The use of adjunctive inhaled antibiotics in VAP has been evaluated in several

studies. A systematic review of 16 observational studies and randomized trials

without blinding revealed that aerosolized colistin was associated with microbial

eradication (OR, 1.61; 95% CI, 1.11–2.35) and improved clinical response (OR,

1.57; 95% CI, 1.14–2.15) but the results were limited by several biases.

131 A

systematic review of 12 observational and randomized trials with some blinding

showed that nebulized antibiotics in patients with VAP had some benefit in patient

outcomes. Nebulized antibiotics were associated with increased rate of clinical cure

(RR, 1.23; 95% CI, 1.05–1.43).

132 Neither studies showed an improvement in

mortality, duration of mechanical ventilation, or length of stay in the intensive care

unit.

ALTERNATIVE DOSING OF ANTIBIOTICS FOR MULTIDRUGRESISTANT PATHOGENS

Carbapenems, cephalosporins, and extended-spectrum penicillins or β-lactamase

inhibitors demonstrate time-dependent killing, and it is known that bactericidal

killing for these drug classes is optimized if their free drug concentrations are greater

than the MIC (30%–40%, 50%–60%, and 60%–70% of the time, respectively).

Prolonged or continuous infusions have been used to increase the time that free drug

concentrations are greater than the MIC, theoretically leading to improved patient

outcomes.

133

p. 1419

p. 1420

Continuous infusions were first used in the late 1970s with suggested improvement

in clinical cure rates,

134 but until recently they were largely abandoned owing to

logistical concerns about medication stability, drug compatibility, and limited IV

access. These concerns were lessened by use of contemporary prolonged infusions.

This latter strategy is supported primarily by Monte Carlo simulation, a mathematical

modeling technique that estimates the probability of pharmacodynamic target

attainment at each MIC for a given MIC range.

Patients diagnosed with VAP and treated with cefepime (2 g every 8 hours for 3

hours) have been evaluated using Monte Carlo methodology. Investigators found that

at an MIC of 1 mcg/mL, all regimens had a probability of target attainment greater

than 90%. However, at an MIC of 8 mcg/mL, when compared with 30-minute

intermittent infusions of 1 to 2 g every 8 hours and 2 g every 12 hours, only the

prolonged infusion (3 hours) of 2 g every 8 hours maintained 90% probability of

target attainment. As one might predict, this phenomenon was only demonstrated in

patients with preserved renal function as defined as a creatinine clearance of 50 to

120 mL/minute.

135

Intermittent and continuous infusion dosing strategies have also been compared

when using piperacillin–tazobactam to treat Pseudomonas infections. Lodise et al.

136

retrospectively compared intermittent infusions of 3.375 g IV piperacillin–

tazobactam (infused over 30 minutes every 6 hours) versus extended infusions of

3.375 g IV piperacillin–tazobactam (infused over 4 hours every 8 hours). Results

indicated a shorter length of hospital stay (21 days vs. 38 days; p = 0.02) and lower

14 day mortality rate among patients with Acute Physiological and Chronic Health

Evaluation-II scores >17 (12.2% vs. 31.6%; p = 0.04) in patients receiving extended

infusion therapy.

136

Ventilator-Associated Pneumonia Prophylaxis

The substantial risk of pneumonia in the ICU has prompted aggressive methods to

prevent this disease.

137 The most important recommendations include the use of the

semi-upright position to reduce the risk of aspiration, infection control (including

hand washing) to prevent the spread of pathogens from one patient to the next, and

surveillance for ICU infections.

138

Several strategies for prevention of VAP are controversial, including selective

decontamination of the digestive tract (SDD), selective oral decontamination (SOD),

and topical antiseptics applied to the oral mucosa. These three strategies address the

concept that VAP occurs after colonization of the upper respiratory tract. Because

digestive tract flora may play a role in this colonization, the impact of various

decontamination approaches has been studied. For SDD a combination therapy

including topical tobramycin, polymixin E, and sometimes amphotericin B is

administered to the stomach and oropharynx 4 times daily in combination with IV

administration of ciprofloxacin or a second-generation cephalosporin. SOD uses a

similar antimicrobial strategy to SDD, except that the IV agents are omitted and the

combination therapy is applied to the oropharynx.

Historically, SDD and SOD are more widely used in Europe, and most of the

literature investigating these techniques in thousands of patients and supporting their

use results from outside the United States. In 2009, De Smet et al.

139 performed a

large crossover study comparing standard of care ventilation bundles versus SDD

versus SOD in mechanically ventilated patients and found a statistically reduced risk

of 28-day mortality with an OR of 0.83 (95% CI, 0.72–0.97) for SDD and 0.86 (95%

CI, 0.74–0.99) for SOD.

139

In 2015, Roquilly et al.

140 produced the largest meta-analysis of VAP prevention

techniques to decrease mortality. Over 37,000 patients were involved from 157

randomized trials. Although the overall mortality reduction was 5% in the

intervention group, in a subgroup analysis, only SDD significantly decreased

mortality compared to control with a RR of 0.84 (95% CI, 0.76–0.92).

140 Despite the

overwhelming evidence supporting SDD, leading clinicians suggest there are still

concerns of North American practitioners who fear that widespread use of antibiotics

for SDD will increase antibiotic resistance and Clostridium difficile infections,

particularly in the United States where drug resistance is more prevalent than in

Northern Europe.

141

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Roquilly et al. Pneumonia prevention to decrease mortality in intensive care unit: a systematic review and metaanalysis. Clin Infect Dis. 2015;60:1449.

Klompas M. Editorial commentary: Evidence vs instinct for pneumonia prevention in hospitalized patients. Clin

Infect Dis. 2015;60:76.

p. 1420

Tuberculosis is an infectious disease caused by Mycobacterium

tuberculosis, and the most common site of infection is the lungs. Active

disease is characterized by fever, chills, cough, night sweats, weight

loss, and changes on chest radiography. Several risk factors for

tuberculosis have been identified, including immune suppression,

exposure to close contacts, and smoking.

Case 68-1 (Questions 1, 2)

Diagnosis of active disease includes tuberculin skin testing, chest

radiography, and sputum collection for acid-fast bacillistain and culture.

Nucleic acid amplification tests and interferon-γ release assays may aid

in the diagnosis of tuberculosis. Human immunodeficiency virus (HIV)

screening is recommended for all patients with tuberculosis.

Case 68-1 (Questions 3–7)

The goals of therapy include cure and prevention of transmission of M.

tuberculosis. Treatment of active pulmonary disease requires

administration of multiple-drug therapy for a minimum of 26 weeks.

Directly observed therapy is a core management strategy for all patients

to ensure adherence to therapy.

Case 68-1 (Questions 8–13)

Patients should be monitored for resolution of symptoms and questioned

about the occurrence of adverse events, especially hepatitis. Sputum

smears and cultures should be obtained every 2 to 4 weeks initially and

then monthly after cultures become negative. If treatment failure

occurs, three new drugs should be added to the treatment regimen.

Case 68-1 (Questions 14, 15)

Patients with latent tuberculosis infection have a positive tuberculin skin

test or interferon-γ release assay but no clinicalsymptoms or

radiographic evidence of active disease. Isoniazid for 6 to 9 months is

preferred, and rifampin for 4 months and weekly isoniazid plus

rifapentine for 12 weeks are alternatives.

Case 68-2 (Questions 1, 2)

Adverse events associated with isoniazid include hepatotoxicity and

peripheral neuropathy. Rifampin is associated with hepatotoxicity, flulike syndrome, thrombocytopenia, and discoloration of body fluids.

Pyrazinamide can cause hepatotoxicity and increased uric acid, whereas

ethambutol can cause optic neuritis.

Case 68-3 (Questions 1–3),

Case 68-4 (Question 1)

The case rate for tuberculosis in the elderly is greater than that in all

other age-groups. Principles of treatment of tuberculosis in the elderly

Case 68-5 (Question 1)

are the same as those for other age-groups.

Multidrug-resistant tuberculosis can develop as a result of nonadherence

to treatment. Successful treatment of multidrug-resistant tuberculosis is

possible depending on the host, adherence to therapy, and the number of

drugs to which the organism remains susceptible. Treatment with six to

seven drugs may be required in the intensive phase.

Case 68-6 (Questions 1, 2)

HIV infection is an important risk factor for tuberculosis. The clinical

manifestations in HIV-infected persons will vary depending on the

severity of immunodeficiency at presentation. Principles and

recommendations for treatment of active disease and latent infection in

HIV-infected persons are the same as those for HIV-negative persons.

Case 68-7 (Questions 1–3),

Case 68-8 (Question 1)

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p. 1422

In antiretroviral-naïve patients, the optimal timing for initiating

antiretroviral therapy is dependent on the patient’s CD4

+

cell count.

Antiretroviral therapy may be delayed to decrease the potential for

immune reconstitution inflammatory syndrome. If patients are receiving

antiretroviral therapy, treatment of tuberculosis should begin

immediately with modification of antiviral therapy as needed.

Case 68-7 (Questions 4, 5)

Treatment of active disease in pregnant women is the same as that for

nonpregnant women. Pyrazinamide is not recommended in pregnancy

due to insufficient safety data. The minimum duration of therapy is 9

months.

Case 68-9 (Question 1)

Infants and children have a higher risk of disseminated tuberculosis, and

treatment should be initiated promptly. Ethambutol is generally avoided

because it is difficult to assess visual acuity in children. Many experts

prefer to initiate therapy in children with three drugs and treat for a

minimum duration of 6 months.

Case 68-10 (Question 1)

Extrapulmonary tuberculosis may require longer durations of therapy.

Tuberculous meningitis may require 9 to 12 months of therapy, and

corticosteroids reduce sequelae and improve survival.

Case 68-11 (Question 1)

HISTORY

Tuberculosis (TB) is an ancient disease with evidence of spinal TB in preColumbian and early Egyptian remains. TB emerged as a major health problem in the

17th and 18th centuries when crowded living conditions of the industrial revolution

contributed to its epidemic spread throughout Europe and the United States. Early

physicians referred to TB as phthisis, derived from the Greek term for wasting,

because its clinical presentation consisted of weight loss, cough, fevers, and

hemoptysis. The etiologic agent was identified in 1882 when Robert Koch isolated

and cultured Mycobacterium tuberculosis and demonstrated its infectious nature.

With this knowledge, early treatment in the mid-1800s to the early 1900s consisted of

placing patients with TB in a sanatorium for bed rest and fresh air. With the advent of

radiographic film, pulmonary cavitary lesions were found to be a pivotal component

in the evolution of the disease. Therapy included pneumoperitoneum, thoracoplasty,

and plombage to reduce the size of the cavitary lesion, and some of these therapies

are still used today for severe and refractory cases.

The modern era of medical TB therapy began in 1944 with the discovery of

streptomycin and, shortly thereafter, p-aminosalicylic acid. Addition of isoniazid in

1952 and rifampin in the late 1960s greatly increased treatment success and provided

hope for the eventual elimination of TB. However, multidrug-resistant TB (MDRTB) emerged in the 1990s as a threat to the control of TB in the United States and

other countries.

1–3

In the subsequent decade, published reports described the

worldwide emergence of extensively drug-resistant TB (XDR-TB)

4–6 and, more

recently, the emergence of totally drug-resistant (TDR) or super XDR-TB strains.

7

Because TB strains become increasingly resistant to currently available agents, the

likelihood of achieving global control and elimination of this disease are diminished.

Therefore, a high index of suspicion for TB, rapid pathogen identification,

susceptibility testing, patient isolation, and appropriate antimicrobial therapy are

critical to prevent further development and spread of drug-resistant TB.

Incidence and Epidemiology

Assuming lifelong infection, approximately 2.0 billion people (30% of the world’s

population) are infected with M. tuberculosis.

8 TB is the second most common

causes of death from an infectious disease in the world after human

immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS).

Globally, there were an estimated 9 million new cases of TB in 2013; the majority of

these new cases were identified in the Southeast Asia, Western Pacific, and the

African regions.

9 The countries with the largest number of new cases were India,

China, Nigeria, and Pakistan.

9 Approximately 13% of the new TB cases in 2013

were identified in patients infected with HIV, with the African region accounting for

78% of these cases.

9

In 2013, approximately 1.1 million deaths were reported among

HIV-negative cases and 0.36 million deaths were reported among HIV-positive

cases.

9 These deaths include 510,000 women and 80,000 children.

9

In the United States, 9,421 cases of TB were reported in 2014, and the incidence

rate was 2.96/100,000 population, which represents the lowest recorded rate since

national reporting began in 1953.

10 However, the incidence rate remained

substantially higher than the national goal for elimination of TB (<1 case per

1,000,000 population).

10 Twenty-one states reported increased numbers of TB cases

in 2014, and four states (California, Texas, New York, and Florida) accounted for

51% of all TB cases.

10 The number of TB cases and the incidence rates declined for

both foreign-born and US-born persons, but foreign-born and ethnic and racial

minorities continue to be disproportionally affected by TB in the United States. In

2014, 66% and 34% of all TB cases were reported in foreign-born and US-born

persons, respectively, and the TB rate was 13 times higher in foreign-born persons

compared with US-born persons (15.4 vs. 1.2 per 100,000 population).

10 Five

countries accounted for more than half of TB cases in foreign-born persons: Mexico

(21%), the Philippines (12%), India (8%), Vietnam (8%), and China (7%).

10 TB

rates for Hispanics, non-Hispanic blacks, and Asians were 8, 8.5, and 30 times

greater than the rate for non-Hispanic Caucasians.

10 Among US-born persons, the

greatest number of TB cases was reported in blacks. Among persons with TB whose

HIV status was known, 6% of these patients were coinfected with HIV.

10

In the United States, 9.3% of isolates from patients with no previous history of TB

were resistant to isoniazid in 2014; resistance was 7.5% in US-born individuals and

10.2% in foreign-born individuals.

10 Globally, there were approximately 480,000

cases of MDR-TB, defined as resistance to both isoniazid and rifampin, resulting in

210,000 deaths in 2013.

9 The largest number of MDR-TB cases were reported in

China, India, the Russian Federation, and South Africa.

9

In the United States, 67

cases of MDR-TB were reported in 2014.

10 The overall proportion of MDR-TB

cases in the United States has been stable over the last decade, ranging from 0.9% to

1.3%.

10 Foreign-born persons accounted for 85% of these MDR-TB cases.

10 The

percentage of MDR-TB is approximately 7 times higher for persons with a previous

history of TB compared with persons with no previous history of TB.

10 Several

conditions and risk factors for persons with increased risk of infection with drugresistant TB are shown in Table 68-1.

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p. 1423

Table 68-1

Conditions and Risk Factors for Persons with Increased Risk of Drug-Resistant

Tuberculosis

History of treatment for latent tuberculosis infection or active disease

Patients from areas with high prevalence of initial or primary drug resistance (urban population, northeast United

States, Florida, California, Texas, United States–Mexico border)

Foreign-born persons from areas with high prevalence of drug-resistant tuberculosis (Southeast Asia, Mexico,

South America, Africa)

Contact with persons with active infection caused by drug-resistant Mycobacterium tuberculosis

Tuberculosis in persons who are homeless, abusers of intravenous drugs, and HIV infected

Patients with positive sputum smears and cultures after 2 months of treatment

HIV, human immunodeficiency virus.

In the mid-2000s, XDR-TB emerged as another major threat to global health.

4–6

The definition of XDR-TB is resistance to isoniazid and rifampin among first-line

agents, resistance to any fluoroquinolone, and resistance to at least one second-line

injectable drug (amikacin, kanamycin, or capreomycin).

11 According to the World

Health Organization, XDR-TB strains have been identified in 100 countries

worldwide, and an estimated 9% of patients with MDR-TB have XDR-TB.

9 One of

the first reports described 53 patients infected with XDR-TB from South Africa.

12

HIV status was known in 44 patients, and all of these patients were HIV positive.

Fifty-five percent of the patients had no prior history of TB treatment, and 98% died

with a median survival period of only 16 days after collection of the first sputum

specimen.

12