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Quick Test posted on 3.1.10:
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Bacterial Pneumonia
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TREATMENT: PNEUMONIA
Desired Outcome
Eradication of the offending organism through selection of the appropriate antibiotic and complete clinical cure are the goals of therapy for bacterial pneumonia. Therapy should minimize associated morbidity, including one or both of the following: reversible or irreversible disease and drug-induced organ toxicity (e.g., renal, lung, or hepatic dysfunction). Most cases of viral pneumonia are self-limiting, although therapy of influenza pneumonia with specific antiviral agents (amantadine or rimantadine) may hasten recovery. All efforts should focus on the design of the most cost-effective approach to therapy. Whenever possible, the oral (versus parenteral) route for drug administration should be selected, encouraging outpatient management rather than hospitalization.
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General Approach to Treatment
The first priority in assessing the patient with pneumonia is to evaluate the adequacy of respiratory function and to determine the presence of signs of systemic illness, specifically dehydration or sepsis with resulting circulatory collapse. Oxygen or, in severe cases, mechanical ventilation and fluid resuscitation should be provided as necessary. Further supportive care of the patient with pneumonia includes humidified oxygen for hypoxemia, administration of bronchodilators (albuterol) when bronchospasm is present, and chest physiotherapy with postural drainage if evidence of retained secretions is seen. Additional therapeutic adjuncts include adequate hydration (intravenously if necessary), optimal nutritional support, and control of fever. Appropriate sputum samples may be obtained to determine the microbiologic etiology. Rehydration should be provided to replace losses that may have occurred as a result of fever, poor intake, and/or associated vomiting. Selection of an appropriate antimicrobial must be made based on the patient's probable or documented microbiology, distribution in the respiratory tract, side effects, and cost.
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Pharmacologic Therapy
Antibiotic Concentrations
Antibiotic concentrations in respiratory secretions in excess of the pathogen MIC are necessary for successful treatment of pulmonary infections. The concept of a blood–bronchus barrier, analogous but dissimilar to the blood–brain barrier, has been used to assess the characteristics of drug penetration into pulmonary secretions. The ability of a drug to penetrate respiratory secretions depends on multiple physicochemical factors, including molecular size, lipid solubility, and degree of ionization at serum and biologic fluid pH and extent of protein binding. Studies performed in animals and cystic fibrosis patients suggest that larger molecular size favors the accumulation of drugs in bronchial secretions. This finding contrasts with data on drug penetration of other physiologic compartments, such as the cerebrospinal fluid, and may be a result of the trapping of lower-molecular-weight compounds in mucin pores. Nevertheless, the rate at which a drug may accumulate in certain respiratory secretions appears to remain an important factor relative to the drug's clinical efficacy in treating pulmonary infections. The un-ionized form of a drug and lipid solubility also appear to favor drug penetration. Of note, the pH of the infected bronchi often is more acidic than that of normal tissue and blood.
Fewer data are available for assessing the influence of drug protein binding on the rate and amount of respiratory secretion penetration. Clearly, it is the free antibiotic fraction reaching the infected site capable of binding to the bacterial cell target that is responsible for antibacterial activity. Given that the degree of protein binding influences a drug's ability to traverse membranes, a similar relationship would be expected within the lung. However, focusing on the absolute amount of an antibiotic bound to plasma/tissue proteins without accounting for the drug's overall antibacterial potency is errant. To completely assess an antibiotic's therapeutic potential in the treatment of pneumonia or any infectious process, it is prudent to assess the antibiotic's integrated pharmacokinetic–pharmacodynamic characteristics (e.g., bacterial killing may be concentration dependent or time dependent) that account for the drug's degree of binding to serum proteins, tissue distribution, and in-vitro potency. Thus, simply focusing on a drug's degree of protein binding is an errant, overly simplistic approach that does not account for the drug's inherent antibacterial activity or distribution characteristics.
These concepts relating to antibiotic activity and overall drug penetration of respiratory secretions have supported the clinical practice of administering certain antibiotics (aminoglycosides) to achieve high peak serum concentrations on the assumption that higher (and possibly more effective) biologic fluid concentrations of the drug will be achieved. The aminoglycosides are large polar molecules that diffuse poorly into tissue and respiratory secretions; however, with increasing concentrations obtained with once-daily dosing, increased target-tissue concentrations would be expected with increasing individual doses. Substantial clinical experience supports this practice for treating pulmonary infections with certain antibiotics (e.g., concentration-dependent antimicrobials), although more data are needed to describe the relationships between these variables and clinical response.
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Sidebar: Clinical Controversy
Prior to the availability of newer β-lactam and fluoroquinolone antibiotics possessing consistently potent activity against multiple gram-negative pathogens, some investigators promoted the administration of antibiotics by direct endotracheal instillation. This method of drug administration attempts to provide increased topical concentrations of antibiotics that do not appear to penetrate respiratory secretions effectively while reducing the likelihood of systemic toxicity. In addition, greater local concentrations of antibiotics, particularly of the polymyxins and aminoglycosides, are believed to overcome partially the substantial decrease in antibiotic bioactivity observed when these agents interact with the purulent material present in infectious foci. Despite these potential theoretical advantages, the role of antibiotic aerosols or direct endotracheal instillation in clinical practice remains controversial.
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Sputum is frequently assessed as possibly representing the pharmacodynamic interface for pulmonary infections. Sputum is only one of many pulmonary fluids and secretions, and it may serve as a reservoir for pathogen growth. These beliefs have led many investigators to assess antibiotic concentrations in sputum, frequently describing sputum drug concentrations as a ratio of serum to sputum drug concentration. Although sputum drug concentrations provide some insight into the characteristics of drug penetration of respiratory secretions, caution should be exercised in the interpretation of these data. Data describing sputum drug concentrations often are difficult to interpret because of differences in analytic techniques, method of sputum sampling, and random nature of sampling times relative to drug dose. Moreover, representation of sputum drug concentrations as a ratio of serum drug concentration can be misleading and most probably should be described relative to absolute drug concentration or apparent area under the drug concentration versus time curve in sputum. To more accurately describe the distribution characteristics of antimicrobial agents in sputum, research studies should be designed to allow sequential repeated sputum sampling over a dosage interval under both first-dose and steady-state conditions. Thus, until greater sophistication is achieved in our understanding of the relationships between antibiotic concentrations in specific anatomic sites, plasma (blood)-based integrated pharmacokinetic–pharmacodynamic correlates should be used for antibiotic and dose selection.
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Selection of Antimicrobial Agents
Treatment of bacterial pneumonia, like the treatment of most infectious diseases, initially involves the empirical use of a relatively broad-spectrum antibiotic that is effective against probable pathogens after appropriate cultures and specimens for laboratory evaluation have been obtained. Therapy should be narrowed to cover specific pathogens after the results of cultures are known. Multiple factors that help to define the potential pathogens involved include patient age, previous and current medication history, underlying disease(s), major organ function, and present clinical status. These factors must be evaluated to select an appropriate and effective empirical antibiotic regimen as well as the most appropriate route for drug administration (oral or parenteral). For a more detailed discussion on the principles of antibiotic selection, see Chap. 109.
Numerous antibiotics are available, and the majority are effective in the treatment of bacterial pneumonia. Superiority of one antibiotic over another when both demonstrate similar in-vitro activity and tissue distribution characteristics is difficult to define. Our opinions on appropriate empirical choices for the treatment of bacterial pneumonias relative to a patient's underlying disease are listed in Table 111–9 for adults and Table 111–10 for children. A complete listing of antimicrobial agents for specific pathogens is beyond the scope of this chapter and is presented in Chap. 108.
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Table 111-9 Empirical Antimicrobial Therapy for Pneumonia in Adultsa
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| Clinical Setting |
Usual Pathogen(s) |
Presumptive Therapy |
| Previously healthy, ambulatory patient |
Pneumococcus, Mycoplasma pneumonia |
Macrolide/azalide,b tetracyclinec |
| Elderly |
Pneumococcus, gram-negative bacilli (e.g., Klebsiella pneumoniae); Staphylococcus aureus, Haemophilus influenza |
Piperacillin-tazobactam, cephalosporin,d carbapeneme |
| Chronic bronchitis |
Pneumococcus, H. influenzae, M. catarrhalis |
Amoxicillin, tetracycline, c trimethoprim-sulfamethoxazole, cefuroxime, amoxicillin-clavulanate, macrolide/azalide, b fluoroquinolone |
| Alcoholism |
Pneumococcus, K. pneumoniae, S. aureus, H. influenzae, possibly mouth anaerobes |
Ticarcillin-clavulanate, piperacillin-tazobactam, plus aminoglycoside; carbapenem, e fluoroquinolone f |
| Aspiration |
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| Community |
Mouth anaerobes |
Penicillin or clindamycin |
| Hospital/residential care |
Mouth anaerobes, S. aureus, gram-negative enterics |
Clindamycin, ticarcillin-clavulanate, piperacillin-tazobactam, plus aminoglycoside |
| Nosocomial pneumonia |
Gram-negative bacilli (e.g., K. pneumoniae, Enterobacter species, Pseudomonas aeruginosa), S. aureus |
Piperacillin-tazobactam, carbapenem,e or extended spectrum cephalosporing plus aminoglycoside; fluoroquinolone f |
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aSee section on treatment of bacterial pneumonia.
bMacrolide/azalide: erythromycin, clarithromycin, azithromycin.
cTetracycline: tetracycline HCl, doxycycline.
dCephalosporin: cefuroxime, ceftriaxone, cefotaxime.
eCarbapenem: imipenem-cilastatin, meropenem.
fFluoroquinolone: ciprofloxacin, gatifloxacin, or levofloxacin.
gExtended-spectrum cephalosporin: ceftazidime, cefepime.
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Table 111–11 lists dosages for the treatment of bacterial pneumonia. The list of commercially available antimicrobial agents with documented bacterial and clinical effectiveness in the treatment of pneumonia appears endless. The large number of expensive drugs mandates critical evaluation for formulary selection and clinical use. Similarities of in-vitro activity, resistance to bacterial-inactivating enzymes, and overall effectiveness often make rational therapeutic decisions difficult and even appear random. However, some general principles can be applied to guide rational antibiotic choice, including direct comparison of the antibiotic's likely attainment of the defined pharmacokinetic–pharmacodynamic target correlate for specific bacterial species within the infected site. For treatment of bacterial pneumonia with concentration-independent antimicrobials (e.g., β-lactams and carbapenems), a plasma drug concentration exceeding the pathogen MIC for more than 50% of the dosing interval correlates with bacteriologic cure. For concentration-dependent antimicrobials (e.g., aminoglycosides and fluoroquinolones), a peak drug concentration to pathogen MIC ratio >8 to 10 or ratio of pathogen MIC to antibiotic area under the curve >25 to 40 for gram-positive pathogens and >100 for gram-negative pathogens correlates with bacteriologic cure. An understanding and application of these inherent drug characteristics appears to be of the utmost importance for the selection of an optimal therapeutic regimen. Thus, whenever possible, identification of the causative pathogen and expected/defined antibiotic activity (e.g., MIC) is of paramount importance to the selection/design of the optimal antibiotic regimen.
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Community-Acquired Pneumonia
Tables 111–12 and 111–13 provide evidence-based guidelines for the treatment of community-acquired pneumonia. The bacterial causes are relatively constant, even across geographic areas and patient populations. Unfortunately, pathogen resistance to standard antimicrobials is increasing (e.g., penicillin-resistant pneumococci), necessitating careful attention by the clinician to local and regional bacterial susceptibility patterns. Thus, whenever possible, initial therapy should be based on presumed antibacterial susceptibility and consist of older, less-expensive agents, with newer and more expensive antibiotics reserved for unresponsive illness or special circumstances. Indiscriminate use of recently introduced agents increases healthcare costs and, in some instances (e.g., widespread use of fluoroquinolones), induces resistance among a significant percentage of community-acquired organisms. It must be emphasized, however, that the rapidly evolving epidemiology of bacterial resistance, including the increasing emergence of penicillin-resistant pneumococcus in many areas of the United States and Europe, forces the clinician to be vigilant and knowledgeable about antibiotic sensitivity patterns in each community. Indiscriminate use of antimicrobials for treatment of pneumonia has contributed to the problem of antimicrobial resistance, underscoring the need for defining the optimal antibiotic regimen for each patient.
Evidence-based empirical therapy differs among outpatients, hospitalized patients, and hospitalized patients admitted to an intensive care unit (Table 111–13). Antimicrobial therapy should be initiated in hospitalized patients with acute pneumonia within 8 hours of admission because an increase in mortality has been demonstrated when therapy was delayed beyond 8 hours of admission.
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Nosocomial Pneumonia
Antibiotic selection within the hospital environment demands greater care because of constant changes in antibiotic resistance patterns in-vitro and in-vivo. Ironically, some β-lactam antibiotics, which were developed to treat multiple-antibiotic–resistant hospital-acquired organisms, can themselves induce broad-spectrum bacterial β-lactamases and thereby lead to even greater problems with resistance. These facts underscore the importance of regularly documenting the epidemiology of pathogens and infectious diseases within a specific practice or institution. As a result, an antimicrobial agent for a specific infectious disease favored in one practice site may not be the most desirable selection in another site despite similarities in size and patient profile. Strict and careful control and, possibly, rotation of empirical antibiotics in the hospital environment may help to limit the emergence of resistant organisms. Newer antibiotics developed for treatment of resistant, hospital-acquired pathogens are costly, so their use must be moderated to some extent in an era where capitated hospital costs and mandated budget cuts will not tolerate careless antibiotic use.
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Quick Test Questions QUESTION 1: Which of the following would be the most appropriate choice as empiric therapy for nosocomial pneumonia?
QUESTION 2: Which of the following is true regarding nosocomial pneumonias?
QUESTION 3: Which of the following would be most appropriate for the empiric treatment of pneumonia where Pseudomonas is a concern?
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