Fever is a common occurrence in the ICU patient with an incidence up to 70%.¹ Therefore, evaluation of a new fever in an ICU patient should always begin with a thorough review of the patient’s history and a focused physical examination, rather than automatic ordering of microbiologic studies.² After a differential diagnosis is formulated based on the history and physical examination, pertinent laboratory and radiologic studies should then be performed.

The differential diagnosis of a new fever in an ICU patient includes both infectious and noninfectious etiologies (Table 56-1).^2-4 The most common infectious etiologies include hospital-acquired pneumonia (including ventilator-associated pneumonia), intravascular catheter-related bloodstream infection, catheter-associated urinary tract infection, surgical site infection, and Clostridium difficile infection. Additional infections common to a neurologic/neurosurgical ICU include (1) superficial and deep surgical site infections that occur after neurosurgical procedures (eg, superficial wound infection after laminectomy or deep abscess after craniotomy) and (2) bacterial meningitis occurring after placement of internal and external ventricular catheters and lumbar catheters. Drug-related fever and intracranial hemorrhage are common noninfectious etiologies of fever in a neurologic/neurosurgical ICU.

Hospital-acquired pneumonia (HAP) is defined as the development of pneumonia ≥ 48 hours after hospital admission. Ventilator-associated pneumonia (VAP) is a subtype of HAP that occurs ≥ 48 to 72 hours after endotracheal intubation. The diagnosis of HAP/VAP is initially suspected on the basis of clinical findings, including fever, peripheral blood leukocyte count, quality and quantity of tracheal secretions, changes in oxygenation, and chest radiography.⁵ The development of a new or progressive radiographic pulmonary infiltrate combined with two of three clinical criteria—(1) fever higher than 38°C (100.4°F), (2) purulent tracheal secretions, and (3) leukocytosis—are highly suggestive of HAP/VAP.^5-7

All patients with suspected HAP/VAP should, whenever possible, have cultures of respiratory tract secretions obtained. Gram staining and culture of respiratory tract sections can help determine the microbial etiology of HAP/VAP and should be collected prior to starting or changing antibiotic therapy. Lower respiratory tract secretion samples may be cultured either (1) semiquantitatively (typically via an endotracheal aspirate sample), which is usually reported as heavy, moderate, light, or no growth; or (2) quantitatively (via bronchoalveolar lavage [BAL], protected specimen brush [PSB], or endotracheal aspirate), where a specific colony count is reported. For quantitative cultures, growth above a certain threshold may help distinguish infection from colonization. The following thresholds are commonly used to diagnose infection, assuming antibiotic therapy was not started or changed in the 24 to 72 hours before obtaining the culture: ≥ 10⁴ colony-forming units (CFU)/mL for BAL samples, ≥ 10³ CFU/mL for PSB samples, and ≥ 10⁶ CFU/mL for endotracheal aspirate samples.^4,7-9 These thresholds may be lowered if recent antibiotic changes were made or if the pretest probability of HAP/VAP is very high.

There is controversy regarding which culture method (semiquantitative or quantitative culture) is preferred. The benefits of obtaining a semiquantitative culture include rapid sampling (via an endotracheal aspirate) and lack of need for specialized microbiology techniques. Although semiquantitative cultures are more sensitive than quantitative cultures, they are less specific because tracheal secretions rather than deeper respiratory tract secretions are sampled and a specific colony count is not reported. This makes it more difficult to distinguish between colonization and infection. Quantitative cultures may be more specific, thus potentially decreasing the rate of false-positive culture results. The disadvantages of quantitative cultures are that bronchoscopy is generally required and specialized microbiologic techniques are needed.

Clinical trials comparing the two methods have not shown a difference in mortality or length of ICU stay,^8-9 and the data are conflicting on whether obtaining quantitative cultures decreases antibiotic use.

Empiric antibiotic therapy should be initiated as soon as possible after a lower respiratory tract sample is obtained for culture. The rationale for prompt treatment is that a delay in appropriate antibiotic therapy has been associated with a higher attributable mortality rate from HAP/VAP.^10,11 In order to increase the probability of administering appropriate antibiotic therapy, the initial empiric antibiotic regimen should be based on the patient’s risk for multidrug-resistant (MDR) pathogens. For patients at risk for MDR pathogens, combination therapy for gram-negative bacilli and coverage for methicillin-resistant Staphylococcus aureus (MRSA) is recommended to maximize the chance of appropriate antibiotic therapy.

After initiating appropriate empiric antibiotic therapy for HAP/VAP, clinical improvement (based on peripheral blood leukocyte count, temperature, oxygenation, and quantity of tracheal secretions) typically begins to occur by 48 to 72 hours.^12,13 By this point in time, the results of lower respiratory tract culture data should be available, and the initial empiric antibiotic therapy regimen can be modified by either narrowing or expanding treatment for an organism not being covered. Narrowing antibiotic therapy is important to minimize the emergence of antibiotic resistance.¹⁴

Modification of the empiric antibiotic regimen should be based on results of lower respiratory tract culture data. Lower respiratory tract cultures can be influenced by prior antibiotic exposure and the technique used to obtain them (semiquantitative vs quantitative). Often organisms may grow in culture that are not typically respiratory pathogens (eg, enterococci and candida species) and should generally be considered to represent colonization. A negative lower respiratory tract culture in an intubated patient may be clinically useful, as it has a strong negative predictive value for HAP/VAP in the absence of a recent change in antibiotic therapy in the preceding 72 hours. In addition, in an intubated patient, a lower respiratory tract culture that does not grow an MDR pathogen, in the absence of a recent change in antibiotic therapy in the preceding 72 hours, suggests that these pathogens are not causing HAP/VAP and antibiotic therapy can be narrowed accordingly.¹⁵

There was improvement in the patient’s fever, leukocytosis, and oxygenation after 48 hours. A semiquantitative endotracheal aspirate culture subsequently grew moderate Klebsiella pneumoniae (susceptible to levofloxacin and cefazolin) and blood cultures were negative. Vancomycin and cefepime were discontinued, and levofloxacin was continued.

The rationale for using empiric combination antibiotic therapy for HAP/VAP while awaiting culture data is to maximize the chance of administering appropriate antibiotic therapy. Once antimicrobial susceptibility data return, therapy can usually be narrowed to a single agent, which includes treatment of P aeruginosa. Although it is true that P aeruginosa has the ability to develop resistance during antibiotic treatment, data do not support the idea that combination therapy improves outcome.^16,17 For patients with pseudomonal pneumonia complicated by bacteremia (usually in the setting of neutropenia), some experts recommend a course of combination therapy, although this is again not strongly supported by data.¹⁸

The current recommendations for treatment of HCAP/VAP-caused MRSA are to use either vancomycin or linezolid. There are insufficient data to suggest an advantage of linezolid over vancomycin. Although a recent clinical trial showed an advantage in bacterial eradication and time to clinical improvement among the linezolid-treated patients, it did not demonstrate a mortality benefit over vancomycon.¹⁹ Furthermore, two recent meta-analyses did not demonstrate superiority in clearance of MRSA from sputum or any clinical outcome.^20,21 However, when treating patients with vancomycin, it is important to ensure adequate blood levels of the drug (with concentrations of 15-20 μg/mL), which often requires high doses. An additional factor that may influence the treatment of MRSA HAP/VAP is the minimum inhibitory concentration (MIC) of MRSA to vancomycin. For patients with MRSA HAP/VAP where the vancomycin MIC is ≥ 2 μg/mL, use of an alternate agent has been suggested (eg, linezolid) because of a concern for treatment failure if vancomycin is used.²²

In the past, the recommended duration of antibiotic therapy for HAP/VAP was as high as 14 to 21 days. However, prolonged antibiotic treatment has been associated with the emergence of drug-resistant bacteria. Furthermore, several clinical trials and meta-analyses have established the safety and efficacy of shorter antibiotic courses for the treatment of HCAP and VAP.^23-28 In a large clinical trial comparing 8 vs 15 days of antibiotic treatment for VAP, there was no difference in mortality rate or recurrent infections between the two groups.²³ Furthermore, among patients who developed recurrent VAP and received 15 days of antibiotic treatment, there was a higher rate of emergence of MDR pathogens compared with patients who received 8 days of treatment. However, in the subgroup of patients who developed pneumonia due to nonfermenting gram-negative bacilli (ie, P aeruginosa and Acinetobacter species), there was a higher VAP recurrence rate in patients in the short-course arm vs the long-course arm. Similarly, for VAP caused by MRSA longer courses may be necessary.²⁷ On the basis of these data, a shorter duration (7-8 days) of antibiotic therapy for HAP/VAP is recommended for patients who clinically respond to treatment and who are not infected with nonfermenting gram-negative bacilli or MRSA.⁵ For patients infected with nonfermenting gram-negative bacilli, longer antibiotic treatment should be considered.

There are several interventions that can reduce the risk of VAP (Table 56-2). These include (1) avoiding intubation when possible through the use of noninvasive positive pressure ventilation when appropriate, (2) minimizing the duration of mechanical ventilation by using protocols to reduce sedation exposure and accelerate ventilator liberation, and (3) preventing aspiration of gastric and oropharyngeal contents by positioning intubated patients in the semi-recumbent position (ie, 30° to 45° elevation of the head of the bed). Continuous suctioning of subglottic secretions by special endotracheal tubes with separate subglottic lumen may also reduce VAP rates but are more expensive and are recommended only in patients in whom mechanical ventilation is anticipated for > 48 hours. Routine oral care with chlorhexidine to reduce bacterial colonization of the mouth is also recommended. Selective decontamination of the digestive tract with oral and/or intravenous antibiotics may reduce the risk of HAP/VAP; however, this strategy is not currently recommended because of the potential for selecting for antibiotic-resistant microorganisms.²⁹

Bacteriuria (ie, significant growth of bacteria in urine) is a very common finding in patients with indwelling urinary catheters, and the majority of patients are asymptomatic.³⁰ It is estimated that the incidence of bacteriuria is between 3% and 8% per day of urinary catheterization.^30-32 The duration of catheterization is the most important risk factor for the development of catheter-associated bacteriuria, and almost all patients develop bacteriuria after 1 month of catheterization.^30,33

The majority of patients with bacteriuria do not develop symptoms or signs of infection. The proportion of patients with catheter-associated bacteriuria that develop symptomatic infection is < 25%.^31,32,35 The proportion of patients with catheter-associated bacteriuria who develop bacteremia is even lower, ranging between < 1% and 4%.^36,37 The reason for the low rates of symptomatic infection in patients with catheter-associated bacteriuria is unclear; however, it has been hypothesized that decompression of the urinary tract with a urinary catheter prevents obstruction, which is known to predispose to symptomatic urinary tract infection and bacteremia.³⁴