Diane M. Cappelletty
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. List the common pathogens that cause community-acquired pneumonia (CAP), aspiration pneumonia, ventilator-associated pneumonia (VAP; early versus late onset), and health care–associated pneumonia.
2. Explain the host defenses that protect against infection.
3. Explain the pathophysiology of pneumonia.
4. Recognize the signs and symptoms associated with CAP and VAP.
5. Identify patient and organism factors required to guide the selection of a specific antimicrobial regimen for an individual patient.
6. Design an appropriate empirical antimicrobial regimen based on patient-specific data for an individual with CAP, aspiration pneumonia, and VAP or health care–associated pneumonia (early versus late onset).
7. Design an appropriate antimicrobial regimen based on both patient- and organism-specific data.
8. Develop a monitoring plan based on patient-specific information for a patient with CAP and health care–associated pneumonia or VAP.
9. Formulate appropriate educational information to be provided to a patient with pneumonia.
KEY CONCEPTS
There are five classifications of pneumonia: community acquired, aspiration, hospital acquired, ventilator associated, and health care associated.
The etiology of bacterial pneumonia varies in accordance with the type of pneumonia.
Streptococcus pneumoniae is the most common bacterial pathogen associated with community-acquired pneumonia (CAP).
The signs and symptoms and severity of pneumonia are needed not only to diagnose the patient but also to determine and assess response to therapy.
The goal of therapy is to eliminate the patient’s symptoms, minimize or prevent complications, and decrease mortality.
Treatment of CAP is predominantly empirical.
Empirical selection of antimicrobial therapy for ventilator-associated, health care–associated, and hospital-associated pneumonia is broad spectrum; however, once culture and susceptibility information are available the therapy should be narrowed (de-escalation) to cover the identified pathogen(s).
Duration of therapy should be kept to the shortest duration possible.
Monitoring response to therapy is essential for determining efficacy, identifying adverse reactions, and determining the duration of therapy.
Prevention of pneumococcal disease by use of vaccination is a national goal.
Pneumonia is inflammation of the lung with consolidation. The cause of the inflammation is infection, which can be caused by a wide range of organisms. There are five classifications of pneumonia: community-acquired, aspiration, hospital-acquired, ventilator-associated, and health care-associated. Patients who develop pneumonia in the outpatient setting and have not been in any health care facilities including wound care and hemodialysis clinics have community-acquired pneumonia (CAP). Aspiration is of either oropharyngeal or GI contents. Hospital-acquired pneumonia (HAP) is defined as pneumonia that occurs 48 hours or more after admission.1,2 Ventilator-associated pneumonia (VAP) requires endotracheal intubation for at least 48 to 72 hours before the onset of pneumonia.2,3 The newest category is health care-associated pneumonia (HCAP), which is defined as pneumonia occurring in any patient hospitalized for at least 2 days within 90 days of the onset of the infection; residing in a nursing home or long-term care facility; received IV antibiotic therapy, wound care, or chemotherapy within the last 30 days of the onset of the infection; or having attended a hemodialysis clinic.2,4,5
EPIDEMIOLOGY AND ETIOLOGY
Etiology and Mortality Rates
The etiology of bacterial pneumonia varies in accordance with the type of pneumonia. Table 71–1 lists the common pathogens associated with the various types or classifications of pneumonia. S. pneumoniae colonizes the nasopharyngeal flora in up to 50% of healthy adults and may colonize the lower airways in individuals with chronic bronchitis.6,7 It possesses many virulence factors enhancing its ability to cause infection in the respiratory tract. Therefore, it is not surprising that S. pneumoniae is the predominant bacterial pathogen associated with CAP. The second most common pathogen is one of the atypical organisms, Mycoplasma pneumoniae. Nontypeable Haemophilus influenzae intermittently colonizes about 80% of the population and the incidence of permanent colonization increases in chronic obstructive pulmonary disease (COPD) patients and those with cystic fibrosis. Therefore the likelihood of nontypeable H. influenzae causing pneumonia increases in COPD patients. Moraxella catarrhalis is a more common cause of pneumonia in the young children and the elderly. Chlamydia pneumoniae and Legionella pneumophila are less frequent causes than the other bacterial and atypical organisms. Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is associated with necrotizing and severe pneumonia in healthy children and young adults. Less than 2% of all CA-MRSA infections are pneumonia (most are skin and soft tissue); however, the number of reports of pneumonia are increasing.8
Table 71–1 Common Pathogens by Type of Pneumonia
Viruses are a common cause of CAP in children (about 65%) and much less common in adults (about 15%).9 Viruses often associated with pneumonia in adults include influenza A and B, adenoviruses while less common causes include rhinoviruses, enteroviruses, cytomegalovirus, varicella-zoster, herpes simplex, and others. In children, viral pneumonia is more commonly caused by respiratory syncyntial virus, influenza A, and parainfluenza, and less commonly the viruses are similar to those listed above for adults.
Mortality associated with CAP is dependent upon the severity of the illness and the age of the patient. In elderly patients admitted to the hospital with severe pneumonia the mortality rate is up to 40%.10–13 In the outpatient setting (mild to moderate disease) the mortality rate is less than 5%.14 Mortality among case reports of CA-MRSA necrotizing pneumonia is 42%.8 Pneumonia owing to aspiration of oral contents is caused by a variety of anaerobes (Bacteroides spp ., Fusobacterium spp ., Prevotella spp., and anaerobic gram-positive cocci) as well as Streptococcus spp. M. catarrhalis and Eikenella corrodensmay be involved but much less frequently15,16 When gastric contents are aspirated enteric gram-negative bacilli and S. aureus are more commonly the pathogens.16
HAP, VAP, and HCAP may be caused by a wide spectrum of organisms. HCAP, early-onset HAP, and VAP commonly can be caused by enteric gram-negative bacilli in addition to the bacteria listed above for CAP. Late-onset HAP and VAP are more likely to be caused by more resistant enteric gram-negative bacilli or , Pseudomonas aeruginosa, or Acinetobacter spp., or S. aureus. Rarely are viruses or fungi a cause of HAP, VAP, or HCAP. The number of infections caused by multidrug-resistant (MDR) bacteria is increasing significantly in hospitalized patients. 17–22
PATHOPHYSIOLOGY
Local Host Defenses
Local host defenses of both the upper and lower respiratory tract along with the anatomy of the airways are important in preventing infection. Upper respiratory defenses include the mucociliary apparatus of the nasopharynx, nasal hair, normal bacterial flora, IgA, and complement. Local host defenses of the lower respiratory tract include cough, mucociliary apparatus of the trachea and bronchi, antibodies (IgA, IgM, and IgG), complement, and alveolar macrophages. Mucous lines the cells of the respiratory tract forming a protective barrier for the cells that minimizes the ability of organisms to attach to the cells and initiating the infectious process. The squamous epithelial cells of the upper respiratory tract are not ciliated but those of the columnar epithelial cells of the lower tract are. The cilia beat in a uniform fashion upward, moving particles up and out of the lower respiratory tract.
Particles greater than 10 microns are efficiently trapped by mechanisms of the upper airway and are removed from the nasopharynx either by swallowing or by expulsion. The mucociliary apparatus of the trachea and bronchi along with the sharp angles of the bronchi, often are effective at trapping and eliminating particles that are 2 to 10 microns in size. Particles in the range of 0.5 to 1 micron may consistently reach the alveolar sacs of the lung. Microorganisms fall within this size range and if they reach the alveolar sacs, then infection may result if alveolar macrophages and other defenses cannot contain the organisms.
Aspiration
Aspiration of the oropharyngeal or gastric contents may lead to aspiration pneumonia or chemical (acid) pneumonitis. Risk factors for aspiration include:
• Dysphagia
• Change in oropharyngeal colonization
• Gastroesophageal reflux (GER)
• Decreased host defenses
Dysphagia can be caused by stroke or other neurologic disorders, seizures, alcoholism, and aging.15 Oropharyngeal colonization may be altered by oral/dental disease, poor oral hygiene, tube feedings, or medications. This could result in a higher number of anaerobic organisms in the oral cavity or colonization with enteric gram-negative bacilli.15 GER occurs in all individuals to a degree; however, those with GER disease (GERD) have it more frequently. Acid suppression is an important factor in the treatment of GERD, which may allow enteric gram-negative bacilli to colonize the gastric contents. Finally, impaired mucous production or cilia function, decreased immunoglobulin in secretions, and altered cough reflex may increase the likelihood of infection following an aspiration. The infection can result in a necrotizing pneumonia or lung abscess.
HAP, VAP, HCAP
Risk factors for the development of HAP fall into four general categories:
• Intubation and mechanical ventilation
• Aspiration
• Oropharyngeal colonization
• Hyperglycemia
Intubation and mechanical ventilation increase the risk of HAP/VAP 6- to 21-fold.2,23 VAP may also be related to colonization of the ventilator circuit.24 Risk of aspiration is increased in these patients due to the supine positioning of the patient, the presence of the endotracheal tube preventing the closure of the epiglottis over the glottis, enteral feedings, GER, and medications.24 Oropharyngeal colonization is affected by the use of antibiotics, oral antiseptics, and poor infection control measures, which may decrease normal commensal flora and allow pathogenic organisms to colonize the oral cavity. Hyperglycemia may directly or indirectly promote infection; two proposed mechanisms are inhibiting phagocytosis and providing additional nutrients for bacteria.
Once breakdown of the local host defenses occurs and organisms invade the lung tissue, an inflammatory response is generated either by the organisms causing tissue damage or by the immune response to the presence of the organisms. This inflammatory response either can remain localized in the infected tissue or can become systemic. The role of the alveolar macrophages is twofold. First, to engulf the organisms and to contain the infection and second to process the antigens for presentation in order to generate a specific immune response by either the cell-mediated or humoral system or both. The macrophages release cytokines in the area of the infection, which result in increased mucous production, constricting the local vasculature and lymphatic vessels, and attraction of other immune cells to the site. The increase in mucous is associated with symptoms such as cough, and sputum production. If tumor necrosis factor α (TNF-α), and interleukins 1 (IL-1) and (IL-6) are released systemically, then the symptoms become more severe and include hypotension, organ dysfunction and/or a septic or septic-shock clinical presentation.
Patient Encounter 2, Part 1
A 73-year-old woman presents to your clinic complaining of difficulty breathing and shortness of breath. Her physical examination reveals that she is alert and oriented ×3, has decreased breath sounds on the left side compared with the right, and has rales in the left lower lobe. Her temperature is 37.4°C (99.3°F), respiratory rate is 20 breaths per minute, and blood pressure is 110/76 mm Hg.
What are her signs and symptoms of pneumonia?
What are the top two organisms that could be causing the pneumonia?
What additional information do you need to know before creating a treatment plan for this patient?
Patient Encounter 1, Part 1
A 52-year-old man was admitted to the hospital for abdominal surgery. He developed complications postoperatively and was intubated 6 days ago. The nurses note an increase in the amount and purulence of his sputum. Attempts yesterday and today to wean the patient off the ventilator have failed. He is sedated but does respond to commands. His temperature is 38.4°C (101°F), his blood pressure is 120/84 mm Hg, and his WBC is 14.2 × 103/mm3 (14.2 × 109/L) with a cell differential of 76% neutrophils, 4% bands, 16% lymphocytes, and 4% monocytes.
What are his signs and symptoms of pneumonia?
What are the top three organisms that could be causing the pneumonia?
CLINICAL PRESENTATION AND DIAGNOSIS
Several scoring systems are available for assessing the severity of the pneumonia: the Pneumonia Severity Index (PSI); Confusion, Uremia, Respiratory rate, Blood pressure (CURB); and CURB-65 (those 65 years and older).10,25Some of the characteristics evaluated with these models include but are not limited to age, comorbidities, blood pressure, mental status, respiratory rate, and organ function. These models are used by physicians to help determine the severity of illness, prognosis (mortality risk), the need for hospitalization, and then to help guide in the selection of antimicrobial therapy along with the use of published guidelines.10,14,25
Clinical Presentation of CAP or Aspiration Pneumonia
General
Patients may experience nonrespiratory symptoms in addition to respiratory symptoms. With increasing age, both respiratory and nonrespiratory symptoms decrease in frequency
Symptoms
• Respiratory—cough (productive or nonproductive), shortness of breath, and difficulty breathing
• Nonrespiratory—fever, fatigue, sweats, headache, myalgias, mental status changes
Signs
• Temperature may increase or decrease from baseline, but most often it is elevated. The temperature may be sustained or intermittent
• Respiratory rate is often increased. Cyanosis, increased respiratory rate, and use of accessory muscles of respiration are suggestive of severe respiratory compromise
• Breath sounds may be diminished. Rales or rhonci may be heard
• Confusion, lethargy, and disorientation are relatively common in elderly patients
Diagnostic Tests
• Chest x-ray should reveal single or multiple infiltrates
• Oxygen saturation should be over 90%, as determined by pulse oximetry
• Arterial blood gases are beneficial primarily in patients with severe pneumonia
Laboratory Tests
• The WBC may or may not be elevated. In elderly patients, a drop in WBCs also can be a sign of infection. The differential should show a predominance of neutrophils if a bacterial infection is present. The presence of bands also could be an indicator of bacterial infection. Elevated lymphocytes are an indication of viral infection
• Blood urea nitrogen (BUN) and serum creatinine are needed to dose antibiotics appropriately and to minimize or prevent drug toxicity (especially in the elderly patient)
Microbiology Tests
• Sputum gram stain should demonstrate the presence of WBCs and the absence of squamous epithelial cells. It may or may not show a predominance of one type of organism
• Sputum culture and susceptibility are not obtained in the outpatient setting. The value of culturing is debated owing to the rapidity in which S. pneumoniae dies in transport media and the inability to reliably or routinely culture atypical organisms
• Bronchoscopy may be performed to improve the ability to diagnose pneumonia. Tracheal secretions often are better specimens than sputum owing to the lack of oral contamination
• Serology (IgM and IgG) is useful in determining the presence of atypical organisms such as Mycoplasma and Chlamydia
• Urinary direct fluorescence antigen (DFA) is used to diagnose L. pneumophila
• Polymerase chain reaction (PCR) is being used more frequently to detect the DNA of respiratory pathogens
• Blood cultures must be obtained in all patients hospitalized with pneumonia to comply with Joint Commission on Accreditation of Healthcare Organizations (JCAHO) pneumonia guidelines. Positive blood cultures are present in about 1% to 20% of patients with CAP
Clinical Presentation of Severe CAP or Aspiration Pneumonia
General
In approximately 10% of patients, CAP will be severe enough to require intensive care or mechanical ventilation
Symptoms
• Respiratory—cough (productive or nonproductive), shortness of breath, difficulty breathing
• Nonrespiratory—fever, fatigue, sweats, headache, myalgias, mental status changes
Signs
• Temperature may increase or decrease from baseline, but most often it is elevated. The temperature may be sustained or intermittent
• Respiratory rate greater than 30 breaths per minute. Cyanosis and use of accessory muscles of respiration along with the increased respiratory rate are suggestive of severe respiratory compromise
• Hypotension (systolic blood pressure less than 90 mm Hg or diastolic blood pressure less than 60 mm Hg)
• Requirement for vasopressors
• Breath sounds may be diminished. Rales or rhonci may be heard
• Urine output less than 20 mL/h or less than 80 mL over 4 hours
• Confusion, lethargy, and disorientation are relatively common in elderly patients
Diagnostic Tests
As stated in the clinical presentation of community-acquired or aspiration pneumonia
Laboratory Tests
As stated in the clinical presentation of community-acquired or aspiration pneumonia
Microbiology Tests
As stated in the clinical presentation of community-acquired or aspiration pneumonia
TREATMENT
Desired Outcomes
The goal of antibiotic therapy is to eliminate the patient’s symptoms, minimize or prevent complications, and decrease mortality. Potential complications secondary to pneumonia include further decline in pulmonary function in patients with underlying pulmonary disease, prolonged mechanical ventilation, bacteremia/sepsis/septic shock, and death. Use of an antimicrobial agent with the narrowest spectrum of activity that covers the suspected pathogen(s) without having activity against organisms not involved in the infection is preferred to minimize the development of resistance.
General Approach to Treatment
Designing a therapeutic regimen for any patient with any type of pneumonia begins with three general categories of consideration:
1. Patient specific factors that will impact therapy
2. The top one to three organisms likely causing the infection, and resistance issues associated with each organism
3. The antimicrobials that will cover these organisms. The spectrum should not be too broad or narrow; they should penetrate into the site of infection and be the most cost effective.
Patient factors that need to be considered include age, renal function, drug allergies and/or drug intolerances, immune status (diabetes, neutropenia, or immunocompromised host), cardiopulmonary disease, pregnancy, medical insurance and prescription coverage, and prior antibiotic exposure(s) (what agents and when).
The most common pathogens vary with the type of pneumonia, and they are listed in Table 71–1. M. pneumoniae lack a cell wall; therefore, β-lactam antimicrobials have no activity against this organism. The atypical organisms have not changed in recent years with respect to antibiotic resistance. β-lactamase production in H. influenzae has remained relatively steady over the last 5 to 10 years and the rate is approximately 35%.26 S. pneumoniae has developed resistance mechanisms against many classes of antimicrobials and the mechanisms include:
• Alteration of the penicillin binding proteins (PBPs) inactivating β-lactams
• Efflux or methylation of the ribosome inactivating macrolides
• Ribosome protection (tetM gene) inactivating tetracyclines
• Alteration of DNA gyrase or topoisomerase IV inactivating fluoroquinolones
Resistance to commonly prescribed antimicrobials such as the penicillins and macrolides/azalides dramatically increased in the late 1980s through the mid- to late 1990s. Table 71-2 provides resistance information collected nationally from 1999 to 2007 using the Tracking Resistance in the US Today (TRUST) surveillance database.27 In 2007, the average national rate of resistance to penicillin and macrolides was approximately 13% and 32%, respectively. Susceptibility results alone do not account for clinical success or failures when treating pneumonia. Therefore, despite the 13% and 32% resistance to penicillin and macrolides, the clinical failure rate is less than this. Because CAP in the outpatient setting is treated empirically, establishing a meaningful clinical failure rate with any therapy is difficult to do. No studies have been performed that established a correlation between clinical failure rates with a particular antimicrobial agent and the percentage of resistant bacterial pathogens.
Patient Encounter 1, Part 2: Medical History, Physical Examination, and Diagnostic Tests
The 73-year-old woman presents again to your clinic complaining of difficulty breathing and shortness of breath. Her daughter also states that she is easily confused and that this is not normal for her.
PMH: COPD for 15 years; hypertension for 4 years, currently controlled
FH: Father died of lung cancer at the age of 68 years; mother died of natural causes
SH: Smoked two packs per day for 23 years, quit 15 years ago; does not drink alcohol; lives with her daughter
Allergies: NKDA
Meds: Lisinopril 10 mg orally once daily; Ipratropium bromide four puffs four times per day; flunisolide three puffs two times per day; albuterol two puffs as needed
ROS: (+) difficulty breathing and shortness of breath; (-) chest pain, N/V/D, weight loss, change in appetite
PE:
VS: BP 110/76, P 82, RR 20, T 37.4°C (99.3°F)
CV: RRR, normal S1, S2; no murmurs, rubs, or gallops
Lungs: Decreased breath sounds on the left side compared with the right and rales in the left lower lobe
Abd: Soft, nontender, nondistended; (+) bowel sounds, no hepatosplenomegaly, heme (-) stool
Neuro: Oriented to name and place but not to date. She is easily confused by questions asked of her
Diagnostic Tests: Chest x-ray: left lower lobe infiltrates; oxygen saturation 92% on room air
Labs: Unavailable in the clinic
Given this additional information, what is your assessment of the patient’s condition?
Identify your treatment goals for the patient
For HCAP, HAP, and VAP, the risk of infection from an MDR pathogen is relatively high. The number and type of organisms that are MDR vary from hospital to hospital making it more difficult to generate guidelines for treatment. Therefore, the treatment recommendations may be too broad or too narrow for any given institution. Treating patients with HCAP, HAP, or VAP is more complex than treating patients with CAP. There are many factors to consider and one of those relates the timing of infection to the most likely pathogens. Early-onset infection is less likely to be caused by MDR pathogens than late-onset infection. In early-onset infection, community pathogens such as pneumococcus, Legionella, and Mycoplasma need to be considered as well as some of the hospital pathogens. Patients developing late-onset pneumonia are at increased risk of having a resistant pathogen or MDR pathogen such as MRSA, enteric gramnegative bacilli, Pseudomonas, and Acinetobacter. Another issue is how HCAP and HAP are studied compared to VAP. The majority of studies were performed using patients that were intubated. Therefore, the body of literature supporting the treatment recommendations is greatest for VAP and not for HCAP or HAP. The evidence-based guidelines generated by the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) were derived from VAP and applied to HCAP and HAP.
Table 71–2 Percentage of Resistance for Various Antimicrobials Against S. pneumoniae
Risk factors for developing infection caused by a resistant pathogen are generally related to the prior use of antibiotics, insertion of catheters or other invasive devices, and hospitalization in a unit contaminated/colonized with resistant organisms. The following is a more complete list of factors influencing infection from a resistant organism:
• Antimicrobial therapy in preceding 90 days
• Current hospitalization of at least 5 days
• High occurrence of antibiotic resistance in the community or in the specific hospital unit
• Immunosuppressive disease and/or therapy
• Presence of the following risk factors for HCAP
• Hospitalization for 2 days or more in the preceding 90 days
• Residence in a nursing home or extended-care facility
• Home infusion therapy (including antibiotics)
• Peritoneal or hemodialysis within 30 days
• Home wound care
• Close contact family member with MDR pathogen
Once these issues are addressed, antimicrobial therapy can be selected and initiated. The patient- and drug-related categories are common to all types of pneumonia, but the organisms vary with the type of pneumonia. Guidelines have been generated by experts in the field for all types of pneumonia. These guidelines were generated to provide practitioners with evidenced-based therapeutic options for the management of patients with pneumonia.
Patient Encounter 2, Part 2: Medical History, Physical Examination, and Diagnostic Tests
The 52-year-old man who developed complications after abdominal surgery was intubated 6 days ago. The nurses note an increase in the amount and the purulence of his sputum. Attempts yesterday and today to wean the patient off the ventilator have failed. He is sedated, but he does respond to commands.
PMH: Small bowel obstruction, surgery 8 days ago; hypertension for 15 years, currently controlled
FH: Father died of acute MI at the age of 68 years; mother, age 72 years is alive, with hypertension and hypothyroid
SH: No tobacco use; drinks two beers per night. He lives with his wife; occupation—carpenter. He is 5’11” (180 cm) and weighs 85 kg (187 lb)
Allergies: Penicillin—hives
Meds: Lisinopril 40 mg orally once daily
PE:
VS: BP 120/84, P 78, T 38.4°C (101°F)
CV: RRR, normal S1, S2; no murmurs, rubs, or gallops
Abd: Soft, nontender, nondistended; (+) bowel sounds, no hepatosplenomegaly, incision looks good and is healing
Diagnostic Tests: Chest x-ray: left middle and lower lobe infiltrates; oxygen saturation 98% on ventilator
Labs: WBCs 18.2 × 103/mm3 (18.2 × 109/L) with a cell differential of 72% neutrophils, 8% bands, 16% lymphocytes, and 4% monocytes; BUN 10 mg/dL (3.57 mmol/L), SCr 0.9 mg/dL (80 μmol/L); sputum gram stain: many gram-negative bacilli, many WBCs; sputum culture is pending
Given this additional information, what is your assessment of the patient’s condition?
Identify your treatment goals for the patient.
Pharmacologic Therapy for CAP
Treatment of CAP is predominantly empiric, that is, treatment is started without knowing the causative pathogen. As a way of incorporating an evidence-based approach to antibiotic selection, several different organizations have generated guidelines for the treatment of bacterial or atypical CAP in adults. The most recent guidelines are the result of a collaboration between the IDSA and the ATS.28 The approach to patient care is based on the classification of patients into two broad categories, outpatient and inpatient, and then further divide the groups by comorbid conditions and location in the hospital, respectively. These guidelines use patient-specific data along with predominant pathogen information to design appropriate empirical antimicrobial regimens. Table 71–3 summarizes these therapeutic options. If influenza virus is the cause, supportive care is the best medical intervention available; antiviral agents against influenza are not very effective.
Adult Outpatient Previously Healthy
First-line therapeutic options for treating previously healthy adults include use of a macrolide (erythromycin, clarithromycin) or an azalide (azithromycin) or doxycycline.28 If a patient has failed therapy with a macrolide, azalide, or doxycycline, one has to consider why the patient failed. The most common reasons are either medication adherence issues or the presence of resistant organisms. If a resistant organism is suspected then use of one of the fluoroquinolones active against S. pneumoniae (gemifloxacin, levofloxacin, or moxifloxacin) is warranted.
Adult Outpatient With Comorbid Conditions
The comorbid conditions that can impact therapy and outcomes in patients with CAP include diabetes mellitus, COPD, chronic heart, liver, or renal disease, alcoholism, malignancy, asplenia, and immunosuppressive condition or use of immunosuppressive drugs.28 If the patient did not receive antibiotics in the last 3 months then either a respiratory fluoroquinolone alone or a combination of an oral β-lactam agent plus a macrolide or azalide is recommended. If the patient received an antibiotic in the last 3 months the recommendation is to use an agent from a different class. Doxycycline is an acceptable alternative to a macrolide or azalide. The β-lactam agents recommended are high-dose (3 g daily) amoxicillin or high-dose (4 g daily) amoxicillin-clavulanate. Alternative β-lactams are second- and third-generation cephalosporins such as cefuroxime, cefpodoxime, or ceftriaxone.
Telithromycin, a ketolide antibiotic approved for the treatment of mild to moderate CAP, is not included in the recommendations because of safety issues related to hepatotoxicity, loss of consciousness, and visual disturbances still pending resolution with the FDA. Telithromycin is similar in spectrum of activity to clarithromycin and azithromycin in that it covers primarily the respiratory pathogens and not gram-negative bacilli.
Adult Inpatient Not in the ICU
For patients admitted to the hospital with CAP, the severity of a illness is generally increased (caused either by the organism itself or underlying comorbidities in the patient) and the pathogens are essentially the same as in the outpatient setting. Recommendations are to use either a respiratory fluoroquinolone alone or a combination of an IV β-lactam agent plus an advanced macrolide/azalide (clarithromycin/azithromycin) or doxycycline. The recommended β-lactams include cefotaxime, ceftriaxone, ampicillin-sulbactam, or ertapenem.28 Therapy should be initiated in the emergency room; however, due to the controversy with a first antibiotic dose time of less than 4 or 8 hours, no recommendations were made regarding time to the first antibiotic dose. Conversion to oral therapy should occur when the patient is hemodynamically stable, improving clinically, and able to take oral medications, which often is within 48 to 72 hours for most patients. Discharge from the hospital should be as soon as the patient is stable and without other medical complications. The need to observe the patient in the hospital on their oral antibiotic is not necessary.28
Table 71–3 Summary of CAP Treatment
Patient Encounter 1, Part 3: Creating a Care Plan
Based on the information presented, create a care plan for this patient’s pneumonia. Your plan should include
(a) the goals of therapy,
(b) a patient-specific detailed therapeutic plan, and
(c) a plan for follow-up to determine whether goals have been achieved and adverse effects avoided.
Adult Inpatient in the ICU
Patients admitted to the ICU have severe pneumonia, and the likely etiology includes S. pneumoniae, H. influenzae as in the other categories; however, the incidence of L. pneumophila increases in this setting and should be included in the organism differential. In addition, enteric gram-negative bacilli and S. aureus are more frequently the cause of the pneumonia. The recommendations are to treat with an IV β-lactam plus either azithromycin or a respiratory fluoroquinolone. This combination therapy minimizes the risk of treatment failure due to a resistant pathogen as well as provides coverage against all of the potential pathogens.28 The preferred β-lactams are ceftriaxone, cefotaxime, or ampicillin-sulbactam. If the patient is allergic to β-lactams then aztreonam plus a respiratory fluoroquinolone are preferred.
If P. aeruginosa is suspected (e.g., patient comes from a long-term care facility, or recent hospitalization) then the antimicrobial treatment must be broadened to cover Pseudomonas as well as the organisms listed above. Owing to the high resistance rates observed in Pseudomonas, the recommended regimens empirically double cover the Pseudomonas to ensure at least one of the antibiotics is active against Pseudomonas. The regimens include the use of an antipneumococcal, antipseudomonal β-lactam (cefepime, ceftazidime, piperacillin/tazobactam, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin or an aminoglycoside. If the aminoglycoside is chosen, then either IV azithromycin or a respiratory fluoroquinolone should be added to cover S. pneumoniae and the atypical bacterial organisms.28
If CA-MRSA is suspected in the patient then the addition of vancomycin or linezolid to the above regimen should be considered. Daptomycin cannot be used because surfactant in the lung inactivates the drug thus rendering it ineffective for pneumonia. CA-MRSA can cause a necrotizing pneumonia, and the cause is believed to be due to the increased pathogenicity of this strain and its multiple toxins including the Panton-Valentine leukocidin toxin.9 In these patients the use of an agent which decreases toxin production may be beneficial. Linezolid does decrease toxin production and the agents recommended to be added to vancomycin therapy are clindamycin or a respiratory fluoroquinolone.28
Influenza
Influenza viruses A and B can cause pneumonia in pediatric and adult patients. Amantidine and rimantidine are available oral agents with activity against influenza virus type A. If started within 48 hours of the onset of the first symptoms, they reduce the duration of the illness by about 1.3 days. Oseltamivir and zanamivir also are oral agents that reduce the duration of the illness by about 1.3 days if initiated within 40 to 48 hours of the first symptoms.29 For active infection beyond the first 48 hours, none of these agents is effective in treating infection, and supportive care is the best treatment for these patients.
Aspiration
Anaerobes and Streptococcus spp. are the primary pathogens if a patient aspirates his or her oral contents and develops pneumonia. Antibiotics active against these organisms include penicillin G, ampicillin/sulbactam, and clindamycin. If the patient aspirates oral and gastric contents then anaerobes and gram-negative bacilli are the primary pathogens. The preferred treatment regimen is a β-lactam/β-lactamase inhibitor combination (ampicillin/sulbactam, amoxicillin/clavulanate, piperacillin/tazobactam, or ticarcillin/clavulanate).28
Patient Encounter 2, Part 3: Creating a Care Plan
Based on the information presented, create a care plan for this patient’s pneumonia. Your plan should include
(a) the goals of therapy,
(b) a patient-specific detailed therapeutic plan, and
(c) a plan for follow-up to determine whether goals have been achieved and adverse effects avoided.
Pediatric Outpatient
If viral pneumonia is diagnosed, then treatment is often supportive (maintaining hydration, antipyretics) since we have very few effective antiviral agents. The bacterial pathogens are the same as for adults with S. pneumoniae as the predominant pathogen, then M. pneumoniae, and then the other organisms. Resistance issues with these organisms are similar to those seen in adult patients. Fluoroquinolones and tetracyclines should not be used in children younger than 5 years of age. High-dose amoxicillin (50 mg/kg/day), amoxicillin/clavulanate (70-90 mg/kg/day), intramuscular ceftriaxone (50 mg/kg/day), azithromycin (10 mg/kg/day), and clarithromycin (7.5 mg/kg/day) are all potential agents for use in children.30 Dosing of antibiotics for pediatrics patients is presented in Table 71–4.
Pediatric Inpatient
If the child is not admitted to the ICU, then the CDC recommends the use of IV cefuroxime, cefotaxime, ceftriaxone, or ampicillin/sulbactam plus a macrolide or azalide. If the child is admitted to the ICU, then only the third-generation cephalosporins (cefotaxime or ceftriaxone) plus a macrolide or azalide should be administered.30
Pharmacologic Therapy for HCAP/HAP/VAP
Nosocomial pneumonia was the term used to describe patients who develop pneumonia in an institutional setting but it has been replaced by the terms health care–associated pneumonia, hospital-associated pneumonia, and VAP. 
Empirical selection of antimicrobial therapy for ventilator-, health care–, and hospital-associated pneumonia is broad spectrum; however, once culture and susceptibility information are available, the therapy should be narrowed (de-escalation) to cover the identified pathogen(s). Two factors important to the empirical selection of antibiotics for these types of pneumonia are onset time after admission and risk factors for MDR organisms. If it is early onset (less than or equal to 5 days since admission) and there are no risk factors for MDR organisms then the most frequent pathogens include S. pneumoniae, H. influenzae, methicillin-susceptible Staphylococcus aureus (MSSA), and enteric gram-negative bacilli. Recommendations for therapy include third-generation cephalosporins such as ceftriaxone or cefotaxime, a respiratory fluoroquinolone such as gemifloxacin, levofloxacin, or moxifloxacin; or ampicillin/sulbactam or ertapenem.31 If it is late-onset pneumonia and/or there are risk factors for MDR organisms, then the pathogen list includes P. aeruginosa, extended-spectrum β-lactamase producing K. pneumoniae, Acinetobacter spp., and MRSA. Empirical antibiotic selection must cover P. aeruginosa, which often then covers the other gram-negative pathogens. Available antibiotics include cefepime, ceftazidime, imipenem, meropenem, piperacillin/tazobactam, ticarcillin/clavulanate, levofloxacin, ciprofloxacin, gentamicin, tobramycin, and amikacin. Empirical therapy for late onset (listed in Table 71–5) could include any of the β-lactams, carbapenems, or fluoroquinolones alone or in combination with one of the aminoglycosides. If MRSA is suspected then either vancomycin or linezolid should be added to the regimen. Recommendations for vancomycin trough concentrations of 15 to 20 mcg/mL were based on expert opinion not evidence from clinical trials.31
Diagnosis of VAP
Clinical Strategy
• Chest x-ray should reveal a new infiltrate plus two of the following:
• Temperature greater than 38°C (100.4°F)
• Leukocytosis or leukopenia
• Purulent secretions
• Semiquantitative cultures are obtained to identify the pathogen(s)
• Tracheal aspirates grow more organisms than invasive quantitative cultures and often result in overuse of antibiotics
• The major limitation of the clinical strategy is the consistent overprescribing of antibiotics
Bacteriologic Strategy
• Uses quantitative culture of endotracheal aspirates, bronchoalveolar lavage (BAL), or protected specimen brush (PSB)
• Greater than or equal to 106 cfu/mL for endotracheal aspirates
• Greater than or equal to 104 to 105 cfu/mL for BAL
• Greater than or equal to 103 cfu/mL for PSB
• The advantage of this method is that it separates colonization from infection better than culturing tracheal aspirates
• The limitation is the potential misinterpretation of negative culture results. These samples should be obtained prior to antibiotics being started
Recommended Diagnostic Strategy
• Combination of the preceding two methods
• Obtain either a quantitative or semiquantitative culture of a lower respiratory sample. Initiate empirical broad-spectrum antibiotic therapy
• Days 2 and 3: Check culture results, and assess clinical response to therapy: temperature, WBCs, chest x-ray, oxygenation, purulent sputum, hemodynamic changes, and organ function
• Assess clinical improvement at 48 to 72 hours:
• Improvement and culture negative—stop antibiotics
• Improvement and culture positive—narrow antibiotic therapy
• No improvement and culture negative—consider other pathogens, complications, or other diagnosis
• No improvement and culture positive—change antibiotic therapy and consider other pathogens, complications, or other diagnosis
Currently there is debate over whether or not double coverage for pseudomonas is required. In vitro studies have shown that aminoglycosides exhibit synergistic k illing against gram-negative bacilli when combined with β-lactams. Dosing of the aminoglycosides is dependent upon the patient’s renal function. A high-dose once-daily regimen (e.g., 4–7 mg/kg gentamicin or tobramycin or 15–20 mg/kg amikacin) can be utilized in patients with good renal function. Most of the studies enrolled patients with estimated creatinine clearances of at least 70 mL/min (1.17 mL/s). Meta-analyses have shown high-dose once-daily regimens to be as efficacious as and less toxic than divided daily dosing.32–36
In addition to obtaining a synergistic effect, another reason for double coverage when treating VAP, HAP, or HCAP is to broaden the coverage empirically to increase the likelihood of covering the majority of resistant pathogens. VAP is the most studied of these types of pneumonias and is often the most severe. Studies have demonstrated an increase in mortality when inadequate therapy is initiated for VAP. Crude mortality ranges from 35% to 92% with inadequate therapy compared to 25% to 47% with adequate therapy.17
Once a pathogen or pathogens have been identified, therapy should be narrowed to cover only those pathogens. Use of broad-spectrum antibiotics for prolonged durations increases the risk of colonization with MDR pathogens.
Table 71–4 CAP Pediatric Dosing
Table 71–5 Empirical Therapy for Late-Onset HAP, HCAP, or VAP in Adults
Duration of Therapy
The duration of therapy for pneumonia should be kept as short as possible and depends upon several factors: type of pneumonia, inpatient or outpatient status, patient comorbidities, bacteremia/sepsis, and the antibiotic chosen. If the duration of therapy is too prolonged, then it can have a negative impact on the patient’s normal flora in the respiratory and GI tracts, vaginal tract of women, and on the skin. This can result in colonization with resistant pathogens, Clostridium difficile colitis, or overgrowth of yeast. In addition, the longer antibiotics are administered, the greater the chance for toxicity from the agent as well as an increase in cost.17
For treating outpatient CAP, two antibiotics are approved for a 5-day duration of therapy, levofloxacin (the 750-mg once daily dose) and azithromycin. The duration of therapy for all other agents used to treat CAP is 7 to 10 days. For treatment of CAP in patients admitted to the hospital, the duration is dependent upon whether or not blood cultures were positive. In the absence of positive blood cultures, the duration of therapy is 7 to 10 days. If blood cultures were positive, the duration of therapy should be 2 weeks from the day blood cultures first became negative.
The duration of therapy cited in the literature for HCAP, HAP, or VAP ranges from 10 to 21 days. Efforts should be made to shorten the duration of therapy from the traditional 14 to 21 days to periods as short as 7 days, provided that the etiologic pathogen is not P. aeruginosa, and that the patient has a good clinical response with resolution of clinical features of infection. Shortening the duration of therapy is acknowledged as beneficial because of the colonization, toxicity, and cost issues. The Clinical Pulmonary Infection Score (CPIS) has been used to determine when to end therapy for VAP. Luna and colleagues used the CPIS and found that patients who survived VAP and were treated with adequate therapy clinically improved within 3 to 5 days.37 This study was instrumental in recommending a shortened duration of therapy of 6 days. Another study found that when the CPIS was six or less, those patients were at low risk of VAP or resistant pathogens and treatment only needed to be for 3 days.38
OUTCOME EVALUATION
For CAP, outcomes include preventing hospitalization, shortening the duration of hospitalization, and minimizing mortality. For patients admitted to the hospital, if antibiotics are initiated within 4 hours of presentation, the duration of hospitalization is decreased compared to when antibiotics are started after 4 hours.39
Improvement of symptoms should occur within 48 to 72 hours after initiation of therapy for most patients with CAP. Response to therapy could be slowed in patients with underlying pulmonary disease such as moderate to severe asthma, COPD, or emphysema. In patients not responding to therapy and when there are no underlying factors that would suggest a slowed response to therapy, then other infectious and noninfectious reasons must be considered. The infection could be caused by a pathogen not covered by the initial therapy, a drug-resistant isolate could be present, or more severe infection could be present (nonpulmonary) and the patient should be reevaluated. Noninfectious reasons to consider include pulmonary embolus, congestive heart failure, carcinoma, lymphoma, intrapulmonary hemorrhage, and certain inflammatory lung diseases.
Outcome parameters for VAP, HAP, and HCAP are similar to those with CAP. Clinical improvement should occur within 48 to 72 hours of the start of therapy. If a patient is not responding to therapy, then, again, consider infectious and noninfectious reasons. Infectious explanations are the same as for CAP, but noninfectious are not. They include atelectasis, acute respiratory distress syndrome (ARDS), pulmonary embolism or hemorrhage, cancer, empyema or lung abscess.
Patient Care and Monitoring
Monitoring response to therapy is essential for determining efficacy, identifying adverse reactions, and determining the duration of therapy.
1. Assess the patient’s symptoms and status (i.e., inpatient, outpatient, or intubated) to determine the type of pneumonia and comorbid conditions. Does the patient have moderate to severe asthma, COPD, or emphysema or is a current smoker?
2. Review any available diagnostic data to determine severity of the disease.
3. Obtain a history of prescription and nonprescription medication use, as well as allergies and drug intolerances, noting the severity of the reaction.
4. What are the top two to three organisms associated with the type of pneumonia the patient has?
5. Select an appropriate empirical antibiotic regimen for the patient, ensuring that the doses are correct for renal function.
6. Develop a plan to assess the effectiveness of the antibiotic therapy after 24 to 72 hours. If the patient is not improving, then reevaluate the diagnosis and pathogen list, and make appropriate changes to therapy. Develop a plan to assess the effectiveness of the antibiotic therapy again at the end of therapy. When can conversion from IV to oral therapy occur?
7. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.
8. For patients who meet the qualifications, discuss the value of vaccination against S. pneumoniae and/or influenza.
PREVENTION
Prevention of pneumococcal disease by use of vaccination is a national goal. Vaccination is used to prevent or minimize the severity of pneumonia caused by S. pneumoniae or the influenza virus.
The influenza vaccine is available in two forms, injectable and nasal inhalation. The injectable product is an inactivated vaccine (containing killed virus) and is approved for use in people older than 6 months of age, including healthy people and people with chronic medical conditions. The nasal-spray influenza vaccine is made with live, weakened influenza viruses that do not cause influenza (live attenuated influenza vaccine). This formulation is approved for use in healthy people 5 to 49 years of age who are not pregnant. The ability of influenza vaccine to protect a person depends on two key factors: the age and health status of the person getting the vaccine, and the similarity or “match” between the virus strains in the vaccine and those in circulation. Given these factors, the vaccine has been effective. The influenza vaccine is recommended for the following groups of people40:
1. People at high risk for complications from the flu :
• People 65 years and older
• People who live in nursing homes and other long-term care facilities that house those with long-term illnesses
• Adults and children 6 months and older with chronic heart or lung conditions, including asthma
• Adults and children 6 months and older who needed regular medical care or were in a hospital during the previous year because of a metabolic disease (like diabetes), chronic kidney disease, or weakened immune system (including immune system problems caused by medicines or by infection with HIV)
• Women who will be pregnant during the influenza season
• Children 6 months to 18 years of age who are on long-term aspirin therapy
• All children 5 to 18 years of age
• People with any condition that can compromise respiratory function or the handling of respiratory secretions (i.e., a condition that makes it hard to breathe or swallow, such as brain injury or disease, spinal cord injuries, seizure disorders, or other nerve or muscle disorders)
2. People 50 to 64 years of age: Comorbid conditions are present in nearly one-third of people 50 to 64 years of age in the United States, and that places them at increased risk for serious flu complications. Therefore, vaccination is recommended for all persons aged 50 to 64 years.
3. People who can transmit flu to others at high risk for complications: Any person in close contact with someone in a high-risk group should get vaccinated. This includes all health care workers, household contacts, and out-of-home caregivers of children 0 to 23 months of age and adults 65 years and older.
There are two pneumococcal vaccines, a seven-valent conjugated vaccine for children younger than 6 years of age and a 23-purified-capsular polysaccharide antigen vaccine for adults. The 23 capsular types in the vaccine represent at least 85% to 90% of the serotypes that cause invasive pneumococcal infections among children and adults in the United States.41 After vaccination, an antigen-specific antibody response, indicated by a twofold or greater rise in serotype-specific antibody, develops within 2 to 3 weeks in 80% or more of healthy young adults.42 However, immune responses may not be consistent among all 23 serotypes in the vaccine.42 Those who should receive the polysaccharide vaccine include40:
1. All adults 65 years of age or older
2. Anyone over 6 years of age who has a long-term health problem such as heart disease, lung disease, sickle cell disease, diabetes, alcoholism, cirrhosis, and leakage of cerebrospinal fluid.
3. Anyone over 6 years of age who has a disease or condition or is taking any drug that lowers the body’s resistance to infection, such as Hodgkin’s disease, lymphoma, leukemia, kidney failure, multiple myeloma, nephrotic syndrome, HIV infection or AIDS, damaged spleen or no spleen, organ transplant, long-term steroids, certain cancer drugs, or radiation therapy
4. Alaskan Natives and certain Native American populations: The conjugated pneumococcal vaccine is recommended for all children aged 2 to 23 months and for certain children aged 24 to 59 months. If there are underlying health issues such as diabetes mellitus, or cardiopulmonary disease then children 24 to 59 months should receive this vaccine as well. The seven capsular types in the vaccine represent at least 85% to 90% of the serotypes that cause invasive pneumococcal infections among children in the United States.41
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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