Clinical relevance of procalcitonin and C-reactive protein as infection markers in renal impairment: a cross-sectional study

Introduction

Although the clinical application of procalcitonin (PCT) as an infection marker in patients with impaired renal function (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m²) has been increasing recently, it is unclear whether PCT is more accurate than C-reactive protein (CRP). We investigated the clinical value of CRP and PCT based on renal function.

Methods

From November 2008 to July 2011, a total of 493 patients who simultaneously underwent CRP and PCT tests were enrolled. The area under the receiver operating characteristic (ROC) curve and characteristics of both markers were analyzed according to infection severity and renal function.

Results

In patients with impaired renal function, the area under the ROC curve was 0.876 for CRP and 0.876 for PCT. In patients with infection, CRP levels differed depending on whether the infection was localized, septic, or severely septic, whereas PCT levels were higher in patients with severe sepsis or septic shock. In patients without infection, CRP did not correlate with eGFR, while PCT was negatively correlated with eGFR.

Conclusion

This study demonstrates that CRP is accurate for predicting infection in patients with impaired renal function. The study suggests that in spite of its higher cost, PCT is not superior to CRP as an infection marker in terms of diagnostic value.     

Mannan-binding lectin and procalcitonin measurement for prediction of postoperative infection

Introduction

Postoperative infection is a major cause of morbidity and mortality. We investigated two serum markers for their ability to identify patients at risk for postoperative infection. Mannan-binding lectin (MBL) is a central molecule of the innate immune system and MBL deficiency is known to predispose to infection. Procalcitonin (PCT) is a sensitive marker for bacterial infection.

Methods

We investigated 162 patients undergoing elective surgery for cancer of the gastrointestinal tract. Patients were classified as having no complications (group A), having infection for unknown reason (group B) or having sepsis after events like aspiration or anastomotic leakage (group C). Analysis was done pre- and postoperatively for serum levels of MBL, PCT and C-reactive-protein. DNA was preoperatively sampled and stored and later analysed for genetic polymorphisms of MBL.

Results

The preoperative serum levels of MBL were significantly lower in group B patients than in group A patients (1332 ± 466 ng/ml versus 2523 ± 181 ng/ml). PCT measured on day one post-surgery was significantly higher in group B patients than in group A (3.33 ± 1.08 ng/ml versus 1.38 ± 0.17 ng/ml). Patients with an aberrant MBL genotype had a significantly higher risk of postoperative infections than wild-type carriers (p < 0.05).

Conclusion

Preoperative MBL and early postoperative PCT measurement may help identify patients at risk for postoperative infection.     

Marked increase of procalcitonin after the administration of anti-thymocyte globulin in patients before hematopoietic stem cell transplantation does not indicate sepsis: a prospective study

Introduction  

Procalcitonin (PCT) and C-reactive protein (CRP) are established markers of infection in the general population. In contrast, several studies reported falsely increased PCT levels in patients receiving T-cell antibodies. We evaluated the validity of these markers in patients scheduled for hemopoietic stem cell transplantation receiving anti-thymocyte globulin (ATG) during conditioning. We also assessed renal and liver functions and their relationship to PCT and CRP changes.     

Procalcitonin measurement to screen medullary thyroid carcinoma: A prospective evaluation in a series of 2705 patients with thyroid nodules

Background

To prospectively evaluate the role of procalcitonin (PCT) in screening of patients with thyroid nodules for medullary thyroid carcinoma (MTC).

Materials and methods

We measured PCT in 2705 patients with thyroid nodules referred to our centre between January 2011 and December 2017. Those with a positive PCT were operated after positive confirmatory tests such as fine‐needle aspiration, measurement of calcitonin (CT) in serum and fine‐needle aspiration washouts or CT stimulation testing. Patients with a negative PCT were operated based on the results of further diagnostics. The diagnostic performance of PCT was evaluated, and the best cut‐off level was selected by ROC curve analysis.

Results

Among 2705 patients, 9 with positive serum PCT (ie, above 0.1 μg/L) and 370 with negative PCT underwent thyroid surgery. MTC was histologically confirmed in all patients with positive PCT but not found in patients with negative PCT. Serum PCT levels were significantly higher in patients with MTC (median 0.64 μg/L, range 0.16‐12.9 μg/L) than in those without (median 0.075 μg/L, range 0.075‐0.16 μg/L; P < .0001). ROC curves were plotted to calculate the optimal PCT value separating patients with MTC from those without. The best cut‐off was 0.155 μg/L with sensitivity, specificity, positive and negative predictive values as well as accuracy of 100%, 99.7%, 91.7%, 100% and 99.7%, respectively. Positive and negative likelihood ratios were 329 and zero, respectively.

Conclusions

Measurement of PCT is a sensitive and accurate method for detecting MTC in patients with thyroid nodules and can thus be a reliable alternative to CT measurement.     

Procalcitonin testing for diagnosis and short-term prognosis in bacterial infection complicated by congestive heart failure: a multicenter analysis of 4,698 cases

Introduction

Procalcitonin (PCT) is a biomarker for the clinical diagnosis of bacterial infection that is more specific and earlier than fever, changes in white blood cell count, and blood cultures. Congestive heart failure is an important cause of endotoxin resorption from the intestine, which significantly increases PCT expression in noninfected patients with heart failure. The diagnostic performance and cut-off value of PCT in patients with bacterial infection complicated by congestive heart failure needs to be confirmed.

Methods

A total of 4,698 cases from different cities in China, including those with different classes of congestive heart failure, bacterial infection, bacterial infection complicated by heart failure and healthy individuals, were chosen for the diagnostic value analysis of PCT and screening candidate predictors of mortality in subjects with bacterial infection complicated by congestive heart failure.

Results

Patients with simple heart failure had significantly higher PCT levels than normal controls (P < 0.01), whereas patients with bacterial infection complicated by congestive heart failure had significantly higher PCT levels than those with simple infection (P < 0.01). Although it was useful for the diagnosis of infection (area under the receiver operating characteristic curve >80%), the positive predictive value of PCT decreased significantly with increasing severity of heart failure (P < 0.05), and the cut-off value of PCT concentrations for infection complicated by classes II, III and IV heart failure were 0.086, 0.192 and 0.657 μg/L, respectively. Heart failure degree, PCT level, and age were the candidate predictors of mortality in patients with bacterial infection complicated by congestive heart failure.

Conclusions

These data suggest that complicated heart failure elevates the PCT level in patients with bacterial infection. Thus, the results of the PCT test must be analyzed correctly in consideration of the severity of heart failure. Close attention should be paid to cardiac function and PCT expression in aged patients with infection complicated by congestive heart failure.     

Procalcitonin in liver transplantation: are high levels due to donors or recipients?

Introduction

To date, a specific marker to evaluate and predict the clinical course or complication of the liver-transplanted patient is not available in clinical practice. Increased procalcitonin (PCT) levels have been found in infectious inflammation; poor organ perfusion and high PCT levels in the cardiac donor appeared to predict early graft failure. We evaluated PCT as a predictor of early graft dysfunction and postoperative complications.

Methods

PCT serum concentrations were measured in samples collected before organ retrieval from 67 consecutive brain-dead donors and in corresponding recipients from day 0, before liver transplantation, up to day 7 after liver transplantation. The following parameters were recorded in donors: amount of vasopressive drug doses, cardiac arrest history 24 hours before retrieval, number of days in the intensive care unit, age of donor, and infection in donor, and the following parameters were recorded in recipients: cold and warm ischemia time, veno-venous bypass, transfusion amount during orthotopic liver transplantation (OLT), and occurrence of postoperative complication or hepatic dysfunction.

Results

In the donor, the preoperative level of PCT was associated with cardiac arrest and high doses of catecholamines before organ retrieval. In the recipient, elevated PCT levels were observed early after OLT, with a peak at day 1 or 2 after OLT, then a decrease until day 7. A postoperative peak of PCT levels was associated neither with preoperative PCT levels in the donor or the recipients nor with hepatic post-OLT dysfunction or other postoperative complications, but with two donor parameters: infection and cardiac arrest.

Conclusion

PCT level in the donor and early PCT peak in the recipient are not predictive of post-OLT hepatic dysfunction or other complications. Cardiac arrest and infection in the donor, but not PCT level in the donor, are associated with high post-OLT PCT levels in the recipient.     

Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial

Introduction  

The development of resistance by bacterial species is a compelling issue to reconsider indications and administration of antibiotic treatment. Adequate indications and duration of therapy are particularly important for the use of highly potent substances in the intensive care setting. Until recently, no laboratory marker has been available to differentiate bacterial infection from viral or non-infectious inflammatory reaction; however, over the past years, procalcitonin (PCT) is the first among a large array of inflammatory variables that offers this possibility. The present study aimed to investigate the clinical usefulness of PCT for guiding antibiotic therapy in surgical intensive care patients.     

Procalcitonin biomarker kinetics fails to predict treatment response in perioperative abdominal infection with septic shock

Introduction

Procalcitonin (PCT) biomarker is suggested to tailor antibiotic therapy in the medical intensive care unit (ICU) but studies in perioperative medicine are scarce. The aim of this study was to determine whether PCT reported thresholds are associated with the initial treatment response in perioperative septic shock secondary to intra-abdominal infection.

Methods

This single ICU, observational study included patients with perioperative septic shocks secondary to intra-abdominal infection. Demographics, PCT at days 0, 1, 3, 5, treatment response and outcome were collected. Treatment failure included death related to the initial infection, second source control treatment or a new onset intra-abdominal infection. The primary endpoint was to assess whether PCT thresholds (0.5 ng/ml or a drop from the peak of at least 80%) predict the initial treatment response.

Results

We included 101 consecutive cases. Initial treatment failed in 36 patients with a subsequent mortality of 75%. Upon admission, PCT was doubled when treatment ultimately failed (21.7 ng/ml ± 38.7 vs. 41.7 ng/ml ± 75.7; P = 0.04). Although 95% of the patients in whom PCT dropped down below 0.5 ng/ml responded to treatment, 50% of the patients in whom PCT remained above 0.5 ng/ml also responded successfully to treatment. Moreover, despite a PCT drop of at least 80%, 40% of patients had treatment failure.

Conclusions

In perioperative intra-abdominal infections with shock, PCT decrease to 0.5 ng/ml lacked sensitivity to predict treatment response and its decrease of at least 80% from its peak failed to accurately predict treatment response. Studies in perioperative severe infections are needed before using PCT to tailor antibiotic use in this population.     

A comparison of high-mobility group-box 1 protein,lipopolysaccharide-binding protein and procalcitonin in severe community-acquired infections and bacteraemia: a prospective study

Introduction  

High-mobility group box-1 protein (HMGB1) has been known as a chromosomal protein for many years. HMGB1 has recently been shown to be a proinflammatory cytokine with a role in the immunopathogenesis of sepsis. Lipopolysaccharide-binding protein (LBP) has a central role in the innate immune response when the host is challenged by bacterial pathogens. Procalcitonin (PCT) has been suggested as a marker of severe bacterial infections and sepsis. The aim of the present study was to investigate levels of HMGB1, LBP and PCT in a well-characterised sepsis cohort. The study plan included analysis of the levels of the inflammatory markers in relation to the severity of infection, to the prognosis and to the ability to identify patients with bacteraemia.     

Procalcitonin for diagnosis of bacterial pneumonia in critically ill patients during 2009 H1N1 influenza pandemic: a prospective cohort study,systematic review and individual patient data meta-analysis

Introduction

Procalcitonin (PCT) is helpful for diagnosing bacterial infections. The diagnostic utility of PCT has not been examined thoroughly in critically ill patients with suspected H1N1 influenza.

Methods

Clinical characteristics and PCT were prospectively assessed in 46 patients with pneumonia admitted to medical ICUs during the 2009 and 2010 influenza seasons. An individual patient data meta-analysis was performed by combining our data with data from five other studies on the diagnostic utility of PCT in ICU patients with suspected 2009 pandemic influenza A(H1N1) virus infection identified by performing a systematic literature search.

Results

PCT levels, measured within 24 hours of ICU admission, were significantly elevated in patients with bacterial pneumonia (isolated or coinfection with H1N1; n = 77) (median = 6.2 μg/L, interquartile range (IQR) = 0.9 to 20) than in patients with isolated H1N1 influenza pneumonia (n = 84; median = 0.56 μg/L, IQR = 0.18 to 3.33). The area under the curve of the receiver operating characteristic curve of PCT was 0.72 (95% confidence interval (CI) = 0.64 to 0.80; P < 0.0001) for diagnosis of bacterial pneumonia, but increased to 0.76 (95% CI = 0.68 to 0.85; P < 0.0001) when patients with hospital-acquired pneumonia and immune-compromising disorders were excluded. PCT at a cut-off of 0.5 μg/L had a sensitivity (95% CI) and a negative predictive value of 80.5% (69.9 to 88.7) and 73.2% (59.7 to 84.2) for diagnosis of bacterial pneumonia, respectively, which increased to 85.5% (73.3 to 93.5) and 82.2% (68.0 to 92.0) in patients without hospital acquired pneumonia or immune-compromising disorder.

Conclusions

In critically ill patients with pneumonia during the influenza season, PCT is a reasonably accurate marker for detection of bacterial pneumonia, particularly in patients with community-acquired disease and without immune-compromising disorders, but it might not be sufficient as a stand-alone marker for withholding antibiotic treatment.     

Substantially elevated C-reactive protein (CRP), together with low levels of procalcitonin (PCT), contributes to diagnosis of fungal infection in immunocompromised patients

Purpose

Serum procalcitonin (PCT) has become a routinely utilized parameter with a high prediction value of the severity of bacterial infectious complications and their immediate outcomes. Whereas the utility of PCT in differentiating between bacterial and viral infection is generally accepted, its significance in fungal infections has yet to be determined. The aim of the study was to determine the role of PCT testing in patients at high risk for invasive fungal infections.

Methods

Immunocompromised hematological patients undergoing cyclic chemotherapy treatment or allogeneic hemopoietic stem cell transplantation with infectious complications in which the infectious agents were identified during the disease course were evaluated. In patients with bacterial infection, positive hemocultures were documented, and in patients with fungal infection, the presence of either proven or probable disease was confirmed according to Ascioglu criteria. C-reactive protein (CRP) and PCT were prospectively assessed from the day following fever onset, for four consecutive days.

Results

Overall, 34 patients were evaluated, 21 with bacterial and 13 with fungal infections. Significant elevations of CRP concentrations (i.e., above the upper normal limit) were observed in all patients, with a tendency toward higher levels in bacterial (both gram-positive [Gr+] and Gr-negative [Gr?]) than in fungal infections. PCT levels were significantly elevated in patients with bacterial infections (e.g., predominantly in Gr? compared to Gr+), whereas in patients with fungal infections, we identified minimal or no PCT elevations, p?<?0.01. For the fungal infections, according to constructed receiver operating characteristic curves, a combination of PCT <0.5 μg/L and CRP 100–300 mg/L offers the best specificity, sensitivity and positive and negative predictive values (81, 85, 73, and 89 %, respectively).

Conclusion

Altogether, our data suggest that the finding of substantially elevated CRP combined with low PCT in immunocompromised patients may indicate systemic fungal infection. The use of this combination might simplify the diagnostic process, which otherwise can often be lengthy and arduous.     

The diagnostic value of CRP, IL-8, PCT, and sTREM-1 in the detection of bacterial infections in pediatric oncology patients with febrile neutropenia

Purpose  

In this study, we evaluated C-reactive protein (CRP), interleukin (IL)-8, procalcitonin (PCT), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as predictors for bacterial infection in febrile neutropenia, plus their usefulness in febrile neutropenia during chemotherapy-induced gastrointestinal mucositis.     

Procalcitonin-guided antibiotics in severe sepsis

Citation

Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J: Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008, 177: 498–505 [1].

Background

The duration of antibiotic therapy in critically ill patients with sepsis can result in antibiotic overuse, increasing the risk of developing bacterial resistance. Procalcitonin (PCT)-guided antibiotic use reduces antibiotic exposure in community-acquired pneumonia. Whether it might also reduce antibiotic exposure in severe sepsis is unknown.

Methods

Objective

To test the hypothesis that an algorithm based on serial measurements of PCT allows reduction in the duration of antibiotic therapy compared with empirical rules, and does not result in more adverse outcomes in patients with severe sepsis and septic shock.

Design

Single-center, non-blinded randomized controlled trial.

Setting

Mixed medical and surgical ICU at a university teaching hospital.

Subjects

79 adult patients with suspected severe sepsis or septic shock.

Intervention

All patients had circulating PCT levels drawn daily. In patients randomly assigned to the intervention group, antibiotics were stopped when PCT levels had decreased 90% or more from the initial value (if clinicians agreed) but not before Day 3 (if baseline PCT levels were <1 mg/L) or Day 5 (if baseline PCT levels were >1 mg/L). In control patients, clinicians decided on the duration of antibiotic therapy based on empirical rules.

Outcome

Systemic antibiotic exposure, measured using three variables: 1) duration of antibiotic treatment, 2) antibiotic exposure days per 1000 inpatient days, and 3) days alive without antibiotics within the 28-day follow-up period.

Results

Patients assigned to the PCT group had 3.5-day shorter median duration of antibiotic therapy for the first episode of infection than control subjects (intention-to-treat, n = 79, P = 0.15). In patients in whom a decision could be taken based on serial PCT measurements, PCT guidance resulted in a 4-day reduction in the duration of antibiotic therapy (per protocol, n = 68, P = 0.003) and a smaller overall antibiotic exposure (P = 0.0002). A similar mortality and recurrence of the primary infection were observed in PCT and control groups. A 2-day shorter intensive care unit stay was also observed in patients assigned to the PCT group (P = 0.03).

Conclusion

Our results suggest that a protocol based on serial PCT measurement allows reducing antibiotic treatment duration and exposure in patients with severe sepsis and septic shock without apparent harm.     

Discriminative value of inflammatory biomarkers for suspected sepsis

Background

Circulating biomarkers can facilitate sepsis diagnosis, enabling early management and improved outcomes. Procalcitonin (PCT) has been suggested to have superior diagnostic utility compared to other biomarkers.

Study Objectives

To define the discriminative value of PCT, interleukin-6 (IL-6), and C-reactive protein (CRP) for suspected sepsis.

Methods

PCT, CRP, and IL-6 were correlated with infection likelihood, sepsis severity, and septicemia. Multivariable models were constructed for length-of-stay and discharge to a higher level of care.

Results

Of 336 enrolled subjects, 60% had definite infection, 13% possible infection, and 27% no infection. Of those with infection, 202 presented with sepsis, 28 with severe sepsis, and 17 with septic shock. Overall, 21% of subjects were septicemic. PCT, IL6, and CRP levels were higher in septicemia (median PCT 2.3 vs. 0.2 ng/mL; IL-6 178 vs. 72 pg/mL; CRP 106 vs. 62 mg/dL; p < 0.001). Biomarker concentrations increased with likelihood of infection and sepsis severity. Using receiver operating characteristic analysis, PCT best predicted septicemia (0.78 vs. IL-6 0.70 and CRP 0.67), but CRP better identified clinical infection (0.75 vs. PCT 0.71 and IL-6 0.69). A PCT cutoff of 0.5 ng/mL had 72.6% sensitivity and 69.5% specificity for bacteremia, as well as 40.7% sensitivity and 87.2% specificity for diagnosing infection. A combined clinical-biomarker model revealed that CRP was marginally associated with length of stay (p = 0.015), but no biomarker independently predicted discharge to a higher level of care.

Conclusions

In adult emergency department patients with suspected sepsis, PCT, IL-6, and CRP highly correlate with several infection parameters, but are inadequately discriminating to be used independently as diagnostic tools.     

Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome

Introduction  

Management of the early stage of sepsis is a critical issue. As part of it, infection control including appropriate antibiotic therapy administration should be prompt. However, microbiological findings, if any, are generally obtained late during the course of the disease. The potential interest of procalcitonin (PCT) as a way to assess the clinical efficacy of the empirical antibiotic therapy was addressed in the present study.     

Procalcitonin,as an early biomarker of colorectal anastomotic leak,facilitates enhanced recovery after surgery

Purpose

Procalcitonin (PCT) is a biomarker used to help sepsis diagnosing and monitoring and guide antibiotic therapy. Anastomotic leak (AL) after colorectal surgery is a severe complication associated with relevant short- and long-term sequelae. The aim of our study is to assess the predictive value of PCT levels to early diagnose AL after colorectal surgery.

Methods

Between September 2011 and September 2012, a series of 99 patients underwent colorectal surgery in our institution. In all cases, white blood cell (WBC) count, C-reactive protein (CRP), and PCT levels were measured in first, third, and fifth postoperative day (POD). Anastomotic leaks and all other postoperative complications were recorded.

Results

We registered 7 ALs (7.1%). Decreased PCT levels had a significant negative predictive value (NPV) for AL in third and fifth POD (96.7% and 96.7%, respectively), compared with CRP and WBC. The best diagnostic performance was obtained with the combination of PCT and CRP measurements in third and fifth POD (area under the curve, 0.87 and 0.94, respectively). In 5th POD, PCT improves diagnosis, but not in a statistically significant way (area under the curve, 0.86).

Conclusions

Compared with more established biochemical values such as CRP and WBC, PCT is an earlier, more sensitive, and reliable marker of AL. Increased PCT levels in early PODs after colorectal surgery may provide a more effective way to detect AL, before clinical symptoms appear. Moreover, normal PCT values might be also a useful marker to facilitate a safe and early discharge of selected patients after colorectal surgery.     

Serum procalcitonin as a diagnostic marker for neonatal sepsis: a systematic review and meta-analysis

Purpose  

To assess the value of serum procalcitonin (PCT) for the differentiation between patients with and without neonatal sepsis.     

Procalcitonin and C-reactive protein during systemic inflammatory response syndrome,sepsis and organ dysfunction

Introduction  

Both C-reactive protein (CRP) and procalcitonin (PCT) are accepted sepsis markers. However, there is still some debate concerning the correlation between their serum concentrations and sepsis severity. We hypothesised that PCT and CRP concentrations are different in patients with infection or with no infection at a similar severity of organ dysfunction or of systemic inflammatory response.     

Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: a multicenter observational study

Introduction

The intent of this study was to determine whether serum procalcitonin (PCT) levels are associated with prognosis, measured as organ dysfunctions and 28-day mortality, in patients with severe pneumonia.

Methods

This was a multicenter, observational study of critically ill adult patients with pneumonia requiring mechanical ventilation conducted in 10 academic hospitals in Canada, the United States, and Central Europe. PCT was measured daily for 14 days using an immuno-luminometric assay.

Results

We included 175 patients, 57 with community acquired pneumonia (CAP), 61 with ventilator associated pneumonia (VAP) and 57 with hospital acquired pneumonia (HAP). Initial PCT levels were higher in CAP than VAP patients (median (interquartile range: IQR); 2.4 (0.95 to 15.8) vs. 0.7 (0.3 to 2.15), ng/ml, P < 0.001) but not significantly different to HAP (2.2 (0.4 to 8.0) ng/ml). The 28-day ICU mortality rate for all patients was 18.3% with a median ICU length of stay of 16 days (range 1 to 142 days). PCT levels were higher in non-survivors than in survivors. Initial and maximum PCT levels correlated with maximum Sequential Organ Failure Assessment (SOFA) score r² = 0.50 (95% CI: 0.38 to 0.61) and r² = 0.57 (0.46 to 0.66), respectively. Receiver operating curve (ROC) analysis on discrimination of 28-day mortality showed areas under the curve (AUC) of 0.74, 0.70, and 0.69 for maximum PCT, initial PCT, and Acute Physiology and Chronic Health Evaluation (APACHE) II score, respectively. The optimal cut-off to predict mortality for initial PCT was 1.1 ng/ml (odds ratio: OD 7.0 (95% CI 2.6 to 25.2)) and that for maximum PCT was 7.8 ng/ml (odds ratio 5.7 (95% CI 2.5 to 13.1)).

Conclusions

PCT is associated with the severity of illness in patients with severe pneumonia and appears to be a prognostic marker of morbidity and mortality comparable to the APACHE II score.     

The utility of presepsin in diagnosis and risk stratification for the emergency patients with sepsis

Objectives

To evaluate the value of presepsin in diagnosis and risk stratification of septic patients in emergency department, and investigate the utility in differentiation of gram-positive and gram-negative bacterial infection.