Prognostic Biomarkers to Guide Antibiotic Therapy in Critically Ill Patients

As the number of antimicrobial agents dwindles, prognostic biomarkers are becoming important for guiding antibiotic therapy and predicting mortality in patients with cancer.^1,2 The biomarkers proadrenomedullin (proADM), procalcitonin (PCT), and C-reactive protein (CRP) can help clinicians detect whether fever is due to an infection or the malignancy and, as a result, can reduce the unnecessary use of antibiotics in this critically ill population.^1,2

Before the use of such biomarkers, clinicians would rely on cultures to detect the offending pathogens, but the process was time-consuming and hematologic malignancies would frequently render false-positive results.¹ Patients were often treated empirically with antibiotics, which promoted antimicrobial resistance.¹ The biomarker approach, however, can help clinicians to determine the severity of the illness and guide antimicrobial therapy.¹

The Landscape of Biomarkers in Immunocompromised Patients

In a literature review, El Haddad and colleagues suggested that proADM and PCT could have a theranostic role in discerning response to antibiotics and in differentiating tumor fevers from infectious fevers in cancer patients with sepsis and bloodstream infections.²

PCT demonstrated sensitivity as a diagnostic tool for bacterial meningitis, acute pyelonephritis, and spontaneous bacterial peritonitis.² PCT also could discern bacteremia in adults with fever compared with other markers such as erythrocyte sedimentation rate (ESR) and CRP.²

ProADM, like PCT, appears to be present in higher levels in patients with sepsis compared with healthy controls. ProADM appears to have more of a dose response to sepsis than does PCT because higher levels of the marker were discovered in patients with more severe sepsis. Additionally, proADM may be a more sensitive indicator of mortality than PCT for patients in the intensive care unit. In a prospective study, proADM levels were significantly higher at sepsis onset in nonsurvivors than in survivors, but PCT levels were similar in both groups.²

Debiane and colleagues compared the diagnostic and prognostic capabilities of proADM and PCT to CRP in a trial comprising 114 febrile patients with cancer (median age, 57 years; 67% male).¹ They found that proADM and PCT had a significantly greater receiver operating characteristic (ROC) curve for diagnosing bloodstream infections compared with CRP.¹ Both proADM (P =.005) and PCT (P =.009) were superior to CRP in predicting mortality within 2 months after the onset of fever in critically ill patients.¹

PCT Guides Treatment in Respiratory Illness

In a meta-analysis of 26 studies (N=6708) on the use of PCT to direct antimicrobial therapy in patients with respiratory diseases, Schuetz and colleagues found that the biomarker helped guide antibiotic treatment in critically ill adults by reducing unnecessary antibiotic exposure and decreasing adverse effects.³ Use of PCT improved clinicians’ antimicrobial management of acutely ill patients and thus improved patients’ overall outcomes while avoiding the spread of antibiotic resistance.³

The mortality rate for patients for whom clinicians used PCT to guide therapy was significantly reduced vs controls (adjusted odds ratio [OR], 0.83; 95% CI, 0.70-0.99; P =.037). Though the mortality rate was low for patients in primary care and those with acute bronchitis, the mortality benefit was comparable among patient subgroups and clinical settings. PCT reduced both the number of days patients were exposed to antibiotic therapy (5.7 vs 8.1 days; 95% CI, –2.71 to –2.15; P <.0001) and adverse effects (16% vs 22%; adjusted OR 0.68; 95% CI, 0.57-0.82; P <.0001).³

“It is important to realize that many infections are not caused by bacteria and thus antibiotics do not bring any benefit. Results of our paper suggest that lowering antibiotic use has positive effects on outcomes,” said lead author Philipp Schuetz, MD, MPH, professor of internal and emergency medicine at the University of Basel in Switzerland in an interview with Infectious Disease Advisor. “It is important to rule out bacterial infection in patients with respiratory infection — PCT is one elegant way to do that — and not start community-acquired pneumonia or sepsis bundles in all these patients. The same is true for duration of treatment where short courses are often helpful and prolonged antibiotic treatment duration causes significant morbidity if not justified.”

Biomarkers in Critically Ill Children

PCT also triumphed over CRP in diagnosing children who had suspected meningitis.⁴ In an 8-study meta-analysis conducted  by Henry and colleagues (N=616 pediatric patients; mean age, 2.3-6 years), PCT was found to have a pooled sensitivity and specificity of 0.96 (95% CI, 0.92-0.98) and 0.89 (95% CI, 0.86-0.92), respectively, in discerning bacterial from viral meningitis. The pooled sensitivity for CRP was just 0.70 (95% CI, 0.64-0.76), and the specificity was comparable to that of PCT at 0.83 (95% CI, 0.79-0.87).⁴

In 6 of the studies, PCT was found to be significantly more effective than CRP, with a diagnostic odds ratio — one of the most useful measures of a biomarker — of 142.3 (95% CI, 59.5-340.4) vs 16.7 (95% CI, 8.8-31.7), respectively.⁴ The research team also found that PCT is a faster diagnostic tool as compared with CRP (20 minutes vs 50 minutes, respectively). While the Kryptor^TM PCT assay costs more than CRP ($40 vs $10, respectively), the more precise yield lowers hospital costs in the long run.⁴

“While lumbar puncture and cerebrospinal fluid analysis remain the gold standard for diagnosing meningitis in children, PCT is emerging as an important, less-invasive diagnostic adjunct in children with suspected meningitis and other critical illnesses to reduce unnecessary antibiotic usage,” said lead author Brandon Michael Henry, MD, research fellow in the division of cardiac critical care at Cincinnati Children’s Hospital Medical Center in Ohio in an interview with Infectious Disease Advisor. “Though further prospective studies are needed to determine the role of PCT in the clinical diagnostic process, we encourage its use in combination with traditional cerebrospinal fluid analysis and when lumbar puncture must be delayed or is contraindicated to better guide empiric therapy.”

References

1. Debiane L, Hachem RY, Al Wohoush I, et al. The utility of proadrenomedullin and procalcitonin in comparison to C-reactive protein as predictors of sepsis and bloodstream infections in critically ill patients with cancer. Crit Care Med. 2014;42(12):2500-2507.
2. El Haddad H, Chaftari AM, Hachem R, Chaftari P, Raad II. Biomarkers of sepsis and bloodstream infections: the role of procalcitonin and proadrenomedullin with emphasis in patients with cancer [published April 16, 2018]. Clin Infect Dis. doi: 10.1093/cid/ciy331
3. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107.
4. Henry BM, Roy J, Ramakrishnan PK, Vikse J, Tomaszewski KA, Walocha JA. Procalcitonin as a serum biomarker for differentiation of bacterial meningitis from viral meningitis in children: evidence from a meta-analysis. Clin Pediatr (Phila). 2016;55(8):749-764.