulkner Stockholm, 1957