Clinical Diagnosis of Infection in Surgical Intensive Care Unit: You're Not as Good as You Think!

Abstract

Background:

Because of the everincreasing costs and the complexity of institutional medical reimbursement policies, the necessity for extensive laboratory work-up of potentially infected patients has come into question. We hypothesized that intensivists are able to differentiate between infected and non-infected patients clinically, without the need to pan-culture, and are able to identify the location of the infection clinically in order to administer timely and appropriate treatment.

Methods:

Data collected prospectively on critically ill patients suspected of having an infection in the surgical intensive care unit (SICU) was obtained over a six-month period in a single tertiary academic medical center. Objective evidence of infection derived from laboratory or imaging data was compared with the subjective answers of the three most senior physicians' clinical diagnoses.

Results:

Thirty-nine critically ill surgical patients received 52 work-ups for suspected infections on the basis of signs and symptoms (e.g., fever, altered mental status). Thirty patients were found to be infected. Clinical diagnosis differentiated infected and non-infected patients with only 61.5% accuracy (sensitivity 60.3%; specificity 64.4%; p = 0.0049). Concordance between physicians was poor (κ = 0.33). Providers were able to predict the infectious source correctly only 60% of the time. Utilization of culture/objective data and SICU antibiotic protocols led to overall 78% appropriate initiation of antibiotics compared with 48% when treatment was based on clinical evaluation alone.

Conclusion:

Clinical diagnosis of infection is difficult, inaccurate, and unreliable in the absence of culture and sensitivity data. Infection suspected on the basis of signs and symptoms should be confirmed via objective and thorough work-up.

Infections are difficult to diagnose, especially in critically ill surgical patients, in whom fever, the most common and easily detectable sign and symptom of infection, affects 44%–70% of all surgical intensive care unit (SICU) admissions [1,2]. Only one-third to one-half of fevers that occur in the SICU actually are attributable to an infectious process, yet fever often is the impetus for diagnostic work-up or initiation of treatment [2,3]. The intensivists' decision to proceed with laboratory evaluation or to start antimicrobial therapy in a possibly infected, critically ill patient ultimately comes down to a balance between four important factors: (1) The certainty of the diagnosis; (2) the risk of delaying therapy effective against the causative pathogen(s); (3) the environmental damage and the potential patient harm caused by the use of antimicrobial drugs in those who are not infected; and (4) the monetary implications of unnecessary testing, with the additional risk of uncovering hospital-acquired infections (HAIs) [4,5].

In 2008, the American College of Critical Care Medicine (ACCM) and the Infectious Diseases Society of America (IDSA) created a task force of 11 experts in critical care and infectious disease for the purpose of updating practice features for the evaluation of new fever in critically ill adult patients. They concluded that a “cost-conscious” approach, using mainly clinical data (history and physical examination) should guide the evaluation [5,6]. Costly laboratory tests and imaging studies in a setting of fever should follow a subjective patient assessment, with elimination of automatic ordering of tests, which also was deemed disruptive to patients and staff [6]. The experts added that empiric antibiotics should be initiated when clinical evaluation suggests that fever is secondary to an infection and withheld them when non-infectious sources of fever, including, but not limited to, stroke, venous thrombosis, or drug fever, are more likely [4]. Therapy should be directed toward the most likely pathogens suggested by the presumed/hypothesized source of infection, patient risk factors, and local knowledge of antimicrobial susceptibilities [6].

Organizations such as IDSA and the Surgical Infection Society (SIS) have advocated for antibiotic stewardship programs that establish guidelines and protocols for appropriate antibiotic utilization in the hope of improving patient outcomes, decreasing hospital costs, preventing misuse and overuse of antibiotics, and minimizing environmental damage [7]. These protocols are, however, based on the least subjective methods of evaluation (in vitro antimicrobial susceptibilities). Despite the full objective work-up of potentially infected patients, with infectious laboratory data available, 30%–50% of antibiotics are thought still to be inappropriately or unnecessarily prescribed, leading to increased short- and long-term patient deaths, antibiotic resistance, and HAIs such as Clostridioides difficile [4,8 –12].

Infectious data that were used in the past for clinical or epidemiologic purposes now are reported to the National Healthcare Safety Network (NHSN) and the Centers for Medicare and Medicaid Services (CMS) and are used to adjust hospital reimbursement rates. Since 2008, CMS has stopped payment for the evaluation and treatment of HAIs, supporting the policy change and encouraging hospitals to provide higher-quality care with fewer adverse events [13]. The CMS Hospital-Acquired Conditions (HAC) Reduction Program began in 2014 in response to Section 3008 of the Affordable Care Act (ACA). This program compares hospitals on the basis of regional and national HAI benchmark data and reduces payments to those classified as poor performers, although the results may not be adjusted appropriately for patient risk factors [5]. Many facilities may be in jeopardy of losing millions of dollars of funding per year for reporting HAIs.

The environment in which the intensivists practice is extremely complex, with great pressure placed on establishing proper diagnosis in a setting of competing interests. Providing high-quality patient care always is the primary goal, but minimization of HAIs also is vital to the health system. The intensivists have the difficult task of ensuring proper diagnosis in highly complicated patients, without over- or under-prescribing of antibiotics in order to minimize patient morbidity and deaths. Imperfect clinical evaluation or laboratory data may result in identification of colonization, among other conditions, subjecting the hospital to erroneous monetary penalties. Whether intensivists are able to diagnose and treat infections on the basis of clinical examination alone, in order to avoid extensive and costly laboratory work-up and in turn prevent identification of unnecessary colonization or treatment of infections, has come into question. We hypothesized that physicians are able to differentiate accurately between non-infectious and infectious causes of fever, choose the location of infection, and discern the appropriate course of treatment without the need for culture data.

Patients and Methods

Study population

This prospective study was conducted as a part of a quality improvement project at Parkland Memorial Hospital, a large safety-net hospital and Level 1 Trauma Center in Dallas, Texas, from December 2013 to July 2014. Nine Board-certified intensivists, who are trauma/acute care surgeons, and four critical care surgical fellows in conjunction with surgical residents manage the 32-bed SICU, which functions as a closed unit. The SICU team members write all patient care orders. This quality improvement project was granted an exemption by the University of Texas Southwestern Medical Center's Institutional Review Board.

All critically injured or ill patients who were admitted to the SICU for longer than 48 hours and were suspected of having a new infection after developing a fever (>38.4°C) were evaluated for inclusion in the study. Subjects were enrolled on the basis of the inclusion criteria presented in Supplementary Data 1.

Infection definitions, diagnosis, and work-up

With the exception of catheter-related infections, definitions of infections followed the U.S. Centers for Disease Control and Prevention (CDC) Guidelines [14,15]. The diagnosis of pneumonia was based on systemic evidence of infection, production of sputum, clinical pulmonary infection score (CPIS), isolation of a predominant organism, development of a new or changing infiltrate or effusion on chest radiograph (CXR), or growth of >100,000 colony-forming units (CFU) on quantitative culture of a specimen obtained by endotracheal aspiration (ETA) or >10,000 CFU in a sample harvested by bronchoalveolar lavage (BAL). Blood stream infections (BSIs) were diagnosed by isolating organisms from any single blood culture obtained using aseptic technique except for coagulase-negative Staphylococcus (e.g., Staphylococcus epidermidis). Diagnosis of coagulase-negative Staphylococcus BSI required growth from two separate blood cultures. Urinary tract infections (UTIs) required growth of either >100,000 organisms/mL of urine or >10,000 organisms/mL in the presence of genitourinary symptoms. Catheter-related infections were defined as isolation of >15 colonies with the semi-quantitative roll plate technique in the setting of clinical infection with possible but not necessarily positive blood culture yielding the same organism(s). Catheter tips were cultured when removed because of suspicion of infection (e.g., white blood cell count, elevated temperature, clinical findings). Infections of the skin, soft tissue, or wound or incision or those involving the peritoneum were confirmed by cultures when indicated.

All study subjects underwent a standard clinical infection evaluation, including urinalysis (UA), urinary and blood cultures, Gram stain, and pulmonary secretion testing [16 –18]. If there was concern about an intra-thoracic or intra-abdominal source of infection, computed tomography (CT) images of the thorax or abdomen and pelvis were carried out. When indicated, cultures were obtained, and surgical control of infection or percutaneous drainage of an abscess was performed. Diagnosis of infections routinely made without extensive testing (e.g., surgical site infections), a full diagnostic work-up typically was not obtained unless the patient suffered from additional signs/symptoms. Supplementary Data 2 outlines the culturing protocols.

For hemodynamically stable patients, SICU protocols followed conservative rather than aggressive initiation of antibiotics as outlined by Hranjec et al. Antibiotics were started when preliminary testing (e.g., UA, Gram stain, CXR) was positive and delayed until culture growth was observed when initial testing was negative [4]. Hemodynamically unstable patients received fluid resuscitation with boluses of crystalloid solution until they were euvolemic (urine output of 0.5 mL/kg per hour), as advocated by the Surviving Sepsis Campaign [16,17]. To help guide resuscitation, lactic acid was measured serially. Persistent hypotension (mean arterial pressure [MAP] <65 mm Hg despite aggressive fluid resuscitation) was treated with vasopressor agents (norepinephrine followed by vasopressin). When possible, a central venous pressure of 8–12 mm Hg was targeted; however, mixed venous saturation of oxygen (ScVO₂) was measured only rarely. Cardiac evaluation was initiated when septic shock failed to resolve. Per sepsis protocols, these patients also were treated with early initiation of a broad-spectrum empiric antibiotic [19]. Intensivist-initiated empiric antibiotic coverage was based on our hospital antibiogram and the guidance of the SICU pharmacists. For all patients, antibiotics were tailored on the basis of culture and sensitivity reports as they became available.

Despite negative culture data, leukocytosis or fever persisted in multiple patients, often without a known cause (infectious or non-infectious). Antibiotics were continued at the discretion of the treatment team but evaluated retrospectively for the accuracy of diagnosis and appropriateness of treatment. Consult from physicians who specialize in infectious disease was obtained at the discretion of the treatment team.

Study protocol

To determine the accuracy of a clinical diagnosis of infection, a group of physicians was surveyed at the time of the infectious work-up, before objective evidence became available. The survey results were later compared with the laboratory data, including cultures and imaging studies, ultimately following “the gold standard” for the presence or absence of infection as described above (except for infections typically diagnosed clinically, such as surgical site infections). The physician survey group, whose clinical decision-making was being evaluated, comprised the three most senior physicians involved in the care of the individual patient. In an academic setting, these decisions most often are made by faculty in conjunction with fellows and senior residents. In order to create the most realistic patient-care scenario, only physicians familiar with the patient and responsible for his or her treatment at the time of the infectious work-up were chosen to disclose their opinion. Survey group members, which included the operating team, answered the infectious disease questionnaire independently at the time of the fever work-up, simply providing a clinical opinion without any culture/laboratory results or relevant objective data.

The survey assessed the clinician's interpretation of the patient's condition, including diagnosis of infection, infectious source, as well as the work-up and treatment. For each patient, data included a degree of certainty (continuous scale from 1 to 5, with 1 being completely uncertain and 5 being absolutely certain) associated with the diagnosis. Paired survey and objective data were compared for each patient. A blinded Board-certified critical care physician or physician specializing in infectious disease or both was consulted if the patient's infectious diagnosis was still in question several days after the objective data became available. Regardless of the physician survey, obtained prior to the availability of objective data (pre-culture), antibiotics were adjusted to align with our institution's antibiogram and post-culture results in order to provide appropriate patient diagnosis and treatment. Antibiotic and Infection Questionnaires are provided as Supplementary Data 3 and 4.

Outcomes and statistical methods

Baseline demographic data, including patient age, gender, and ethnicity, were collected for each subject. Data describing the patient's body habitus (body mass index [BMI]), co-morbidities, hospital care (e.g., diagnosis, operative details, imaging results, and basic laboratory data), hospital and SICU length of stay (LOS), and disposition/death were collected prospectively. At the time of the suspected infection, each patient's risk of death was calculated using two scoring systems: Acute Physiology and Chronic Health Evaluation (APACHE) IV and Acute Physiology Score (APS) [20].

Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the physician's clinical ability to discriminate between patients with and without infection on the basis of clinical signs, symptoms, and early diagnostic findings. A χ² test determined the correlation of the physician survey and work-up results. Continuous variables were compared with the two-tailed Student t-test; continuous variables with a skewed distribution were compared with the Mann-Whitney U or Wilcoxon rank sum test. All continuous values were expressed as mean ± standard error (SE) or median with interquartile range (IQR). Inter-rater concordance was evaluated by the Fleiss κ test. All statistical analyses were performed using SAS software, V. 9.1.3 (SAS Institute Inc., Cary, NC).

Secondary outcomes were in-hospital death, incidence of SICU-acquired infections, appropriateness of initial and overall antimicrobial therapy, and identification of resistant pathogens. Appropriate antimicrobial treatment was defined as effective use of antibiotics active against all pathogens (in vitro culture confirmation). Appropriate therapy of an infected patient was defined as initiation of the correct antibiotic with the proper length of treatment and timely termination when the treatment was completed; in the case of empiric therapy, antibiotics required de-escalation. In non-infected patients, the appropriateness of treatment was marked as being treated appropriately if no antibiotics were initiated. If, however, antibiotics were started empirically, discontinuation of treatment was paramount once cultures were found to be negative, and infection was excluded. Continued antibiotic use after a negative culture was considered appropriate only if clinically indicated for reasons determined by the care team (e.g., fever with continued hypotension, pressor use, clinical decline, etc.).

Results

Thirty-nine patients (15.1%) of 258 consecutive SICU admissions developed signs and symptoms implying a new infection and were enrolled prospectively in the study. At the time of infectious work-up, fever (hyperthermia or hypothermia as outlined in Supplementary Table 2) was noted in 11 of 15 infected and 31 of 37 non-infected patients. The study generated 52 laboratory/objective evaluations and 156 independent physician surveys (three per infectious episode). Note that several patients experienced multiple infectious episodes; work-up confirmed 37 infectious episodes, eight of which involved multiple sources of infection, resulting in 46 total confirmed infections (Fig. 1).

FIG. 1.

Evaluation of 52 potentially infected patients. Ultimately, 37 patients were found to have a positive infectious work-up, 15 patients a negative one.

Table 2.

Sources of Fever

Infection source	N (%)	Clinical diagnosis accuracy (%)	Non-infection source	N (%)
Pneumonia	31 (67.4)	65.6	Aspiration pneumonitis	2 (13.3)
Bacteremia	5 (10.9)	32.0	Extremity ischemia	2 (13.3)
Intra-abdominal	4 (8.7)	80.0	Intra-abdominal ischemia	3 (20.0)
Urinary tract	4 (8.7)	31.3	Brain injury related	2 (13.3)
Soft tissue	2 (4.3)	83.3	Unknown/unidentified	6 (40.0)
Total	46		Total	15

Summary of patient fever sources, including 46 total individual infection sources (in 37 infectious episodes) and 15 non-infection related sources. Percentages identify proportion of each confirmed source of infection or non-infectious source triggering suspected infectious episode. Percentage of correct diagnoses by clinicians for infection source also are reported for each type of infection.

Patient demographics and co-morbidities are presented in Table 1. The population was diverse despite the large proportion of trauma patients (n = 24; 61.5%). High APS and APACHE IV scores indicated that the patients were severely ill, required prolonged hospital and SICU LOS, and had a predicted mortality rate of almost 30%. Approximately 20% of the patients died during the study period (n = 8). Additionally, 90% of the patients underwent at least one surgical procedure during their hospital stays, and more than 50% received more than two procedures. The median time from SICU admission to infectious work-up was 4.5 days (IQR 2.0–8.25 days). The median time from the surgical procedure until infectious work-up was 2.0 days (IQR 0.0–7.0 days).

Table 1.

Patient Demographics, History, and Outcomes

Demographics	Patients ( n = 39) (%)
Age^a (years)	48.2 ± 2.9
Male	31 (79.5)
Race/ethnicity
Caucasian	21 (53.9)
Black	5 (12.)8
Hispanic	12 (30.8)
Asian	1 (2.6)
Disease/co-morbidities^b
Hypertension	15 (28.5)
Obesity	14 (25.9)
Body Mass Index^a (BMI)	29.6 ± 0.9
High-density lipoprotein	9 (23.1)
Trauma	24 (61.5)
Transfusion <24 h	13 (34.2)
Sepsis/shock	14 (35.9)
APS^a	60.9 ± 3.6
WBC^a	15.4 ± 1.8
Temp max^a	38.5 ± 0.2
ICU LOS^a (days)	25.7 ± 9.2
Hospital LOS^a (days)	47 ± 11.4
Deaths	8 (20.5)
Predicted mortality rate^a	28.7 ± 3.5

Mean ± standard error of the mean.

Other co-morbidities: pulmonary disease = 6; acute renal failure = 6; diabetes mellitus = 5; coronary artery disease/congestive heart failure = 4; cerebrovascular accident = 4; seizures = 4; dysrhythmia = 3; chronic kidney disease = 3; immunosuppression = 3; liver disease = 3; malignant disease = 3; obstructive sleep apnea = 3; end-stage renal disease = 2; pulmonary embolism/deep vein thrombosis = 2; psychiatric history = 1; posterior vitreous detachment = 1; thyroid disease = 1.

APACHE = Acute Physiology and Chronic Health Evaluation; APS = Acute Physiology Score; ICU = intensive care unit; LOS = length of stay; WBC = white blood cell count.

Objective data

Pneumonia was the most common source of infection, followed by BSI, intra-abdominal, urinary tract, and soft tissue (Table 2). Infectious work-up, in addition to blood cultures, CXR, UA, and physical examination, required eight patients (15.4%) to undergo a CT scan, with five studies revealing a source of infection. Fifteen infectious episode evaluations (28.8%) revealed no infectious source (Fig. 1) despite extensive work-up, prompting early discontinuation of antibiotic therapy in cases in which it was initiated empirically.

Survey data

A total of 96 of the 156 surveys (61.5%) identified infection or lack thereof correctly in patients whose signs and symptoms prompted a full infectious work-up (e.g., fever, hypotension, altered mental status, leukocytosis). Clinical diagnosis demonstrated only moderate diagnostic accuracy, with a sensitivity of 60.3%, specificity of 64.4%, PPV of 80.7%, and NPV of 39.7% (Table 3).

Table 3.

Summary of Physician's Ability to Diagnose Infection Accurately on the Basis of Clinical Signs and Symptoms vs. Confirmed Laboratory Work-up

Survey-based clinical evaluation	Laboratory-confirmed infection	Laboratory found no infection	Total
Concern for infection	67	16	83
No concern for infection	44	29	73
Total	111	45	156

Pearson χ²; p = 0.0049.

Sensitivity 60.3% (interquartile range [IQR} 50%–69); specificity 64.4% (IQR 49%–78%); positive predicted value = 80.7% (IQR 70%–88%); negative predictive value 39.7% (IQR 29%–52%).

Overall, clinicians did not have strong confidence in their diagnosis of infection, as the average score was 3.5, indicating only moderate certainty. Interestingly, they seemingly were more confident when making an erroneous diagnosis, with a score of 3.56 compared with 3.28 for the correct diagnoses, although this difference was not statistically significant (p = 0.12). All three physicians agreed on the diagnosis (sometimes erroneously) only 50% of the time; 35% of the time they agreed on the correct diagnosis, and 15% of the time, they agreed on an incorrect diagnosis (Table 4). Overall, survey inter-rater reliability was poor (Fleiss κ = 0.33).

Table 4.

Physician Survey Concordance for All Suspected Infectious Episodes

Physician agreement	All patients (n = 52) (%)	Infected (n = 37) (%)	Non-infected (n = 15) (%)
Rate of concordance, κ^a	0.33	0.36	0.12 -
Agreement by three physicians	26 (50)	20 (54)	6 (40)
Correct clinical diagnosis	18 (35)	13 (35)	6 (40)

Intra-reviewer reliability is reported with Fleiss κ.

Antibiotic treatment

Objective infectious data ensured overall appropriate antibiotic use—initiation (starting or withholding) and discontinuation—in 40 of the 52 infection episodes; 30 (81%) infected and 10 (66.7%) non-infected episodes, yielding an overall success rate of 77%. More specifically, appropriate antibiotic initiation occurred in 32 of 37 infected (86.5%) and 8 of 15 non-infected (53.3%) episodes; appropriate discontinuation occurred in 33 of 37 infected (89.2%) on completion of therapy and 9 of 15 non-infected episodes (60%) when cultures failed to grow any organisms. In non-infected patients, antibiotic treatment continued in three of six episodes (20%), in which fever persisted despite negative cultures. The remaining three patients with persistent negative cultures were marked as neither appropriate nor inappropriate for antibiotic discontinuation: (1) patient required antibiotic prophylaxis after rib plating; (2) prophylactic antibiotics were used because of an open fracture; and (3) fever was considered to be secondary to traumatic brain injury. Therefore, antibiotics were never started, and the patient was marked as having had appropriate antibiotic treatment.

When antibiotics were administered on the basis of clinical judgment alone (without protocols or objective data), antibiotics would have been initiated correctly in 25 infectious episodes: 14 infected (37.8%) and 11 non-infected (73.3%), an overall 48.1% success rate. In hypotensive patients, in whom rapid intervention is paramount, initiation of antibiotics on the basis of clinical judgment alone was correct in 23 evaluations: 19 infected (70.4%) and 4 non-infected (44%), an overall 63.8% success rate. Without objective evidence of infection (e.g., CT, CXR, UA, culture data), clinical diagnosis would have led to four non-infected patients receiving antibiotics needlessly and 16 infected patients being undertreated (17 pneumonias, four UTIs, two BSIs, and one intra-abdominal infection). Patients with multiple infections were the most vulnerable to under-treatment, with only 26.7% of co-infections suspected. Resistant organisms were cultured in 13 evaluations (28.8%), 5 of which (38.5%) were organisms resistant to the empiric antibiotics used.

Discussion

This study was designed to evaluate the need for objective laboratory/radiographic data prospectively for the purpose of diagnosing infections in critically ill and injured surgical patients. The need for full infectious work-up has been called into question because of the fear that simply colonization, rather than infection, would be uncovered, leading to inappropriate treatment and a simultaneous “wrongful” (monetary) penalty for HAIs. Conversely, inappropriate treatment or delay in appropriate treatment may increase patient morbidity and death [4,17]. We demonstrated that clinicians were able to discriminate between infectious and non-infectious physiology based on clinical evaluation alone only 61.5% of the time, consistent with previously published studies [21 –23]. This suggests that obtaining objective infectious data in surgical patients, who are critically ill, may be an essential component of the diagnosis and management in order to improve patient outcomes [24,25]. This continues to be evident as microbial resistance to antibiotics increases and infectious treatment becomes more complex.

The uncertainty attached to the clinical diagnosis of infection in critically ill patients is well known, given that patients often exhibit signs and symptoms of infection (e.g., systemic inflammatory response) having non-infectious causes (e.g., pancreatitis, burns, venous thrombosis, aspiration, transfusion, ischemia, neurologic injury) [21]. Barie et al. studied 2,419 critically ill patients with fever and found an infectious origin only 46% of the time: Most commonly secondary to intra-abdominal infection, pneumonia, or skin/soft tissue infections [21]. Aarts et al. reported initiation of antibiotics based on clinical findings and suspicion of infection in 143 patients, yet only 26 (18.2%) were found to be truly infected, highlighting the fact that signs and symptoms are woefully imprecise and that even experienced intensivists have a difficult time identifying infected patients correctly without objective data [22]. Additionally, clinical models using CPIS, APACHE score, and pro-calcitonin concentration were found to be poor predictors of infection in critically ill surgical populations [23,26].

The fact that clinical evaluation may not be adequate should not be surprising. Among critically ill patients with a medically and surgically complicated history, the presence of a variety of invasive supportive devices (e.g., endotracheal tubes, nasogastric tubes, central venous or arterial catheters, and urinary catheters) provides a wide array of potential infectious and non-infectious sources of fever. Clinically, only 60.4% of infected and 64.4% of the non-infected conditions were identified correctly by surveyed physicians, who were intimately involved in patient care. Consequently, overall sensitivity, specificity, PPV, and NPV were discouragingly low. In addition, agreement among physicians was low—only 50% of the time did all three physicians agree on the diagnosis—and 15% of the time, an erroneous diagnosis was agreed on. According to the evidence presented in this study, attempts at a site-directed diagnostic work-up (without pan-culturing) based solely on clinical suspicion would result in delay or incorrect diagnosis in a critically ill population.

Although diagnosis of infection alone is difficult, identifying the source of infection may be even more challenging. On occasion, even objective laboratory data (e.g., pan-culturing) falls short in revealing the site of infection; therefore, reliance on clinical assessment alone may be impossible. Kalil et al. recommend non-invasive sampling (e.g., ETA) with semi-quantitative cultures over invasive sampling (e.g., bronchoalveolar lavage, protected specimen brush) with quantitative cultures to diagnose ventilator-associated pneumonia (VAP) [27]. However, ETA was found to have the highest sensitivity (75%) and comparable specificity ranges (47%–80%) for ETA with any growth compared with other diagnostic methods [27]. In our study, pneumonia was the most frequently encountered infection, but intra-abdominal infection was the easiest infection to diagnose clinically, likely because of the abdominal physical findings of peritonitis, abdominal distention, and ileus. Accuracy of infectious diagnosis in pneumonia increased with more classical presentation: Difficulty weaning from mechanical ventilation, purulent tracheal aspirates, and cough. However, without obvious clinical findings, and in cases when multiple/simultaneous infections occur, many infections would remain undiagnosed without further objective work-up.

When infection and infectious source in a setting of fever are difficult to identify, physicians often start antibiotics empirically to avoid a delay in antibiotic administration. Conservative, rather than aggressive, initiation of antibiotics improves the mortality rate in hemodynamically stable patients, yet withholding antimicrobial therapy has been difficult in critically ill patients [4]. Numerous studies, including the Surviving Sepsis Campaign, have shown that early administration of antibiotics is associated with better outcomes, including a reduction in in-hospital death [16,17]. Yet when fever continues without objective data identifying the infection, the decision to stop antibiotics is difficult, especially when clinical diagnosis suggests an infectious origin. On the other hand, overuse of antibiotics leads to a higher mortality rate and is associated with the development of resistant infections such as methicillin-resistant Staphylococcus aureus and opportunistic infections such as Clostridioides difficile [4,11,28 –33]. In our study, the rate of overall appropriate use of antibiotics following objective data and antibiotic initiation protocols was high at 78%. Without these set protocols or data, clinical assessment alone would have resulted in only 48% of patients receiving appropriate antibiotic therapy, with non-infected patients (20%) often receiving prolonged treatment because of clinical uncertainty. Concerningly, the survey found that experienced clinicians would have initiated antibiotics inappropriately half the time in hemodynamically stable patients.

Several previous studies have established a direct link between appropriate antibiotic administration and decreased patient deaths, but clinician uncertainty over infectious diagnosis has led to antimicrobial overuse or occasional under-prescribing. Although many physicians have suggested that early administration of antibiotics is necessary to prevent death, a prospective study by Hranjec et al. demonstrated that antimicrobial appropriateness, even when treatment is slightly delayed, in the setting of active resuscitation was critical in reducing deaths, ventilator days, and hospital LOS [4,12,34]. Avoiding antibiotic overuse, decreasing antimicrobial resistance, and applying de-escalation protocols on the basis of objective data may hold the key to improving patient outcomes. Hurford et al. demonstrated that rates of Pseudomonas infection with resistant strains were decreased by implementation of protocols aimed at reduction of antibiotic use in the ICU [31]. Garnacho-Montero et al. showed that appropriate de-escalation of antimicrobial therapy was associated with a better 90-day mortality rate [35]. Furthermore, antibiograms can provide guidance for application and de-escalation of therapy based on aggregated data. In our study, resistant organisms were cultured almost 30% of the time; and of those, one-third were inappropriately treated without objective data. Appropriate antibiotic administration can, therefore, be achieved only when culture and sensitivity data are available via thorough and objective patient evaluation.

Since 2005, CMS has not reimbursed for treatment of HAIs, which account for the majority of infections in the SICU. However, as Brown et al. found, not all HAIs are preventable, given that interventions aimed at eliminating them cannot alter host responses or pathogen virulence [36]. Empiric treatment of HAIs without culture data, in order to avoid CMS penalties, risks inappropriate or inadequate treatment, ultimately increasing medical expenditure, but more importantly, worsening patient outcomes. Paul et al., in a meta-analysis combining 70 studies, found an overall rate of 46.5% of inappropriate empiric coverage with a 35% mortality rate and a pooled odds ratio of 2.11 for death with inadequate and inappropriate antibiotic use [34]. Piskin et al. demonstrated longer times to resolution of symptoms, duration of intubation, and overall hospital LOS when patients were treated inadequately for VAPs [12]. Hospital-associated infections, with their reported cost of $6.65 billion in 2007, continue to impose significant economic strain [37].

Probably HAIs will continue to occur in critically ill patients until new ways are discovered to prevent the onset of these infections. Therefore, objective data gathering via imaging and standardized work-up that includes blood, urine, or bronchial cultures, although costly, is necessary to preserve patient life and prevent the downstream consequences of incorrect or delayed therapy.

There were some limitations of this study. It was a single-site study with a small sample, which limits the generalizability of our data despite the significant findings. Our culturing, diagnostic, and treatment protocols may not be reflective of protocols at other institutions. A future study should include medical ICU patients to have a more inclusive hospital population. Although our goal was to replicate a traditional hospital setting, we recognize that including different training levels (e.g., fellows) also may be a limitation. The inherent disadvantages of customized surveys also are applicable: Inaccurate reporting, question misinterpretation, and data errors. Respondents may not have been comfortable providing accurate and honest answers, especially if those responses presented them in an unfavorable manner.

Conclusion

Clinical diagnosis of infection in critically ill patients is complicated. Initial decision-making often is based on clinician experience and patient presentation, causing opinions to differ widely among practitioners. Systematic and thorough work-up, including cultures, is required for targeted and appropriate management, as well as good facility-wide antibiotic stewardship practices. Our study confirmed that clinical judgement alone is insufficient to diagnose infection and treat patients appropriately. A triad of clinical judgment, cultures, and antibiotic stewardship is required to enhance patient outcomes.

Footnotes

Author Disclosure Statement

The authors have no commercial associations that might create a conflict of interest and have nothing to disclose.

Supplementary Material

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