Gail Itokazu, Pharm.D.
Spring 1998

Pneumonia

  1. Pneumonia
  2. Case 1

Required Readings

1. Toltzis P, et al. Lower Respiratory Tract Infections. In: Pharmacotherapy: A Pathophysiologic Approach. DiPiro JT, et al eds. Elsevier, NY, 3rd Edition, 1997. Chapter 100 pp 1995-2016.

Optional Readings

The following readings are not required, but may enhance your understanding of the material in this section.

1. Guidelines for the initial Management of Adults with Community-acquired Pneumonia: Diagnosis, Assessment of Severity, and Initial Antimicrobial Therapy. Am Rev Respir Dis 1993; 148:1418-26.

2. Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med 1995; 153:1711.

GOALS

1. Understand the pathophysiology of pneumonia in various clinical settings.

2. Be able to recommend appropriate antimicrobial therapy for patients with pneumonia.

3. Understand the goals of therapy for patients with pneumonia.

LUNG DEFENSES

1. List 3 ways in which organisms gain access to the lung.

BRONCHITIS

1. Define bronchitis.

2. Know the usual infectious agents which cause bronchitis.

Acute Bronchitis

1. Describe the clinical presentation of acute bronchitis.

2. Discuss the treatment of acute bronchitis.

Chronic Bronchitis

1. Discuss the etiology of chronic bronchitis.

2. What is the definition of chronic bronchitis (as defined by clinical assessment and history).

The role of antimicrobials in patients with acute exacerbations of chronic bronchitis is controversial. Since up to 25% of episodes of acute exacerbations of chronic bronchitis are due to treatable infections, it would be reasonable to begin antibiotics in these patients when they present with increased cough and sputum production, increased sputum purulence, and increased dyspnea (but without pneumonia). Antibiotic therapy should be directed against H. influenzae and S. pneumoniae. Therefore, agents such as amoxicillin (although in some areas, 30% of H. influenzae may be resistant to amoxicillin), trimethoprim-sulfamethoxazole, tetracyclines, and cefuroxime axetil could be administered. Erythromycin will be active against S. pneumoniae. Fluoroqinolones (e.g., ciprofloxacin, ofloxacin) are active against H. influenzae, but have moderate to no activity against S. pneumoniae, and therefore are not the agents of choice.

PNEUMONIA

Pneumonia is the 6th most common cause of pneumonia in the United States and the most common cause of death due to an infectious disease. Mortality associated with community acquired pneumonia for patients treated as an outpatient ranges from 1-5%, while patients requiring hospitalization have a higher mortality (25%). Mortality associated with hospital-acquired pneumonia may be as high as 70%. Appropriate antimicrobials can improve outcomes of hospital-acquired pneumonia, with survival rates of 70-80%.

Goals of therapy for patients with pneumonia include alleviation of the signs and symptoms of pneumonia such as fever, shortness of breath, cough, chest pain; and prevention of complications such as sepsis, lung abscess, and empyema.

PATHOGENESIS

1. Know the major mechanism via which organisms gain access to the lower airways and alveoli.

2. Discuss the mechanism via which lung infection with viruses predisposes the patient to secondary bacterial infection.

3. List 3 factors which impair mucocilliary clearance of bacteria.

4. List the 2 most common organisms which cause community acquired pneumonia.

5. List 4 groups of patients who are predisposed to pneumonia caused by gram-negative bacilli (gram-negative rods).

6. Discuss the situations in which anaerobic bacteria are likely to cause pneumonia.

CLINICAL PRESENTATION

1. Identify 4 clinical and 4 laboratory manifestations of pneumonia.

Note: a gram-stain of the sputum will assist in determining the bacteriologic etiology of pneumonia. A gram-stain which is supportive of the diagnosis of bacterial pneumonia includes the presence of >25 polymorphonuclear leukocytes and <10 epithelial cells per low-power field, especially when large numbers of organisms of uniform morphology are present.

2. Identify the common pathogens of pneumonia in the following clinical settings: 1) previously healthy ambulatory patient (community acquired pneumonia), 2) elderly (nursing home resident), 3) alcoholic, 4) community acquired aspiration pneumonia, 5) hospital acquired aspiration pneumonia, and 5) hospital-acquired pneumonia (not aspiration).

3. Select an empiric antimicrobial regimen for each of the above settings of pneumonia. Be able to defend your selection of antimicrobial(s) based on the most likely pathogen, and the adverse reaction profiles of the various antimicrobial(s) selected for your empiric therapy.

GENERAL COMMENTS

As you read this chapter, keep in mind that specific bacteria are more prone to cause pneumonia in certain clinical settings (DiPiro, Table 95.3, pg 1554). This information can help in the selection of empiric antibiotics in patients with pneumonia.

Previously healthy, ambulatory patient. Erythromycin is a good empiric regimen in these patients when it is not clear if S. pneumoniae and/or Mycoplasma pneumoniae is causing infection. If the gram stain and/or clinical presentation of the patient is suggestive of pneumonia due to Streptococcus pneumoniae penicillin would be the drug of choice (providing susceptibility of the pathogen to penicillin). For non-meningeal infections (e.g., pneumonia) caused by S. pneumoniae with intermediate resistance to penicillin, high dose penicillin has been successful.

In many instances, Mycoplasma is a self-limiting infection, and therefore need not be treated. Furthermore, erythromycin is noted for causing gastrointestinal side effects in many patients. Some patients may tolerate the newer (and more expensive) macrolides clarithromycin and azithromycin better than erythromycin. These newer macrolides are also active against H. influenzae.

Alcoholic. Since Hemophilus influenzae, Klebsiella pneumoniae, and Streptococcus pneumoniae are common pathogens, a second generation cephalosporin such as cefuroxime would constitute reasonable empiric therapy in this setting. Depending on institutional policies, selected 3rd generation cephalosporins (ceftizoxime, cefotaxime, or ceftriaxone) are are also used.

Aspiration (community). Penicillin is usually very active against oral anaerobes. More recently, there has been an increase in the prevalence of penicillin-resistant anaerobes, especially of the Bacteroides species. The primary mechanism of resistance is via the production of beta-lactamases (enzymes that hydrolyze and thus destroy the beta-lactam ring), rendering penicillin inactive against these bacteria. If beta-lactamase producing anaerobes are prevalent within the community, or the patient is not responding to penicillin, oral alternatives include clindamycin, or amoxicillin-clavulanate. Clavulanate is a beta-lactamase inhibitor which inactivates the beta-lactamase enzyme, thus protecting the amoxicillin molecule from being destroyed by these enzymes.

NOSCOMIAL PNEUMONIA

Despite the fact that the management of noscomial pneumonia or hospital-acquired pneumonia (HAP) is filled with controversy, the American Thoracic Society has made an attempt to provide clinicians with guidelines to assist them in the management of this infection (if interested, see optional reading on "Hospital-acquried Pneumonia in Adults…" for additional details). Their approach is to recommend antimicrobial therapy for patients based on certain characteristics:

1)severity of disease – patients with severe disease would require admission to the intensive care unit (ICU); other indicators of severe illness are also used.

2)presence of risk factors that would predispose patients to specific organisms – see Table 2 for risk factors.

3)time of onset of pneumonia in relation to hospital stay – early onset is defined as <5 days in the hospital, late onset is defined as > 5 days in the hospital.

Table 1. Mild-Moderate HAP, No Risk Factors, Onset Anytime or Severe HAP with Early Onset

Core OrganismsCore Antimicrobials  
Enteric gram-negative bacilli

(non-pseudomonal)

Enterobacter species

E.coli

Klebsiella species

Proteus species

Serratia marcescens

H. influenzae

Methicillin-sensitive S. aureus

S. pneumoniae

 2nd generation cephalosporin

Non-pseudomonal 3rd generation cephalosporin

Beta-lactam/inhibitor combination

If penicillin allergic

Flurorquinolone or

Clindamycin + aztreonam

Table 2. Mild-Moderate HAP with Risk Factors, Onset Anytime

Core Organisms plus Core Antimicrobials plus
Anaerobes – recent abdominal surgery, witnessed aspiration Clindamycin or beta-lactam/inhibitor (alone)
S. aureus – coma, head trauma, diabetes, renal insufficiency +/- vancomycin if methicillin resistant
Legionella – high dose steroids Erythromycin +/- rifampin
P. aeruginosa – prolonged ICU stay, steroids, antibiotics, lung disease Treat as severe HAP (Table 3)

Table 3. Severe HAP with Risk Factors, Early Onset or Severe HAP, Late Onset

Core Organisms plus Therapy
P. aeuginosa

Acinetobacter species

 Aminoglycoside or ciprofloxacin plus one of the following:

Antipseudomonal Penicillin

Beta-lactam/inhibitor

Ceftazidime or cefoperazone

Imipenem

Aztreonam
Consider methicillin-resistant S. auresu +/- Vancomycin

Recommendations in Tables 1-3 excludes patients with immunosuppression.

Other Considerations

1. The selection of antimicrobials may need to be altered for individual hospitals based upon their usual susceptibility patterns for the organisms of interest.

2. Not all patients with a clinical diagnosis of pneumonia have lower respiratory tract infection. Thus, non-infectious causes of lung infiltrates and fever need to be considered (e.g., congestive heart failure, atelectasis, pulmonary thromboembolism, drug reactions, pulmonary hemorrhage, and adult respiratory distress syndrome).

3. Early switch to oral therapy may be possible in patients responding to therapy (Khan et al. Sequential intravenous-oral administration of ciprofloxacin vs ceftazidime in serious bacterial respiratory tract infections. Chest 1989; 96:528).

4. Prior antimicrobials need to be considered in patients not responding to therapy, (i.e.), may not want to use a class of antimicrobials which are likely to be cross-resistant to antimicrobials the patient has recently been exposed to or antimicrobials the patient is failing on.

5. Ciprofloxacin is an oral alternative to beta-lactams for the treatment of nosocomial acquired gram-negative infections. It has marginal activity against streptococci and reports of infectious complications due to Streptococcus pneumoniae in the face of treatment with ciprofloxacin warrants caution when using ciprofloxacin for the treatment of these infections. (N Engl J Med 1991; 325:520).

Selection of an acceptable regimen based on the patient based on clinical characteristics:

1. renal insufficiency. Avoidance of an aminoglycoside may be desirable in these patients. Alternatives include: third generation cephalosporins, aztreonam, ciprofloxacin, or carbapenems. Dosage modification is required with most of these agents. If imipenem/cilastatin is selected, dosage modification is necessary to minimize the potential for seizures. Patients at risk for CNS toxicity are those with renal insufficiency, history of stroke or seizure disorder, and the elderly.

2. beta-lactam allergy. Aztreonam or ciprofloxacin are alternatives to beta-lactams for gram-negative coverage.

3. Activity in sputum. Aminoglycosides have poor penetration into respiratory secretions and are less active in the acid pH of infected lung and is not recommended for use alone for gram-negative respiratory infections (see optional reading, "Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med 1995; 153:1711).

Duration of Therapy

Gram-negative pneumonia – 14-21 days

S. aureus, H. influenzae, 7-10 days may be adequate

Case 1.

CC: elective surgery for removal of appendix

HPI: AA is an 75 year old male admitted on 6/10/97 for an elective appendectomy . Post-operative complications arise on 6/20/97 (e.g., sudden onset of shortness of breath, productive sputum production) and he is transferred to the intensive care unit where he remains on a respirator. Past medical history is significant for hypertension, peptic ulcer disease, and diabetes. He has no known drug allergies.

PE: temp 102 degrees Fahrenheit, HR 95, RR 30, B/P 130/90

Chest: decreased breath sounds on auscultation, inspiratory crackles

CXR: left lower lobe consolidation suggestive of pneumonia.

LABS: WBC 35,000 with 60% segs, 20% bands, 15% lymphs, 5% others. BUN 10, serum creatinine 1.0, serum glucose is normal. Arterial Blood gas shows a reduced PO2.

Sputum gram stain: many gram-negative rods, <5 squamous epithelial cells per low power field, 40 polys/low power field

1.What is your assessment (i.e., problem list and possible cause(s) for each problem). Providing subjective and objective data to support each problem is helpful when preparing your assessment of the patient.

This is an elderly male with subjective complaints related to the respiratory tract (sudden onset of shortness of breath, productive sputum production). Objective data supporting a problem in the respiratory tract include reduced oxygenation via blood gas, an abnormal CXR, abnormal chest exam, and a sputum with few squamous epithelial cells and many polys.

Fever should prompt a search for an infectious etiology of his respiratory complaints.

Other problems in the patient’s PMH should also be noted in your problem list.

2. What empiric antimicrobial regimen would you recommend in this patient? Be able to support your recommendation, i.e., consider a discussion of the most likely pathogens, potential drug toxicities of selected regimens, etc.?

The patient required admission to the intensive care unit and thus has severe hospital-acquired pneumonia. Based on Table 3, Pseudomonas aeruginosa is a common gram-negative pathogen causing hospital acquired pneumonia. Therefore, empiric therapy with an aminoglycoside and anti-pseudomonal penicillin was initiated. Of the potential antispseudomonal cephalosporins, ceftazidime is more active against this pathogen than is cefoperazone. If the patient had a penicillin allergy, aztreonam would provide activity against P. aeruginosa and other aerobic-gram negative bacilli that may cause nosocomial pneumonia. Other potential regimens are also listed in Table 3.

3. If you recommended an aminoglycoside, what monitoring parameters would you recommend?

Monitor renal function and peak and trough aminoglycoside concentrations to minimize the potential for nephro- and oto-toxicity. Alternatively, if single daily dosing of aminoglycosides is begun, some experts recommend maintaining aminoglycoside levels of <1.0mcg/ml at 18 hours post-dose. Data on the efficacy of once-daily aminoglycoside dosing in severely ill patients with more resistant pathogens, e.g., P. aeruginosa are limited.

4. If cultures reveal that Staphylococcus aureus (gram-positive cocci in clusters) is also a pathogen, which antimicrobial(s) would you consider adding?

Staphylococcus aureus is also a common pathogen causing nosocomial pneumonia. Depending on the susceptibility of the isolate, nafcillin or vancomycin can be used. Isolates of Staphylococcus aureus that are nafcillin-resistant are usually treated with vancomycin. Pending the antimicrobial susceptibility of the S. aureus, the choice of empiric therapy in part will depend on the usual sensitivity patterns of S. aureus in each hospital. If nafcillin-resistant S. aureus are uncommon, then empiric nafcillin may be appropriate. However, if nafcillin resistance is prevalent, empiric vancomycin may be instituted until susceptibility results are available.

5. By day 10 of intravenous antimicrobial therapy, the patient is transferred out of the intensive care unit and is eating well. Current medications include gentamicin, mezlocillin, maalox 30ml Q6 hours for peptic ulcer disease and glyburide. Labs: CBC w/ differential, serum electrolytes, bun, serum creatinine and serum glucose are all within normal limits. Develop a therapeutic plan for completion of his therapy for nosocomial pneumonia.

The patient appears ready to complete therapy with an oral agent. Drugs with activity against aerobic-gram negative bacilli such as P. aeruginosa would be reasonable. It is decided to complete a 21 day course (combined IV and oral) of therapy with ciprofloxacin 750mg orally, twice daily.

6. Is there anything you would recommend to the physician before initiating this oral regimen?

Be aware of drug interactions with cations and quinolones that result in a significant reduction in oral bioavailability of the quinolone. Either discontinue the maalox, switch to an H2-receptor antagonist if possible, or space out the administration of the quinolone and maalox.

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