Time matters for antimicrobial treatment

In terms of patient outcomes, why is time so important for patients with drug-resistant infections?

Tiziana Di Martino: Rapid disease identification, diagnostics and treatment play a key role in improving patient survival rates. In septic patients, inappropriate empiric antimicrobial therapy and delayed initiation of appropriate therapy are risk factors for higher mortality rates. Increasing numbers of bacterial clinical isolates commonly responsible for bloodstream infections and sepsis have become multidrug resistant, which delays the initiation of appropriate antimicrobial therapy. Sepsis guidelines emphasise the importance of early broad-spectrum antimicrobial treatment, aimed at ensuring adequate therapy to reduce mortality. On the flip side, though, the use of broad-spectrum antimicrobials has led to concerns about patient exposure to the overuse of antimicrobials, which may result in the promotion of antimicrobial resistance (AMR) and antimicrobial side effects. For this reason, targeted therapy is an important component of antimicrobial stewardship. In practice, this means time matters in relation to both appropriate empiric therapy and de-escalation related decisions.

Why is determining the minimum inhibitory concentration (MIC) of antimicrobials necessary?

MIC determination enables clinicians to select the most appropriate antimicrobial and individualise antibiotic dosing. This is done by defining the target exposure that an optimised antimicrobial dosing regimen should achieve. Dosage modification is driven by the pharmacokinetic/ pharmacodynamic (PK/PD) characteristics of the antimicrobial, the chosen PK/PD target, the antimicrobial concentration, and MIC data. The use of therapeutic drug monitoring combined with the MIC has gained recognition as an increasingly important tool to individualise antimicrobial dosage and avoid over and under-exposure to antimicrobials. However, the clinical relevance of the MIC is not limited to critically ill patients. For some antimicrobials and bacteria, MIC determination is the only reliable phenotypic method to assess antimicrobial susceptibility since qualitative antimicrobial susceptibility testing (AST) methods fail to provide reliable results.

The in vitro susceptibility of a pathogen to an antimicrobial does not necessarily mean that the antibiotic can always be safely and effectively used. An example of this is the treatment of S. aureus infections with vancomycin, for which a PK/PD target AUC0- 24/MIC of 400 is used. A MIC of 2.0mg/L for vancomycin carries the risk of therapeutic failure despite the strain being classified as susceptible. In fact, a vancomycin MIC of 2.0mg/L requires an AUC0-24 of 800mg.h/L, which would dramatically increase the risk of toxicity. In this case, the vancomycin MIC value points the clinician to better antimicrobial alternatives.

Unlike qualitative AST methods, the MIC value allows one to assess the degree of susceptibility or resistance of a microorganism to an antibiotic. This is done by looking at the MIC distance from the susceptibility breakpoint and whether the MIC is below the epidemiological cut-off value. This information reduces the likelihood of selecting an antibiotic against which the strain might develop a resistant subpopulation during treatment.

MIC determination can have clinical significance when a mechanism of bacterial resistance is detected. Carbapenemases may have a different spectrum and degree of hydrolytic activity against certain betalactams, such as carbapenems. The detection of the resistance mechanism does not completely eliminate the possibility of using carbapenems to treat infections caused by carbapenemase-producing bacteria. The clinical interpretation and susceptible, intermediate or resistant classification of the strain, and consequent decisions regarding high dosing and combination therapy, should be based on the MIC value.

How does Q-linea’s ASTar system improve on current methods of AST?

Now that ASTar has received CE-IVD mark, Q-linea is planning to start health economic outcome research (HEOR) studies proving the value of ASTar implementation for the patient, the microbiology laboratory and the hospital as a whole. With conventional AST methods, physicians can optimise antimicrobial treatment two or three days after the patient is started on empiric therapy. ASTar provides accurate MIC values in about six hours, enabling physicians to reduce time to optimal antimicrobial therapy by one or two days. This means that patients who are treated with antimicrobials that are not effective against the infection can receive appropriate antimicrobials at the optimal dosage faster.

Optimising treatment and reducing AMR could be expected to reduce mortality rates, and could also support a decrease in healthcare costs by reducing hospital stay. By utilising broth microdilution, the ASTar system provides true MIC results which support antimicrobial stewardship efforts in the fight against antimicrobial resistance. Another anticipated advantage of ASTar implementation is a streamlined laboratory workflow, as ASTar is completely automated; it does not require highly skilled personnel and the samples can be prepared for analysis in around two minutes.