Introduction

Despite persistent efforts, sepsis remains the number one killer in hospitals, associated with about 20% of deaths in the world.¹ In the US, it is reported to be the most expensive condition treated, responsible for over 6% of total US healthcare costs at a massive expense of $62 billion.²

This is not caused by patients dying upon arrival or within hours of hospitalization alone. Rather, it is more likely driven by the fact that many patients are hospitalized for a long time with sepsis and bloodstream infections (BSI) due to inefficient treatment, complications, intubations, and adverse effects. Sepsis patients admitted to the ICU spend 14 days there on average at a cost of $3,000–4,000/day in the US. In high-income countries, the average hospitalization cost for a sepsis patient is about $32,000.³

What keeps septic patients hospitalized, despite all efforts with early empiric treatment? Sepsis itself is associated with multi-system organ failure and other significant complications. Increasing antibiotic resistance is also a contributing factor. In fact, as antibiotic resistance increases, empiric treatment will often fail. The “one-size-fits-all” approach unfortunately leads to suboptimal antibiotic selection or dosing, as well as failed adjustment of treatment over time.

Failure to adjust therapy can prolong a patient’s clinical course, because sepsis management is a marathon, not a sprint. The answer is precision-guided antibiotic treatment, providing the right therapy, to the right person, at the right time. It relies on access to accurate ultra-rapid diagnostics with low variability, real-time patient monitoring, and a deeper understanding of pharmacokinetics and pharmacodynamics for improved dosing.

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The Challenges of Sepsis Patient Management

Sepsis is a consequence of a dysregulated host response to infection. The most clinically significant cases of sepsis are caused by bacteria.⁴,⁵ Patients with bacterial sepsis frequently go from relatively mild symptoms to multi-organ system failure in a matter of hours. Thus, a clinician must resort to initial empiric therapy, often using broad-spectrum antibiotics in high doses, even though these therapies come with a risk of suboptimal success, adverse effects, and increased global antibiotic resistance. The recommendations from the International Surviving Sepsis Campaign are to initiate antibiotic therapy within the first hours of suspected bacterial sepsis.⁴ Several studies identify increased morbidity and mortality linked to suboptimal and delayed antibiotic therapy.⁶⁻⁹

While early empirical antimicrobial therapy is fundamental for successfully managing bacterial sepsis, it is clearly not the final answer. If that were the case, there would be fewer fatalities, fewer days of hospitalization, and lower costs to our healthcare systems. Sepsis management is not only a sprint to see how fast patients can get antibiotics; it is also a marathon of adjusting treatment to fit the patient’s changing needs and to eradicate the infection. To win the race, both diagnostic tools and healthcare workflows must align to treat sepsis quickly and accurately with the right drug for pathogen involved.

Treat empirically – then identify, adjust and monitor!
Sepsis management in critically ill patients is particularly challenging because the pathophysiological state of the patient can be severely compromised, altering rapidly with catastrophic consequences. In these cases, standard fixed-dose schedules are often insufficient. In fact, they may even contribute to mortality, especially in dealing with highly resistant bacterial infections.

In this context, the apparent convenience of fixed-dosing regimens can be a dangerous lure, promising expedient protocols based on a stepwise broth microdilution series to generate “one-size-fits-all” cures for any infection. But does it always make sense that the same dose of antibiotics is given to an 85-year-old with multiple high-risk medical conditions as to a 25-year-old healthy young athlete? Of course not, and yet antibiotic dosing is often established to try to cover both with the same dose.

The clinical needs and fundamental challenges of bacterial sepsis management

There is no doubt that more precise sepsis management is needed. Any clinician managing a patient with suspected bacterial sepsis is facing at least a four-step process during patient management where each step includes decisions that can determine the success or failure of treatment.¹,¹⁰⁻¹³

Clinical management of bacterial sepsis in four steps

  1. Treat empirically if the patient’s disease severity requires it

  2. Identify the true source of infection and establish source control

  3. Adjust the antibiotic therapy based on clinical response and laboratory results

  4. Monitor and continuously adjust the antibiotic therapy to minimize adverse effects, compensate for the patient’s clinical condition, and optimize dosing during the total duration of therapy

Standardized Treatment

Practitioners in infectious disease have a long history as pioneers in precision and personalized medicine. They integrate laboratory results along with patient-related factors to guide antibiotic treatment effectively. Yet, most antibiotics are still administered based on standardized doses, at best empirically guided by information on background epidemiology and antibiotic resistance levels.¹¹,¹³

Dose-adjusted therapy is usually limited to conventional doses altered only at time of initiation based on patient renal function. However, the actual antibiotic dose is rarely adjusted throughout the course of treatment based on susceptibility results.

In addition, host parameters such as severity of the infection, renal function, hepatic function, sex, height, and weight may vary significantly between different patient groups, leading to changes in antibiotic drug clearance and volume of distribution.¹,¹¹⁻¹⁵ The general immune status of the individual patient also plays a vital role in determining how well he or she responds to different bacterial virulence factors. Moreover, the optimal antibiotic treatment changes over time with each individual patient since the patient’s physiological condition changes over time.

Patient-related factors can also influence potential over- or underdosing, presenting risks of treatment failure or drug-related toxicity and subsequent hepatic or renal failure. If the administered dose is lower than the optimal dose, the treatment can be ineffective and contribute to the increase of antibiotic resistance.

If the administered dose is higher than the optimal dose, the risks of adverse effects are increased. Such “underdosing” or “overdosing” are likely to occur during initial empiric therapy before laboratory results are at hand.

As a result, reliable and timely diagnostics are essential to incorporate both patient, pathogen, and antibiotic factors as well as their interactions over time. This underscores the need for a precision-guided management of bacterial sepsis to reduce mortality, hospitalization time, and cost.

precision-guided-antibiotic-treatment-basis

Entering a New Era

A new era of precision-guided antibiotic treatment not only requires the aforementioned improvements to technology and process, but also an improved understanding and a shift in thinking from all parties. The “precision-guided antibiotic treatment triangle” illustrates the relationships between the patient, the pathogen (in this case bacteria or fungi), and the antibiotic. They all contribute to the resulting antibiotic concentration in the plasma of the patient and the antibiotic exposure to the pathogens.

Therapeutic drug monitoring (TDM) is the practice during which the drug concentration is being monitored in real time to assess the resulting antibiotic exposure. In some cases, the standard treatment can result in a low antibiotic concentration due to the patient’s physiological conditions, but by adjusting the dose the antibiotic exposure is increased as well as the patient’s chance of recovery. Other times, the dose is too high and dose adjustment can help reduce both risks of adverse effects and unnecessary use of antibiotics. Precision-guided antibiotic treatment aims to treat infections on an individual basis, because each case is different, and the success of treatment is determined by multiple factors.

Efforts must be made to improve healthcare workflows and shorten the diagnostic feedback loop for faster access to actionable data, in order for the results to matter to the patient. In addition, strong antibiotic stewardship is needed to drive the advancement of precision-guided antibiotic treatment and increase the whole community’s understanding and willingness to implement measures like rapid AST methods and PK/PD dose optimization, especially in critically ill patients.

For these emerging technologies to fulfill their promise of rapid and precise care, an increased understanding of antibiotic dosing as well as a review of our healthcare workflows is crucial. Most important to drive change may therefore be to promote a strong antibiotic stewardship team and the coalitions between the clinical teams, clinical laboratories, and the pharmacies.

Delivering an accurate, precise, and rapid single MIC measurement is not possible based on legacy AST methods.

The primary challenge for implementing true precision-guided antibiotic treatment in bacterial sepsis has been the difficulty to obtain accurate and precise susceptibility data in time, based on a single run on a single patient sample. Because legacy AST methods are not only inherently slow, they are also subject to considerable variation that arises from factors such as two-fold dilution and truncation errors, manual handling or manual readout.¹⁴ In fact, a test run with legacy AST on the same sample, by the same person, in the same lab, can vary up to 200%.¹⁴ For these reasons, delivering an accurate, precise, and rapid MIC measurement from such single runs is not possible based on legacy methods.

Today, best practice and gold standard AST are methods based on disc diffusion and broth microdilution, which have both been available for decades. Disc diffusion is a qualitative method, while broth microdilution is a quantitative method providing an MIC value. The MIC value is the most common measurement of antibiotic susceptibility.¹⁵ Unfortunately, broth microdilution generates a MIC value with low precision and high variability due to two-fold dilutions of antibiotic concentrations, and the accepted variation is ±1 two-fold dilution.¹⁴⁻¹⁶ Since the clinical breakpoints determining the AST categories are narrow, an MIC value with its magnitude of variation is questionable. Indeed, broth microdilution and other related methods based on two-fold dilution must be run in multiple replicates to provide reliable results with precision.

Even with these limitations, MIC values generated by legacy AST methods are used by clinicians in conjunction with TDM and included in PK/PD-based dose optimization.¹⁶ However, the variability may lead to serious dosing adjustment errors, which could ultimately be harmful to patients, and contribute to development of antibiotic resistance due to suboptimal antibiotic dosing.¹⁷

Through the establishment of emerging next-generation AST in everyday healthcare practice, we are rapidly moving into a new era of precision-guided antibiotic treatment for bacterial sepsis. The MIC value for an antibiotic is closely associated with bacterial growth rate, pharmacodynamics, and a marker for antibiotic susceptibility.

Case: Sophie, 6 years old

Sophie, a 6-year-old with a history of complex congenital heart disease, developed fevers and shortness of breath after multiple surgical repairs. As her condition worsened, an urgent evaluation in the emergency department took place. Blood cultures were drawn and she was given loading doses of vancomycin and cefepime.

Sophie was transferred to the cardiac ICU for further care, where her condition declined further. Blood cultures grew methicillin-resistant Staphylococcus aureus (MRSA), and the initial dosing of vancomycin was 15 mg/kg/dose given intravenously every 6 hours. The resulting antibiotic concentration in plasma was monitored using TDM (Therapeutic Drug Monitoring).

On day two, repeat blood cultures remained positive, and Sophie’s heart function continued to deteriorate. She went to the operating room for surgical evaluation of MRSA endocarditis. Postoperatively, she stabilized but remained in critical condition. The vancomycin concentration in plasma was found to be 19 μg/mL, and Sophie’s renal function continued to decline.

On the third day, the lab reported a vancomycin MIC value for the MRSA isolate of 1 μg/mL (potentially 0.5–2 μg/mL). Following current vancomycin guidelines, the goal was to maintain 10× concentration above the MIC, or an AUC of 400–600 mg·h/L, to clear the infection. But with two-fold MIC variability of 0.5 to 2, maintaining a high vancomycin dose was needed to ensure treatment. Sophie’s blood cultures eventually cleared, but her exposure to vancomycin contributed to progressive renal failure, requiring continuous renal replacement therapy.

With close TDM and constant dose adjustments, Sophie’s renal function slowly improved over time. By day 21, she was discharged home on every 8-hour dosing of vancomycin, completing 6 weeks of therapy for MRSA endocarditis.

What if precision-guided antibiotics treatment and PK/PD dose optimization had been applied?
If an ultra-rapid and precise AST system had demonstrated a vancomycin MIC of precisely 0.6 μg/mL on Day 1–2 of hospitalization, PK/PD dose optimization could have been used to target for a goal trough of 7–10 μg/mL, potentially saving Sophie’s kidneys and reducing morbidity, mortality, hospital cost, and length of stay associated with it.

Case: Emma, 20 years old

 

Emma, a 20-year-old woman with high-risk acute lymphoblastic leukemia, was admitted to the emergency department due to high fever and a low neutrophil count. She was started on empiric cefepime 2g IV every 8 hours, but her blood pressure dropped rapidly. She was transferred to the ICU, where antibiotic coverage was broadened to include an aminoglycoside and vancomycin.

On her second day of hospitalization, she continued to perform poorly in the ICU, needing increased ventilatory and pressor support. Her initial blood culture grew Pseudomonas aeruginosa, which was identified as a multi-drug resistant organism. Due to a relatively high cefepime MIC of 8 μg/mL (potentially 4–16 μg/mL) and slow clinical response, the treatment was switched to meropenem. Emma began to improve clinically over the next few days.

By hospital day 6, her condition was slowly demonstrating improvement. She was extubated and transferred out of the ICU on day 8. She was discharged home on hospital day 11 to complete a 14-day course of meropenem. However, concerns were raised about the potential for carbapenem-resistant organisms appearing with her next neutropenic sepsis event, given her recent course.

What if precision-guided therapy and PK/PD dose optimization had been applied?
If the cefepime MIC value could have been determined to be precisely 5 μg/mL on day two based on ultra-rapid and precise AST results, Emma’s cefepime treatment could have been continued, eliminating her exposure to meropenem and reducing potential antibiotic resistance development. Future TDM of cefepime will help clinicians further target antibiotic concentrations or T > MIC values.

QuickMIC®

Next-generation AST

QuickMIC® is an ultra-rapid AST system which generates high-accuracy MIC values with unmatched precision within 2–4 hours. Studies have shown that QuickMIC can reduce the total turnaround time from patient sampling to clinically actionable MIC result by up to 40%.¹⁸ This shortening of the diagnostic feedback loop can enable improved guidance of antibiotic therapy for the clinician managing bacterial sepsis patients.

QuickMIC uses innovative microfluidics to generate a linear antibiotic concentration gradient with high resolution around the clinical breakpoints. As a result, QuickMIC can provide antimicrobial susceptibility results that are:

  • Accurate – accuracy >95%

  • Precise – variability <5%

  • Ultra-rapid – MIC results in 2–4 hours

Accuracy

Highly accurate MIC results with unprecedented resolution

A recent study by Gradientech suggests that the reference broth microdilution method has a variability exceeding 40%* for the specific set of clinically relevant organisms in the study, most likely due to truncation errors inherent in two-fold dilution methods.¹⁴ In comparison, QuickMIC exhibited a low variability of 5%.

*internal study data

table-2-accuracy

Figure 1.
The variability inherent in legacy AST methods based on logarithmic two-fold dilutions compared to QuickMIC.
QuickMIC would report an MIC value of, for example, 5.60 with 5% variability, while two-fold dilution would have generated an answer of 4, 8, or 16 mg/L, which could be the difference between susceptible (S), susceptible increased exposure (I), or resistant ®.

Precision

High precision provides repeatable and reliable MIC results from single runs

QuickMIC uses microfluidics to generate linear antibiotic concentration gradients with high resolution around clinical breakpoints. This enables the system to deliver high precision MIC results with 5% variability. This single-run preciseness is the key to improved accuracy.

table-3-precision

Figure 2 illustrates how QuickMIC provides MIC values with increased repeatability compared to the reference method (broth microdilution).

Speed

Results in 2–4 hours and same-shift reporting to shorten the diagnostic feedback loop

QuickMIC is the first ultra-rapid AST system, meaning it delivers results in 2–4 hours, enabling the laboratory to complete the entire test process—from sample receipt to reporting—within a single work shift, rather than reporting the next day. This can cut the turnaround time and shorten the diagnostic feedback loop by an average of 40%.¹⁸ and thus save many lives.

table-4-speed

Figure 3 shows how same-shift AST reporting with QuickMIC compares to legacy methods in terms of diagnostic speed.

Summary

Further improvements can be achieved by reviewing hospital workflows and reassessing routines, optimizing them specifically for sepsis patients to further reduce turnaround times leveraging these new capabilities.

However, substantial advancement in sepsis treatment on a global scale cannot be accomplished by solitary efforts within individual clinical laboratories or hospitals. The complexity of these issues requires a strong coalition of clinicians, pharmacists, nurses, laboratorians, and healthcare administration to drive the advancement of precision-guided antibiotic treatment. These coalitions need the power and courage to challenge the status quo and the one-size-fits-all mentality in current sepsis patient management.

Let’s work toward a paradigm shift to fulfill the potential of precision-guided antibiotic treatment in sepsis management—saving lives, reducing unnecessary antibiotic exposure, and lowering healthcare costs.

References

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  2. Torio CM, Moore BJ. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 [cited 2024 Jan 4]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK368492/

  3. Global report on the epidemiology and burden of sepsis: current evidence, identifying gaps and future directions. Geneva: World Health Organization; 2020.

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  5. Dolin HH, Papadimos TJ, Chen X, Pan ZK. Characterization of Pathogenic Sepsis Etiologies and Patient Profiles: A Novel Approach to Triage and Treatment. Microbiol Insights. 2019 Jan 27;12:1178636118825081.

  6. Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009 Nov;136(5):1237–48.
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  8. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589–96.

  9. Barie PS, Hydo LJ, Shou J, Larone DH, Eachempati SR. Influence of antibiotic therapy on mortality of critical surgical illness caused or complicated by infection. Surg Infect. 2005;6(1):41–54.

  10. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet Lond Engl. 2022 Feb 12;399(10325):629–55.

  11. Bulman ZP, Wicha SG, Nielsen EI, Lenhard JR, Nation RL, Theuretzbacher U, et al. Research priorities towards precision antibiotic therapy to improve patient care. Lancet Microbe. 2022 Oct;3(10):e795–802.

  12. Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Individualized antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014 Jun;14(6):498–509.

  13. Rello J, van Engelen TSR, Alp E, Calandra T, Cattoir V, Kern WV, et al. Towards precision medicine in sepsis: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect. 2018 Dec;24(12):1264–73.

  14. Doern GV, Brecher SM. The Clinical Predictive Value (or Lack Thereof) of the Results of In Vitro Antimicrobial Susceptibility Tests. J Clin Microbiol. 2011 Sep;49(9 Suppl):S11–4.

  15. Mouton JW, Muller AE, Canton R, Giske CG, Kahlmeter G, Turnidge J. MIC-based dose adjustment: facts and fables. J Antimicrob Chemother. 2018 Mar 1;73(3):564–8.

  16. Magréault S, Jauréguy F, Carbonnelle E, Zahar JR. When and How to Use MIC in Clinical Practice? Antibiotics (Basel). 2022 Dec 3;11(12):1748.

  17. Landersdorfer CB, Nation RL. Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward. Front Pharmacol. 2021;12:770518.

  18. Malmberg C, Torpner J, Fernberg J, Öhrn H, Ångström J, Johansson C, et al. Evaluation of the Speed, Accuracy and Precision of the QuickMIC Rapid Antibiotic Susceptibility Testing Assay With Gram-Negative Bacteria in a Clinical Setting. Front Cell Infect Microbiol. 2022;12:758262.

Meet the authors

gradientech-author

Guest Post for GRADIENTECH

Gradientech

This in focus paper was compiled by Gradientech presenting data from the article: García-Rivera C, Ricart-Silvestre A, Parra Grande M, Ventero MP, Tyshkovska-Germak I, Sánchez-Bautista A, Merino E, Rodríguez JC. 2024. Evaluation of the QuickMIC system in the rapid diagnosis of gram-negative bacilli bacteremia. Microbiol. Spectr. 12:10.  The study was funded in part by Gradientech on a cost-per-sample basis. Reagents, instruments, and consumables were provided by Gradientech.