WORKUP

Lab Studies:

• Leukocytosis with a left shift, although commonly observed in any bacterial infection, may be absent in patients who are elderly or debilitated.

• Leukopenia (defined as a WBC count of <5000) is an ominous sign of impending sepsis and portends a poor outcome.

• Sputum examination (see Image 4) provides an accurate diagnosis in approximately 50% of patients.

• An adequate specimen must have less than 10 squamous epithelial cells and more than 25 WBCs per low-power field. However, the number of WBCs in the sputum of a neutropenic patient may be fewer than 25 WBCs per low-power field, despite origination from the lower respiratory tree.

• A single pathogen present on the Gram stain is indicative of pneumonia; mixed flora may indicate oral contamination or anaerobic infections.

• An adequate specimen uncontaminated by oral flora is required for a proper workup.

• Sputum cultures are submitted only from specimens that are deemed satisfactory after Gram stain.

• The Legionella-specific direct fluorescent antibody test is performed when indicated, even though this technique is associated with a high rate of false-negative results.

• Other tests may include the following:

• Urinary antigen testing for Legionella serogroup 1 has a high yield. A urinary antigen test for pneumococcus is available and may be performed at the bedside. Experience with this test is limited.

• A Legionella serum antibody titer rising by 1:128 confirms the diagnosis retrospectively. Mycoplasma and Chlamydia immunoglobulin M antibodies contribute to the diagnosis.

• Serology is essential in the diagnosis of unusual causes of pneumonia such as Q fever and brucellosis.

• Culture and Gram stain of pleural effusions or empyema fluid has a high yield. Pleural fluid pH determination should be made to classify the effusion as simple versus complicated.

• Performing blood cultures is important, but the results have a limited value. When positive, the results confirm a causative agent. Blood cultures are positive only in approximately 40% of cases, but performing them is necessary for epidemiologic surveillance and documentation of resistance patterns in a community.

Imaging Studies:

• Chest radiograph findings may indicate the following:

• A segmental or lobar opacity with air bronchogram - May be observed in S pneumoniae pneumonia

• Cavitary lesions and bulging lung fissures - May be observed in pneumonia caused by K pneumoniae or S aureus

• Presence of cavitation and associated pleural effusions - May suggest pneumonia caused by S aureus, anaerobic infections, gram-negative infections, and tuberculosis

• Legionella - Predilection for the lower lung fields

• Klebsiella - Tendency to involve the upper lung zones

• In a patient with a clinical picture of pneumonia, pathogenic organisms may be suggested based on the chest radiographic pattern. The common patterns are described as follows:

• Focal opacity (segment or lobar pneumonia) (see Images 2-3) - S pneumoniae, M pneumoniae, L pneumophila, S aureus, C pneumoniae, M tuberculosis, B dermatitidis

• Interstitial pattern (diffuse process identified as reticulonodular or reticular process) - M pneumoniae, P carinii, C psittaci

• Interstitial pattern with hilar and/or mediastinal lymphadenopathy - Epstein-Barr virus, Francisella tularensis, C psittaci, M pneumoniae, fungi

• Cavitation or necrotizing pneumonia (see Image 1) - Mixed aerobic-anaerobic infection (lung abscess), aerobic gram-negative bacilli, M tuberculosis, L pneumophila, C neoformans, Nocardia asteroides, Actinomyces israelii, C immitis

• Bulging oblique or horizontal fissure - K pneumoniae, L pneumophila

• Multifocal bilateral segment or lobar opacities - S aureus, C burnetii, L pneumophila, S pneumoniae

• Miliary (diffuse micronodular) pattern - M tuberculosis, H capsulatum, C immitis, B dermatitidis, varicella zoster

• Pneumatoceles (thin-walled cavities) - S aureus, Streptococcus pyogenes, P carinii

• "Round" pneumonia (often presents as solitary pulmonary nodule) - C burnetii, S pneumoniae, L pneumophila, S aureus

Other Tests:

• Arterial blood gas (ABG) determination: Evaluation of the patient's gas exchange is essential in order to decide if hospital admission, oxygen supplementation, or other efforts are indicated.

• Pulse oximetry of less than 90% indicates significant hypoxia; an ABG determination should be performed in these patients.

Procedures:

• Bronchoscopy: Bronchial washing specimens can be obtained. Protected brush and bronchoalveolar lavage can be performed for quantitative cultures.

• Transtracheal aspiration for culture: This procedure is mentioned primarily for historical significance. This method of obtaining lower respiratory secretions has been replaced by fiberoptic bronchoscopy.

• Thoracentesis: This is an essential procedure in patients with a parapneumonic pleural effusion. Obtaining fluid from the pleural space for laboratory analysis allows for the differentiation between simple and complicated effusions. This determination helps guide further therapeutic intervention.

1. The recently infected lungs demonstrate engorgement of alveolar capillaries with frothy, serous, and blood-tinged fluid in the alveolar spaces.

    

2. The "red hepatization" stage is a rapid progression from engorgement. This stage is characterized by a dry, granular, dark-red lung surface on gross appearance. The alveoli are filled with copious, clotted, inflammatory exudates, and a fibrin network extends from one alveolus into the next through the pores of Kohn. Little tissue destruction or necrosis occurs at this stage, and the patient and lung architecture may recover fully.

    

3. As pneumonia progresses over 2-3 days, leukocytes pack into the alveoli, erythrocytes are lysed, and epithelial cells degenerate, leading to "gray hepatization.” Dying pneumococci release a preformed toxin, further contributing to this damage. The pneumococci are opsonized by leukocytes and begin to be cleared. Resolution results in the formation of jellylike yellowish-colored exudates. Absorption of these exudates is remarkably efficient, with little organization or permanent scaring.

TREATMENT

Medical Care: The initial approach to treating patients with community-acquired pneumonia involves a determination of 3 factors. (1) Should the patient with pneumonia be treated in the hospital or as an outpatient? (2) Does the patient have a serious coexisting illness or is the patient elderly? (3) How severely ill is the patient at the time of the initial evaluation?

Once these assessments have been made, initial antimicrobial therapy can be selected based on to the recommendations given in Tables 1-7. The choices cover the most common pathogens for a given clinical setting. Evaluating the response to therapy is important. Patients who are not improving with initial empirical antibiotic therapy should be identified and re-examined.

• Risk stratification of community-acquired pneumonia

   

  • Patients with community-acquired pneumonia can be categorized into 1 of 4 groups based on information collected at the time of the initial evaluation.

     

  • The risk factors for stratification include the need for hospitalization, the severity of illness, the presence of coexisting disease, and the patient's age.

     

  • The 4 major categories not only speculate the microbial etiology but also predict ultimate prognosis and outcome. These categories are (1) community-acquired pneumonia occurring in patients aged 60 years or younger who have no evidence of comorbidity and who can be treated in an outpatient setting, (2) community-acquired pneumonia occurring in patients with evidence of comorbidity and/or who are aged 60 years or older who can be treated in an outpatient setting, (3) community-acquired pneumonia requiring hospitalization but not admission to an ICU, and (4) severe community-acquired pneumonia requiring ICU care.

• Nosocomial pneumonia

   

  • Nosocomial pneumonia remains a prevalent hospital-acquired infection. The gaps in knowledge and controversies regarding diagnosis, treatment, and prevention of nosocomial pneumonia continue. The initial empiric therapy of nosocomial pneumonia in immunocompetent patients is directed at the core organisms. In immunocompromised hosts, the additional bacteria are targeted and therapy is modified based on the results of microbiologic investigations.

     

  • Modifications to the empirical antibiotic therapy may be necessary after assessment of 3 factors; these are (1) the severity illness in the patient, (2) the presence of any conditions that can lead to infection with specific pathogens, and (3) the length of time the patient has been hospitalized before the development of nosocomial pneumonia.

     

  • Following these determinations, patients are categorized into 1 of 3 groups because a different microbiologic spectrum is suggested in each group. These groups are (1) patients without unusual risk factors who present with mild-to-moderate nosocomial pneumonia any time during hospitalization or present with severe nosocomial pneumonia at early onset, (2) patients with risk factors who present with mild-to-moderate nosocomial pneumonia occurring any time during hospitalization, and (3) patients with severe nosocomial pneumonia either of early onset with specific risk factors or of late onset without risk factors.

     

  • Patients belonging to risk group 1 usually are infected with E coli or S aureus; Klebsiella, Proteus, Serratia, or Haemophilus, species; or streptococci. Patients in risk group 2 have infection with the previous organisms, but anaerobes, S aureus, Legionella species, and P aeruginosa also may be present. In risk group 3, the core organisms are present and P aeruginosa, Acinetobacter species, and methicillin-resistant S aureus are the additional possibilities.

• Definition of severe hospital-acquired pneumonia

• Admission to the ICU is indicated.

   

• Respiratory failure is defined as the need for mechanical ventilation or the requirement for fraction of inspired oxygen to be greater than 35% in order to maintain oxygen desaturation of greater than 90%.

   

• Rapid radiographic progression, multilobar pneumonia, or cavitation of a lung infiltrate is present.

   

• Evidence of severe sepsis with hypotension and/or an organ dysfunction is present.

   

• Shock state is present, as indicated by a systolic blood pressure of less than 90 mm Hg or a diastolic blood pressure of less than 60 mm Hg.

   

• Vasopressors are required for more than 4 hours.

   

• Urine output is less than 20 mL/h, or total urine output is less than 80 mL in 4 hours.

   

• Acute renal failure is present that requires dialysis.

• Empiric therapy for community-acquired bacterial pneumonia - Based on recommendations by the American Thoracic Society (1993) and consensus guidelines by the Canadian Infectious Disease Society/Canadian Thoracic Society (2000)

  Table 1. Outpatient Pneumonia Without Comorbidity in Patients Aged 60 Years or Younger*

  Organisms † S pneumoniae M pneumoniae C pneumoniae H influenzae Miscellaneous Legionella species, S aureus, aerobic gram-negative bacilli Therapy 1st choice - Macrolide ‡ 2nd choice - Doxycycline

  *Excludes patients at risk for HIV † In roughly one third to one half of the cases, no etiology was identified. ‡ Erythromycin, clarithromycin, or azithromycin

  Table 2. Outpatient Bacterial Pneumonia With Comorbidity in Patients Aged 60 Years or Older*

  Organisms † S pneumoniae H influenzae Aerobic gram-negative bacilli S aureus Miscellaneous M catarrhalis, Legionella species, Mycoplasma Therapy COPD (no recent antibiotics or oral steroids within past 3 mo) 1st choice – Newer macrolides 2nd choice – Doxycycline COPD (recent antibiotics or oral steroids in past 3 mo) 1st choice – Respiratory fluoroquinolone* 2nd choice – Amoxicillin/clavulanate + macrolide or second-generation cephalosporin + macrolide Suspected microaspiration – Oral anaerobes 1st choice –Amoxicillin/clavulanate and/or macrolide or fourth-generation fluoroquinolone (eg, moxifloxacin) 2nd choice – Third-generation fluoroquinolone (eg, levofloxacin plus clindamycin or metronidazole

  *Excludes patients at risk for HIV † In roughly one third to one half of the cases, no etiology was identified.

  Table 3. Hospitalized Patients with Community-Acquired Bacterial Pneumonia (admission to medical ward)*

  Organisms † S pneumoniae H influenzae Polymicrobial (including aerobic bacteria) Aerobic gram-negative bacilli Legionella species S aureus C pneumoniae Miscellaneous M pneumoniae, M catarrhalis Therapy 1st choice - Respiratory fluoroquinolone 2nd choice – Second-generation or third-generation cephalosporin + macrolide

  *Excludes patients at risk for HIV † In roughly one third to one half of the cases, no etiology was identified.

  Table 4. Severe Hospitalized Patients With Community-Acquired Bacterial Pneumonia (admission to ICU)*

  Organisms † S pneumoniae Legionella species Aerobic gram-negative bacilli M pneumoniae Miscellaneous H influenzae Therapy 1st choice – Antipseudomonal fluoroquinolone (eg, ciprofloxacin) plus antipseudomonal beta-lactam (eg, ceftazidime, piperacillin- tazobactam, carbapenem) or aminoglycoside (eg, gentamicin, tobramycin, amikacin) 2nd choice – Triple therapy with antipseudomonal beta-lactam plus aminoglycoside plus macrolide

  *Excludes patients at risk for HIV † In roughly one third to one half of the cases, no etiology was identified.

  Table 5. Patients with Mild-to-Moderate Hospital-Acquired Bacterial Pneumonia, No Unusual Risk Factors, and Onset at Any Time; or, Patients with Severe Hospital-Acquired Pneumonia with Early Onset*

  Core Organisms	Core Antibiotics
  Enteric gram-negative bacilli	Cephalosporin
  (Nonpseudomonal) Enterobacter species, E coli	Second-generation or nonpseudomonal third-generation
  Klebsiella species	Beta-lactam/beta-lactamase inhibitor combination
  Proteus species S marcescens	If allergic to penicillin, fluoroquinolone or clindamycin + aztreonam
  H influenzae
  Methicillin-sensitive S aureus S pneumoniae
  *Excludes patients with immunosuppression

  Table 6. Patients with Mild-to-Moderate Hospital-Acquired Bacterial Pneumonia with Risk Factors, Onset at Any Time*

  Core Organisms, Plus the Following:	Core Antibiotics, Plus the Following:
  Anaerobes (recent abdominal surgery, witnessed aspiration)	Clindamycin or beta-lactam/beta-lactamase inhibitor (alone)
  S aureus (coma, head trauma, diabetes mellitus, renal failure)	+/-vancomycin (until methicillin-resistant S aureus is excluded)
  Legionella (high-dose steroids)	Erythromycin +/- rifampin
  P aeruginosa (prolonged ICU stay, steroids, antibiotics, structural lung disease	Treat as severe hospital-acquired pneumonia (see Table 7)
  *Excludes patients with immunosuppression

  Table 7. Patients with Severe Hospital-Acquired Bacterial Pneumonia with Risk Factors and Early Onset or Patients with Severe Hospital-Acquired Pneumonia and Late Onset*

  Core Organisms, Plus the Following	Therapy
  P aeruginosa Acinetobacter species Consider methicillin-resistant S aureus	Aminoglycoside or ciprofloxacin plus one of the following: Antipseudomonal penicillin Beta-lactam/beta-lactamase inhibitor Ceftazidime or cefoperazone Imipenem +/-vancomycin
  *Excludes patients with immunosuppression

Consultations: Consultation with infectious disease and/or pulmonary specialists is suggested in difficult cases.

• Patients requiring noninvasive mechanical ventilation or intubation may need consultation with a critical care medicine specialist to aid in management after admission to the ICU.

• A pharmacist and/or infection control specialist may be of assistance in providing information on hospital or regional bacterial resistance and sensitivity patterns.

MEDICATION

The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.

Drug Category: Antibiotics -- The initial antibiotic to treat low-risk patients is a macrolide. Macrolides are effective against most likely organisms in community-acquired bacterial pneumonia. Macrolides are used for gram-positive organisms, Legionella, and Mycoplasma. Azithromycin administered IV has the advantage of once-daily dosing over IV erythromycin.

Macrolides, as a class, have the potential to cause adverse GI effects. Newer agents are expensive, have fewer adverse GI effects, and fewer drug interactions compared to erythromycin. Macrolides are used for community-acquired pneumonia in patients younger than 60 years who are nonsmokers and have no comorbidity. Newer macrolides offer better compliance through reduced dosing frequency and improved activity against H influenzae and Mycoplasma.

Patients with community-acquired pneumonia who are older than 60 years or have comorbidity still are susceptible to S pneumoniae, but broader coverage is required to include Haemophilus, Moraxella, and other gram-negative organisms. Therefore, empiric therapy would include one of the macrolide agents outlined above plus one of the second-generation or third-generation cephalosporins, amoxicillin-clavulanate, or respiratory fluoroquinolone.

The choice of antimicrobial agent is based on the severity of patient illness, host factors (eg, comorbidity, age), and presumed causative agent (see Table 1, Table 2, and Table 3). Outpatients are prescribed oral agents, and parenteral antibiotics are prescribed to patients admitted to the hospital.

Second-generation cephalosporins have added activity against P mirabilis, H influenzae, E coli, K pneumoniae, and M catarrhalis in addition to the gram-positive activity of first-generation cephalosporins.

Third-generation cephalosporins have wider activity against most gram-negative bacteria, such as Enterobacter, Citrobacter, Serratia, Neisseria, Providencia, and Haemophilus species, including beta-lactamase–producing strains.

Second-generation cephalosporins are not effective against Legionella or Mycoplasma. Generally, they are well tolerated but expensive. Oral second-generation and third-generation cephalosporins offer increased activity against gram-negative agents and may be effective against ampicillin-resistant S pneumoniae.

IV cephalosporins may be combined with a macrolide agent in patients with community-acquired pneumonia who are admitted to the hospital. They broaden the gram-negative coverage and, in the case of third-generation agents, may be effective against resistant S pneumoniae. Also, ceftazidime, a third-generation agent, is effective against Pseudomonas.

When a severely ill patient has features of sepsis, respiratory failure, or neutropenia, treatment with an IV macrolide is combined with an IV third-generation cephalosporin. An alternative regimen may include imipenem, meropenem, or piperacillin/tazobactam plus a macrolide plus vancomycin. A fulminant course should lead to consideration of Legionella, Mycoplasma, psittacosis, and Q fever as the cause of bacterial pneumonia.

Drug Name	Azithromycin (Zithromax) -- Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose	Day 1: 500 mg PO Days 2-5: 250 mg PO qd Alternatively: 500 mg IV qd
Pediatric Dose	Day 1: 10 mg/kg PO once; not to exceed 500 mg/d Days 2-5: 5 mg/kg PO qd; not to exceed 250 mg/d
Contraindications	Documented hypersensitivity; hepatic impairment; sudden death may occur when taken concurrently with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, elderly, or debilitated patients

Drug Name	Clarithromycin (Biaxin) -- Another initial DOC in otherwise uncomplicated pneumonia. Appears to cause more GI symptoms than azithromycin (eg, gastric upset, metallic taste).
Adult Dose	500 mg PO bid for 10 d
Pediatric Dose	<6 months: Not recommended >6 months: 7.5 mg/kg PO bid for 10 d; not to exceed 500 mg/dose
Contraindications	Documented hypersensitivity; those taking pimozide or cisapride
Interactions	Toxicity increases with coadministration of fluconazole, astemizole, and pimozide; clarithromycin effects decrease and adverse GI effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, omeprazole, carbamazepine, ergot alkaloids, triazolam, and HMG CoA-reductase inhibitors; serious cardiac arrhythmias may occur with coadministration of cisapride; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increase in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25 mL/min; administer half dose or increase dosing interval if CrCl <30 mL/min; diarrhea may be sign of pseudomembranous colitis; superinfections may occur with prolonged or repeated antibiotic therapies

Drug Name	Erythromycin (EES, Erythrocin, Ery-Tab) -- Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. May result in GI upset, causing some to prescribe an alternative macrolide or change to tid dosing. Covers most potential etiologic agents, including Mycoplasma species. PO regimen may be insufficient to adequately treat Legionella species. Erythromycin is less active against H influenzae. Although standard course of treatment seems to be 10 d, treating until patient has been afebrile for 3-5 d seems to be a more rational approach.
Adult Dose	500 mg PO qid (some choose 333 mg tid) Hospitalized patients with severe pneumonia: 1 g IV q6h; alternatively, 15-20 mg/kg/d IV in divided doses q6h
Pediatric Dose	7.5 mg/kg/d PO divided bid; alternatively, 20-40 mg/kg/d IV divided q6h or by constant infusion; not to exceed 4 g/d
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; adverse GI effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Name	Amoxicillin and clavulanate (Augmentin) -- Alternative for patient who is allergic to or intolerant of macrolides. Usually well tolerated and gives good coverage to most infectious agents. Not effective against Mycoplasma and Legionella species. Cost is a major factor.
Adult Dose	500-875 mg PO for 10 d or until afebrile for 3-5 d
Pediatric Dose	25-45 mg/kg/d amoxicillin PO divided q12h
Contraindications	Documented hypersensitivity
Interactions	Risk of increased bleeding when coadministered with warfarin or heparin, possibly because of additive effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Give for a minimum of 10 d to eliminate organism and prevent sequelae (eg, endocarditis, rheumatic fever); following treatment, perform cultures to confirm eradication of streptococci

Drug Name	Doxycycline (Doryx, Bio-Tab) -- Alternative agent for patients who cannot be given macrolides or penicillins. Inhibits protein synthesis and thus bacterial growth by binding with 30S and, possibly, 50S ribosomal subunits of susceptible bacteria.
Adult Dose	100 mg PO bid for 10 d or until afebrile for 3-5 d
Pediatric Dose	<8 years: Not recommended >8 years: 2-5 mg/kg/d qd or divided bid; not to exceed 200 mg/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Vancomycin (Vancocin) -- Classified as glycopeptide agent that has excellent gram-positive coverage, including methicillin-resistant S aureus. To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to next dosing. Use creatinine clearance to adjust dose in patients diagnosed with renal impairment.
Adult Dose	500 mg IV q6h or 1 g IV q12h; not to exceed 10 mg/min
Pediatric Dose	40 mg/kg/d divided tid/qid
Contraindications	Documented hypersensitivity
Interactions	Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure and neutropenia; red man syndrome is caused by IV infusion that is too rapid (dose administered over a few min) but rarely happens when dose administered as 2-h administration or as PO or IP administration; red man syndrome is not an allergic reaction

Drug Name	Trimethoprim and sulfamethoxazole (Bactrim DS, Septra) -- Inhibits bacterial synthesis of dihydrofolic acid by competing with paraaminobenzoic acid, inhibiting folic acid synthesis. Results in inhibition of bacterial growth. Antibacterial activity of TMP-SMX includes common urinary tract pathogens, except P aeruginosa.
Adult Dose	160 mg TMP/800 mg SMX PO bid for 10 d
Pediatric Dose	<2 months: Not recommended >2 months: 8 mg TMP/kg/d divided bid
Contraindications	Documented hypersensitivity; megaloblastic anemia due to folate deficiency
Interactions	May increase PT of warfarin; thus, monitor coagulation tests and adjust dose as required; increased serum levels of both dapsone and TMP may occur when both medications are administered concomitantly; in patients who are elderly, incidence of thrombocytopenic purpura may increase when used concurrently with diuretics; hepatic clearance of phenytoin may be decreased and half-life prolonged; sulfonamides can displace MTX from plasma protein-binding sites, thus increasing free MTX concentrations, which may potentiate MTX effects in bone marrow depression; hypoglycemic response of sulfonylureas may increase with coadministration of both medications; may decrease renal clearance of zidovudine, causing increase in zidovudine levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, those with chronic alcoholism, elderly persons, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in individuals who are G-6-PD deficient; patients with AIDS may not tolerate or respond to TMP-SMX; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation

Drug Name	Levofloxacin (Levaquin) -- Rapidly becoming a popular choice in pneumonia. L-stereoisomer of the D/L parent compound ofloxacin, the D form being inactive. Good monotherapy that gives extended coverage against Pseudomonas species and excellent activity against pneumococcus. Agent acts by inhibition of DNA gyrase activity. PO form has bioavailability that reportedly is 99%.
Adult Dose	500 mg/d PO/IV Hemodialysis, CAPD, or CrCl <20 mL/min: 250 mg q48h CrCl 20-49 mL/min: 250 mg q24h
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT); do not administer within 24 h of live typhoid vaccine because reduces effects of vaccine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; rapid infusion may cause hypotension; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Gemifloxacin (Factive) -- Fluoroquinolone antibiotic with wide range of activity against gram-negative and gram-positive organisms. Acts by inhibiting both DNA gyrase and topoisomerase IV (TOPO IV), which are essential for bacterial growth. Because of this dual mechanism, MIC values remain in the susceptible range for some double mutants (eg, Streptococcus pneumoniae). Indicated for mild-to-moderate CAP caused by S pneumoniae (including penicillin-resistant strains; MIC value for penicillin >2 mg/mL), Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae.
Adult Dose	320 mg PO qd for 7 d
Pediatric Dose	<18 years: Not established >18 years: Administer as in adults
Contraindications	Documented hypersensitivity to gemifloxacin or other fluoroquinolones
Interactions	Coadministration with antacids and divalent or trivalent cations (eg, aluminum, magnesium, iron) significantly reduces absorption (administer 3 h before or 2 h after gemifloxacin); sucralfate decreases absorption and should be administered 2 h following gemifloxacin; may increase QT interval prolongation risk if coadministered with class IA (eg, quinidine, procainamide) or class III antiarrhythmic agents (sotalol, amiodarone), or other drugs known to prolong QT interval (eg, erythromycin, antipsychotics, antidepressants)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Decrease dose by 50% with CrCl <40 mL/min; may prolong QT interval; may cause maculopapular rash

Drug Name	Cefprozil (Cefzil) -- Binds to one or more of the penicillin-binding proteins, which inhibits cell wall synthesis and results in bactericidal activity.
Adult Dose	500 mg PO qd for 10 d
Pediatric Dose	<12 years: 7.5-15 mg/kg/d PO divided q12h for 10 d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid increases effects; coadministration with furosemide and aminoglycosides increases nephrotoxic effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dosage in renal impairment

Drug Name	Cefuroxime (Ceftin, Kefurox, Zinacef) -- Second-generation cephalosporin maintains gram-positive activity that first-generation cephalosporins have; adds activity against P mirabilis, H influenzae, E coli, K pneumoniae, and M catarrhalis. Condition of patient, severity of infection, and susceptibility of microorganism determine proper dose and route of administration.
Adult Dose	250 mg PO bid for 10 d
Pediatric Dose	<6 months: 20-50 mg/kg/d IV q12h Infants and children: 75-150 mg/kg/d IV q8h; not to exceed 6 g/d
Contraindications	Documented hypersensitivity
Interactions	Disulfiramlike reactions may occur when alcohol is consumed within 72 h after taking; may increase hypoprothrombinemic effects of anticoagulants; may increase nephrotoxicity in patient receiving potent diuretics (eg, loop diuretics); coadministration with aminoglycosides increases nephrotoxic potential
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Administer half dose if CrCl is 10-30 mL/min and one-quarter dose if <10 mL/min; fungal and microorganism overgrowth may occur with prolonged therapy

Drug Name	Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum and gram-negative activity, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.
Adult Dose	1-2 g IV qd or divided bid; not to exceed 4 g/d
Pediatric Dose	>7 days to 6 months: 25-50 mg/kg/d IV/IM; not to exceed 125 mg/d >6 months: 50-75 mg/kg/d IV/IM divided q12h; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; caution in breastfeeding women and allergy to penicillin

Drug Name	Ceftazidime (Ceptaz, Fortaz, Tazicef, Tazidime) -- Third-generation cephalosporin with broad-spectrum and gram-negative activity, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.
Adult Dose	1-2 g IV q8-12h
Pediatric Dose	<6 months: 30 mg/kg IV q12h >6 months to 12 years: 30-50 mg/kg/dose IV q8h; not to exceed 6 g/d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Nephrotoxicity may increase with aminoglycosides, furosemide, and ethacrynic acid; probenecid may increase levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment

Drug Name	Cefaclor (Ceclor) -- Second-generation cephalosporin indicated for infections caused by susceptible gram-positive cocci and gram-negative rods. Determine proper dosage and route based on condition of patient, severity of infection, and susceptibility of causative organisms.
Adult Dose	500 mg PO tid for 10 d
Pediatric Dose	20-40 mg/kg/d PO divided q8-12h; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	Alcoholic beverages consumed <72 h after taking may produce disulfiramlike reactions; may increase hypoprothrombinemic effects of anticoagulants; coadministration with potent diuretics and aminoglycosides (eg, loop diuretics) may increase nephrotoxicity; monitor renal function closely
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Reduce dosage by one half if CrCl is 10-30 mL/min and by one fourth if <10 mL/min; bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged or repeated therapy

FOLLOW-UP

Further Inpatient Care:

• Hospitalization versus ambulatory care

• The decision to hospitalize patients with community-acquired pneumonia is dictated by a series of well-recognized risk factors that increase either the risk of death or the risk of a complicated course for a patient with community-acquired pneumonia. Specific risk factors for mortality or a complicated course of pneumonia include the following:

   

  • Advanced age (>65 y)

     

  • Comorbid illness or other findings - (1) COPD, including chronic suppurative diseases of the lung (eg, bronchiectasis, cystic fibrosis); (2) diabetes mellitus; (3) chronic renal failure; (4) congestive heart failure; (5) chronic liver disease of any etiology; (6) suspicion of aspiration; (7) postsplenectomy state; and (8) chronic alcohol abuse or malnutrition

• Certain physical findings may predict a poor outcome from community-acquired bacterial pneumonia. These physical findings include the following:

   

  • Respiratory rate in excess of 30 breaths per minute

     

  • Diastolic blood pressure less than 60 mm Hg or systolic blood pressure less than 90 mm Hg

     

  • Temperature higher than 38.3°C (101°F)

     

  • Evidence of extrapulmonary sites of disease (eg, septic arthritis, meningitis)

     

  • Confusion, decreased level of consciousness, or both

• The following series of laboratory findings predicts severe disease and, possibly, a complicated course of illness:

   

  • WBC count of fewer than 4000/mm³ or more than 30,000/mm³, absolute neutrophil count of fewer than 1000/mm³

     

  • ABG determinations showing a PaO₂ of less than 60 mm Hg or PaCO₂ of greater than 50 mm Hg on room air

     

  • Respiratory failure requiring mechanical ventilation

     

  • Abnormal renal function as indicated by serum creatinine of greater than 1.2 mg/dL or blood nitrogen of greater than 20 mg/dL (>7 mmol/L)

     

  • Chest radiographic findings for multilobar involvement, the presence of a cavity, rapid radiographic progression, and the presence of a pleural effusion

     

  • Evidence of sepsis or organ dysfunction as manifested by a metabolic acidosis, an increased prothrombin time, increased partial thromboplastin time, or decreased platelets (a picture of disseminated intravascular coagulation).

   

• The decision to hospitalize also should take in to account social considerations, which include the absence of a responsible caregiver and or an unstable home situation.

   

• The Pneumonia Severity of Illness Scoring System (PSISS) was developed by Fine et al (Fine, 1997). This scoring system evaluates 20 different clinical and laboratory indices that are readily available. The PSISS is used to assist in deciding whether patients can be safely treated in an outpatient setting.

  Table 8. Pneumonia-Specific Severity of Illness Scoring System for Patients with Community-Acquired Pneumonia

  Patient Characteristics	Number of Points
  Demographic factors
  Age
  Men	Age in years
  Woman	Age in years minus 10
  Nursing home resident	10
  Coexisting Illnesses (definitions listed below)*
  Neoplastic disease	30
  Liver disease	20
  Congestive heart failure	10
  Cerebrovascular disease	10
  Renal disease	10
  Physical Examination Findings
  Altered mental status	20
  Respiratory rate >30 breaths per min	20
  Systolic blood pressure <90 mm Hg	20
  Temperature <35°C (95°F) or >40°C (104°F)	15
  Pulse rate >125 breaths per min	10
  Laboratory and Roentgenographic Findings
  Arterial pH <7.35	30
  Blood urea nitrogen >30 mg/dL (11 mmol/L)	20
  Sodium <130 mmol/L	20
  Glucose >250 mg/dL (14 mmol/L)	10
  Hematocrit <30%	10
  PaO2 <60 mm Hg	10
  Pleural effusion	10

  *Coexisting illnesses: The diagnosis of congestive heart failure is documented by history or by findings on physical examination, chest radiograph, echocardiogram, multiple-gated acquisition scan, or left ventriculogram. The clinical diagnosis of stroke or transient ischemic attack is documented by magnetic resonance imaging or CT scan findings. A history of chronic renal disease or abnormal blood urea nitrogen and creatinine concentrations should be documented in the medical record. Altered mental status is defined as disorientation to person, place, or time that is not known to be chronic or as stupor or coma.

• Hospitalization versus ambulatory care is determined by the total points calculated from the PSISS. Patients are categorized in to 5 risk classes, as follows:

   

  • Risk class I - Older than 50 years, no preexisting illness or vital sign abnormality

     

  • Risk class II - Fewer than 70 points

     

  • Risk class III - 71-90 points

     

  • Risk class IV - 91-130 points

     

  • Risk class V - More than 131 points

   

• Although further epidemiologic studies are required to make definite recommendations for hospital versus home care for patients with community-acquired pneumonia, preliminary data (Fine, 1997) indicate that patients in risk classes I and II can be treated at home with planned outpatient follow-up evaluations. Patients in risk class III should be observed in the emergency department before their disposition is decided. Patients in risk classes IV and V are ill and usually require admission to the hospital.

• Response to therapy

• Having initiated a course of therapy based on empiric guidelines, carefully evaluating the patient's response to therapy is essential. With appropriate antibiotic therapy, improvement in the clinical manifestations of pneumonia should be observed in 48-72 hours. Because of the time required for antibiotics to act, antibiotics should not be changed within the first 72 hours unless marked clinical deterioration occurs.

   

• With pneumococcal pneumonia, the cough usually resolves within 8 days and crackles heard on auscultation clear within 3 weeks. The timing of radiologic resolution of the pneumonia varies with patient age and the presence or absence of an underlying lung disease. The chest radiograph usually clears within 4 weeks in patients younger than 50 years without underlying pulmonary disease. In contrast, resolution may be delayed for 12 weeks or longer in older individuals and those with underlying lung disease.

• Patients who do not respond to treatment

• A common concern is patients who do not improve despite antibiotic treatment. If patients do not improve within 72 hours, consider an organism that is not covered by the initial empiric antibiotic regimen. Lack of response also could be secondary to drug resistance, nonbacterial infection, unusual pathogens (eg, P carinii, M tuberculosis), drug fever, or a complication such as empyema or abscess formation. One must broaden the differential diagnosis to include noninfectious etiologies such as malignancies, inflammatory conditions, or congestive heart failure.

   

• When reevaluating a patient who is not responding, a careful history of travel and animal exposure should be obtained to rule out unusual pathogens. If this is unrevealing, then further diagnostic procedures may be required. Bronchoscopy helps evaluate the airway for obstruction due to a foreign body or malignancy. Infection with previously unsuspected pathogens such as P carinii or M tuberculosis often is diagnosed using bronchoscopy. During bronchoscopy, protected brushing and bronchioalveolar lavage specimens may be obtained for microbiologic examination and quantitative cultures. Transbronchial biopsy also may be helpful in some cases. Routine bacterial cultures have limited utility when obtained from bronchoscopy after antibiotics have already been administered.

   

• A retrospective study evaluated the use of fiberoptic bronchoscopy in nonresolving pneumonia. A specific diagnosis that could account for the prolonged course was found in 12 of 14 patients. The etiologies included Pneumocystis, mycobacteria, cytomegalovirus, and actinomycosis and noninfectious entities such as bronchioalveolar carcinoma, adenocarcinoma, and eosinophilic pneumonia. A second prospective study found the diagnostic sensitivity of video bronchoscopy after the initiation of antibiotics to be 41%.

   

• In addition to bronchoscopy, further imaging studies, such as CT scan of the thorax, may be helpful. Finally, open or thoracoscopic lung biopsy may need to be performed if all other procedures do not aid in diagnosis and the patient continues to be ill. Thoracoscopic lung biopsy is associated with less morbidity compared to the open lung biopsy.

• Other inpatient care

   

  • Antibiotic therapy should be reevaluated based on laboratory data and clinical response.

     

  • Adequate respiratory support (eg, low-flow oxygen, assisted ventilation) is provided as dictated by the patient's clinical situation.

     

  • Bronchial hygiene includes suctioning of secretions, chest physiotherapy, and positioning to encourage dependent drainage. These are used to optimize the elimination of purulent sputum and to avoid atelectasis.

     

  • General supportive measures include proper hydration, nutrition, and patient ambulation.

Further Outpatient Care:

• When treated in an outpatient setting, arranging adequate follow-up evaluations for the patient is mandatory. Patients also should be instructed to return if their condition deteriorates.

• Patients should have a follow-up chest radiograph in approximately 6 weeks to ensure resolution of consolidation.

• Chest radiograph findings indicating nonresolution of symptoms should raise the consideration of an endobronchial obstruction as a cause of postobstructive pneumonia. A CT scan may be of benefit in these cases.

Deterrence/Prevention:

• Prevention of community-acquired pneumonia

• Influenza vaccination for elderly individuals results in a reduction of the rate of hospitalization for pneumonia and influenza by 48-57%.

• The role of the pneumococcal vaccine has not been defined as clearly as that of the influenza vaccine. However, the advisory committee on immunization practice recommends pneumococcal vaccination for persons older than 65 years and for younger patients with chronic illnesses.

• Prevention of nosocomial pneumonia

• A number of preventative strategies have been applied. Some of these probably are effective or promising, and some are currently being evaluated.

• The efficacious regimens are hand washing and isolation of patients with multiple resistant respiratory tract pathogens. Hand washing between patient contacts is a basic and often neglected behavior by medical personnel.

• Interventions that should be considered or undertaken include nutritional support, attention to the size and nature of the GI reservoir of microorganisms, careful handling of ventilator tubing and associated equipment, subglottic secretion drainage, and lateral-rotation bed therapy.

• The regimens of unproven value in preventing nosocomial pneumonia, although used on limited investigational bases, are selective digestive decontamination with a regimen of topical and systemic antibiotic prophylaxis. Selective digestive contamination has been studied for many years with a goal of eliminating all potential pathogens from the GI tract. Incidence of nosocomial pneumonia is not always reduced; therefore, efficacy of these regimens has been questioned. Also, mortality reduction often is not observed.

• Some experimental regimens are undergoing clinical evaluation. These are monoclonal antibodies to specific bacterial antigens and reduction of endogenous sources of bacterial infection by mechanical means. The development of new biomaterials for endotracheal tubes is one such therapy, leading to the eradication of a reservoir of a large number of bacteria in the airway.

• Smoking cessation

Complications:

• Destruction of lung tissue from infection (leading to bronchiectasis)

• Necrotizing pneumonia

• Empyema

• Pulmonary abscess

• Respiratory failure

• Acute respiratory distress syndrome

• Ventilator dependence

• Superinfection with gram-negative organisms

• Death

Prognosis:

• Generally, prognosis is good in otherwise healthy patients with uncomplicated pneumonia.

• Advanced age, aggressive organisms (eg, Klebsiella, Legionella, resistant S pneumoniae), comorbidity, respiratory failure, neutropenia, and features of sepsis, alone or in combination, increase morbidity and mortality.

MISCELLANEOUS

Medical/Legal Pitfalls:

• The guidelines for empiric management of community-acquired bacterial pneumonia are formed with the intent of following evidence-based recommendations, but the recommendations of these guidelines are not based on a firm scientific foundation. Future studies should focus on the following issues:

• Duration of therapy

• Duration of therapy related to severity of initial illness

• Appropriate time to switch hospitalized patients from parenteral therapy to oral therapy

• Pathogens responsible for pneumonia when no organism is identified with extensive diagnostic testing

• In the future, a number of unresolved questions about nosocomial pneumonia need to be examined. These should focus on the diagnosis of nosocomial pneumonia, determinants of specific pathogens, duration of therapy, and timing of switch to oral therapy. Ultimately, prevention of nosocomial pneumonia is the most effective way to avoid disease associated with mortality.

• In patients who are elderly or debilitated, if bacteremia is present with pneumococcus, the mortality rate remains approximately 40% even if treated.

• Empiric therapy for hospitalized patients initially should be broad and cover the likely causative organisms.

• Always consider the possibility of Legionella when evaluating community-acquired pneumonia because delayed treatment increases mortality significantly.

• Remember that the most prevalent causative organism is pneumococcus, regardless of the host; empiric therapy must be selected with this consideration in mind.

PICTURES

Caption: Picture 1. Bacterial pneumonia. Lung specimen from a patient who died from severe Klebsiella pneumonia.
Picture Type: Photo

Caption: Picture 2. Bacterial pneumonia. Pneumococcus on sputum Gram stain.
Picture Type: Photo

Caption: Picture 3. Bacterial pneumonia. Histopathological micrograph of bacterial pneumonia showing extensive infiltration with inflammatory cells.
Picture Type: Photo

Caption: Picture 4. Bacterial pneumonia. Sputum Gram stain is performed prior to culture. An inadequate specimen contains more than 25 epithelial cells per high-power field.
Picture Type: Image

Caption: Picture 5. Bacterial pneumonia. Numerous pus cells indicate an adequate specimen that should be cultured.
Picture Type: Image

Caption: Picture 6. Bacterial pneumonia. Haemophilus influenzae on sputum culture.
Picture Type: Image

Caption: Picture 7. Bacterial pneumonia. Klebsiella pneumoniae on sputum Gram stain.
Picture Type: Image

Caption: Picture 8. Bacterial pneumonia. Legionella pneumophila on Gram stain of lung tissue obtained by open lung biopsy.
Picture Type: Image

Caption: Picture 9. Bacterial pneumonia. Bilateral airspace infiltration secondary to community-acquired pneumonia, subsequently confirmed to be Legionella pneumonia.
Picture Type: X-RAY

Caption: Picture 10. Bacterial pneumonia. Rarely, severe pneumococcal infection may be associated with necrotizing pneumonia.
Picture Type: X-RAY

Caption: Picture 11. Bacterial pneumonia. A posteroanterior chest radiograph shows left lower pneumonia. Sputum Gram stain showed gram-positive diplococci.
Picture Type: X-RAY

Caption: Picture 12. Bacterial pneumonia. Lateral chest radiograph of a patient with left lower pneumonia. Sputum Gram stain showed gram-positive diplococci.
Picture Type: X-RAY

Caption: Picture 13. Bacterial pneumonia. Chest radiographs showing right middle lobe pneumonia.
Picture Type: X-RAY

Caption: Picture 14. Bacterial pneumonia. Right upper lobe lobar pneumonia secondary to Streptococcus pneumoniae infection.
Picture Type: X-RAY

Caption: Picture 15. Bacterial pneumonia. Hospital-acquired right lower lobe pneumonia; sputum culture confirmed this to be secondary to gram-negative organisms.
Picture Type: X-RAY

Caption: Picture 16. Bacterial pneumonia. Postobstructive right lower lobe pneumonia and an associated pleural effusion. There is loss of volume of right hemithorax, shift of trachea and mediastinum to the right.
Picture Type: X-RAY

Caption: Picture 17. Bacterial pneumonia. Bilateral pneumococcal pneumonia in a patient who is an intravenous drug user but does not have HIV infection.
Picture Type: X-RAY

Caption: Picture 18. Bacterial pneumonia. CT scan of a patient not infected with HIV who has Pneumocystis carinii pneumonia.
Picture Type: CT

Caption: Picture 19. Bacterial pneumonia. Chest radiograph of a patient not infected with HIV who has Pneumocystis carinii pneumonia.
Picture Type: X-RAY