Early infection diagnosis and targeted antibiotic guidance

Fever is often the only symptom of an ongoing infection in infants and young children. As a result, it can be difficult to correctly assess the type and severity of the infection. Knowing that any   bacterial infection can quickly escalate to a severe  infection such as pneumonia and even sepsis , pediatricians often choose to prescribe antibiotics despite the risk of antibiotic overuse and resistance.The biomarker procalcitonin (PCT), in conjunction with the patient’s medical history and presentation, gives clinicians what they need most in these cases: a way to quickly verify initial suspicions of bacterial infection in order to prescribe empiric antibiotics more judiciously and reduce antibiotic exposure.

It is estimated that 50% of all pediatric antimicrobial prescriptions are unnecessary1

PCT supports differential diagnosis in pediatric emergency departments

 

Fever with an unknown source

Although most children presenting with fever have a benign and self-limiting illness, a small percentage are at risk of developing a severe bacterial infection requiring rapid therapeutic intervention with antibiotic therapy.

In a multicentric study on 1,112 febrile pediatric patients, <3 months of age, admitted to European emergency departments, PCT was the only independent risk factor for invasive bacterial infection with an odds ratio of 21.69. for PCT ≥0.5 µg/L.2 The study used a step-by-step approach that was subsequently validated and showed a negative predictive value for ruling out an IBI of 99.3%. Compared with the Rochester criteria and the Lab-score, the Step-by-Step algorithm, which includes PCT, confirmed its superior accuracy in identifying patients at low risk of IBI, and could be more suitable for outpatient management.3

Diagnostic value of PCT in children with fever without source (FWS)4
PPV = positive predictive value
NPV = negative predictive value

Meningitis

Acute bacterial meningitis is a rare but life-threatening infection requiring immediate antibiotic treatment.

A European multicenter case-cohort study (six study centers, n=198) identified PCT as the best biomarker, with an odds ratio of 139 to distinguish between bacterial and aseptic meningitis in children.5 PCT was therefore also included into a clinical decision rule for meningitis in children and in clinical guidelines.5-7

Receiver operating characteristics (ROC) curves of the best predictors differentiating bacterial from aseptic meningitis (n=198).5

Diagnostic value of PCT in children with meningitis.5
PPV = positive predictive value
NPV = negative predictive value

Neutropenic fever

Bacterial infections are life-threatening for neutropenic patients. Therefore, rapid differentiation of bacterial infection from other causes of fever is essential in decision-making around care.8,9 In a meta-analysis of 3,585 febrile episodes in neutropenic children, PCT was shown to be superior to other biomarkers (e.g., CRP, IL6) for early prediction of bacterial infection.10

Diagnostic value of PCT in children with neutropenic fever.10
PPV = positive predictive value
NPV = negative predictive value

Urinary tract infection (UTI)

PCT appears to be the most useful marker in differentiating lower urinary tract infection (cystitis) from upper urinary tract infection (pyelonephritis).11 Elevated PCT levels may also predict vesicoureteral reflux and subsequent renal scarring, which can result in a 38% reduction in unnecessary cystourethrographies with DMSA (technetium-99m [99mTc]-dimercaptosuccinic acid) in children, lowering costs by about 30%.12,13

Diagnostic value of PCT in children with urinary tract infection (UTI),11 and clinical performance characteristics of PCT for prediction of vesicoureteral reflux (VUR) and renal scarring in children with first febrile pyelonephritis.13
PPV = positive predictive value
NPV = negative predictive value

 


 

PCT-aided antibiotic therapy in children 

Fever and other signs of inflammation occur in 82% of patients admitted to pediatric intensive care units (PICUs). Of these patients, 23% are experiencing sepsis. However, in the PICU it is difficult to reliably distinguish infected versus non-infected patients because clinical and laboratory signs may be similar.8

PCT has been proven to be the most useful tool for early identification of sepsis in the PICU, superior to other markers such as CRP or leukocyte count.14

Receiver operating characteristics (ROC) curves for prediction of sepsis in patients admitted to the PICU; comparing PCT, CRP, and leukocyte count (n=94).14

PCT-aided antibiotic therapy in children 

Upper and lower respiratory tract infection (LRTI) is the most common infection in children. Pneumonia is the number one cause of childhood mortality worldwide.15 Etiologic diagnosis is not generally achieved and the pathogen eludes identification in most cases. As a result, over-prescription of antibiotics is frequently observed in hospital departments treating very young children.16

 

PCT has been proven to be a useful guide for safe and efficient antibiotic treatment, meeting the individual needs of both adults and children.15,17-19 The use of PCT-aided antibiotic therapy in children with respiratory tract infections of varying severity leads to a significant reduction of antibiotic exposure, for two reasons: reduced prescription rate and earlier discontinuation of antibiotics.15,18 This was associated with a significant reduction of antibiotic-related side effects like diarrhea.

 

PCT-aided antibiotic therapy in children with respiratory tract infections leads to a significant reduction of antibiotic exposure and related adverse effects like diarrhea.

PCT group had an overall reduction of 3.4 days in comparison to the control group

Pediatric patients (n=215) with community-acquired pneumonia (CAP) were randomized into two groups: a control group, with regular standards of care; and another group in which PCT-aided algorithms for antibiotic prescriptions were used. Antibiotic treatments were tracked for both groups over a 22-day period.15  

PCT-based clinical algorithms support a more targeted use of antibiotics for pediatric patients

In a Cochrane study two sets of randomized-controlled studies were reviewed: 14 studies with n=4,221 adult patients and seven studies with n=2,605 patients from the emergency department. The review found that physicians can safely use PCT in making decisions about the initiation and duration of antibiotic therapy, without affecting mortality or treatment failure. 20

 

In the studies, the initiation, continuation, or termination of antibiotic treatment in pediatric patients was also strictly guided by PCT cut-off levels used in previous trials in adults with LRTI. In the control group, antibiotic treatment was initiated based on physician assessment and clinical guidelines.15 

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References
  1. McCaig LF, Besser RE, Hughes JM. Trends in antimicrobial prescribing rates for children and adolescents. JAMA. 2002;287:3096-102.
  2. Gomez B, Bressan S, Mintegi S, Da Dalt L, Blazquez D, Olaciregui I, et al. Diagnostic value of procalcitonin in well-appearing young febrile infants. Pediatrics. 2012 Nov 1;130(5):815-22.
  3. Gomez B, Mintegi S, Bressan S, Da Dalt L, Gervaix A, Lacroix L. Validation of the “step-by-step” approach in the management of young febrile infants. Pediatrics. 2016 Aug 1;138(2).
  4. Yo CH, Hsieh PS, Lee SH, Wu JY, Chang SS, Tasi KC, et al. Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: A systematic review and meta-analysis. Ann Emerg Med. 2012 Nov 1;60(5):591-600.
  5. Dubos F, Korczowski B, Aygun DA, Martinot A, Prat C, Galetto-Lacour A, et al. Serum procalcitonin level and other biological markers to distinguish between bacterial and aseptic meningitis in children: a European multicenter case cohort study. Arch Pediatr Adolesc Med. 2008 Dec 1;162(12):1157-63.
  6. AMWF guideline “Viral Meningoenzephalitis [Internet]. AWMF. [cited 2021Mar23]. Available here.
  7. Société de pathologie infectieuse de langue française (SPILF. Practice guidelines for acute bacterial meningitidis (except newborn and nosocomial meningitis). Medecine et maladies infectieuses. 2009 Jun;39(6):356-67.
  8. Pacifico L, Osborn JF, Natale F, Ferraro F, De Curtis M, Chiesa C. Procalcitonin in pediatrics. Adv Clin Chem. 2013 Jan 1;59:203-63.
  9. Hatzistilianou M, Rekleity A, Athanassiadou F, DeLutiis MA, Conti P, Catriu D. Serial procalcitonin responses in infection of children with secondary immunodeficiency. Clin Invest Med. 2007 Apr 1:E75-85.
  10. Phillips RS, Wade R, Lehrnbecher T, Stewart LA, Sutton AJ. Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer. BMC Med Educ. 2012 Dec;10(1):1-3.
  11. Chen SM, Chang HM, Hung TW, Chao YH, Tsai JD, Lue KH, et al. Diagnostic performance of procalcitonin for hospitalised children with acute pyelonephritis presenting to the paediatric emergency department. Emerg Med J. 2013 May 1;30(5):406-10.
  12. Leroy S, Romanello C, Galetto-Lacour A, Smolkin V, Korczowski B, Rodrigo C, et al. Procalcitonin to reduce the number of unnecessary cystographies in children with a urinary tract infection: a European validation study. J Pediatr. 2007 Jan 1;150(1):89-95.
  13. Liao PF, Ku MS, Tsai JD, Choa YH, Hung TW, Lue KH, et al. Comparison of procalcitonin and different guidelines for first febrile urinary tract infection in children by imaging. Pediatr Nephrol. 2014 Sep;29(9):1567-74.
  14. Rey C, Los Arcos M, Concha A, Medina A, Prieto S, Martinez P, Prieto B. Procalcitonin and C-reactive protein as markers of systemic inflammatory response syndrome severity in critically ill children. Intensive Care Med. 2007 Mar;33(3):477-84.
  15. Baer G, Baumann P, Buettcher M, Heininger U, Berthet G, Schäfer J, Bucher HC, Trachsel D, Schneider J, Gambon M, Reppucci D. Procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infection in children and adolescents (ProPAED): A randomized controlled trial. PLoS One. 2013 Aug 6;8(8):e68419.
  16. Versporten A, Sharland M, Bielicki J, Drapier N, Vankerckhoven V, Goossens H. The antibiotic resistance and prescribing in European Children project: a neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide. Pediatr Infect Dis J. 2013 Jun 1;32(6):e242-53.
  17. Esposito S, Tagliabue C, Picciolli I, Semino M, Sabatini C, Consolo S, Bosis S, Pinzani R, Principi N. Procalcitonin measurements for guiding antibiotic treatment in pediatric pneumonia. Respir Med. 2011 Dec;105(12):1939-45.
  18. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. ProHOSP Study Group. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009 Sep 9;302(10):1059-66.
  19. Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet Inf Dis. 2004 Feb 21;363(9409):600-7.
  20. Schuetz P, Muller B, Christ‐Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Evidence‐Based Child Health: Cochrane Database Syst Rev. 2013 Jul;8(4):1297-371.