Harrison's Principles of Internal Medicine, 19e Section 6: Diseases Caused by Gram-Negative Bacteria

• Active TB does not acutely present with very high fever, and rapid clinical presentation of few days. While checking for TB, and isolation are not an error, it is not the next best step in this patient. 
• If Pseudomonas is a suspected cause for CAP which given the history of alcohol, then double coverage is needed given the risk of resistance. Hence, Levofloxacin should be added. 
• Doing Legionella Ag test is very important. While current abx regimen would cover for Pneumococcal pneumonia (and given the risk of resistance, does appropriately double cover for severe pneumonia even though guidelines do not mention of the same), it does not cover for Legionella. Levofloxacin empirically would cover for Legionella. If Legionella test is positive, then perhaps addition of Azithromycin would suffice. Note: Legionella needs antibiotic with good intracellular penetrateion. 

• Aerobic gram-negative bacilli that do not grow on routine microbiologic media. Buffered charcoal yeast extract (BCYE) agar is used. 
• Two clinical syndromes www.cdc.gov/legionella
• Pontiac fever is an acute, febrile, self-limited illness 
• Legionnaires’ disease or pneumonia. Legionnaires’ disease was first recognized in 1976, when an outbreak of pneumonia took place at a Philadelphia hotel during an American Legion convention.

• Source of Infection: 
• Drinking-water systems in hospitals and extended-care facilities have been the source for infection. Legionella is responsible for 10–50% of cases of nosocomial pneumonia. 
• Cooling towers use water to remove heat from a process or building. They are often part of the air conditioning systems of large buildings. In contrast, home and car air conditioning units do not use water to cool, so they do not aerosolize water (spread small droplets of water in the air) and are not a risk for Legionella growth. www.cdc.gov
• Mode of Transmission:
• Aerosolization: breathing in a mist or vapor (small droplets of water in the air) containing the bacteria. Aspiration is more commonly recognized now (aspiration of drinking water). Instrumentation in hospital is also the cause. Legionella cannot spread from one person to another person. www.cdc.gov 
• Host-Defense Mechanism: References: Harrison's 
• Attachment to host cells is mediated by bacterial type IV pili, heat-shock proteins, a major outer-membrane protein, and complement. Because the organism possesses pili that mediate adherence to respiratory tract epithelial cells, conditions that impair mucociliary clearance, including cigarette smoking, lung disease, or alcoholism, predispose to Legionnaires’ disease.
• Both innate and adaptive immune responses play a role in host defense. Toll-like receptors mediate recognition of L. pneumophila in alveolar macrophages and enhance early neutrophil recruitment to the site of infection. Alveolar macrophages phagocytose legionellae by a conventional or a coiling mechanism. After phagocytosis, L. pneumophilaevades intracellular killing by inhibiting phagosome–lysosome fusion. Although many legionellae are killed, some proliferate intracellularly until the cells rupture; the bacteria are then phagocytosed again by newly recruited phagocytes, and the cycle begins anew. The role of neutrophils in immunity appears to be minimal: neutropenic patients are not predisposed to Legionnaires’ disease. Although L. pneumophila is susceptible to oxygen-dependent microbiologic systems in vitro, it resists killing by neutrophils
• Immunized animals develop a specific antibody response, with subsequent resistance to Legionella challenge. However, antibodies neither enhance lysis by complement nor inhibit intracellular multiplication within phagocytes.
• Clinical Features:  www.cdc.gov
• Cough; Shortness of breath; High fever; Muscle aches; Headaches
• Fever is almost universal. In one observational study, 20% of patients had temperatures in excess of 40°C (104°F). 
• CAP: Legionella among the top four microbial causes of community-acquired pneumonia, finding that it accounts for 2–13% of cases. (Streptococcus pneumoniae, Haemophilus influenzae, and Chlamydia pneumoniae are usually ranked first, second, and third, respectively). Per CDC's once estimate, only around 3 % 3% of community-acquired cases of Legionnaires’ disease are diagnosed.
• The symptoms and signs may range from a mild cough and a slight fever to stupor with widespread pulmonary infiltrates and multisystem failure. The mild cough of Legionnaires’ disease is only slightly productive. Sometimes the sputum is streaked with blood. Chest pain—either pleuritic or nonpleuritic—can be a prominent feature and, when coupled with hemoptysis, can lead to an incorrect diagnosis of pulmonary embolism. Shortness of breath is reported by one-third to one-half of patients. Gastrointestinal difficulties are often pronounced; abdominal pain, nausea, and vomiting affect 10–20% of patients. Diarrhea (watery rather than bloody) is reported in 25–50% of cases. The most common neurologic abnormalities are confusion or changes in mental status; however, the multitudinous neurologic symptoms reported range from headache and lethargy to encephalopathy. Nonspecific symptoms—malaise, fatigue, anorexia, and headache—are reported early in the illness. Myalgias and arthralgias are uncommon but are prominent in a few patients. Upper respiratory symptoms, including coryza, are rare
• Legionnaires’ disease is often included in the differential diagnosis of “atypical pneumonia,” along with pneumonia due to C. pneumoniae, Chlamydia psittaci, Mycoplasma pneumoniae, Coxiella burnetii, and some viruses. The clinical similarities among “atypical” pneumonias include a nonproductive cough with a low frequency of grossly purulent sputum. The clinical manifestations of Legionnaires’ disease are usually more severe than those of most “atypical” pneumonias - closely resemble those of bacteremic pneumococcal pneumonia than those of pneumonia due to other “atypical” pathogens. Patients with community-acquired Legionnaires’ disease are significantly more likely than patients with pneumonia of other etiologies to be admitted to an intensive care unit (ICU) on presentation.
• Relative bradycardia has been overemphasized as a useful diagnostic finding; it occurs primarily in older patients with severe pneumonia. Rales are detected by chest examination early in the course, and evidence of consolidation is found as the disease progresses. Abdominal examination may reveal generalized or local tenderness.
• In a review of 13 studies of community-acquired pneumonia, clinical manifestations that occurred significantly more often in Legionnaires’ disease included diarrhea, neurologic findings (including confusion), and a temperature of >39°C. Hyponatremia, elevated values in liver function tests, and hematuria also occurred more frequently in Legionnaires’ disease. Other laboratory abnormalities include creatine phospho­kinase elevation, hypophosphatemia, serum creatinine elevation, and proteinuria.
• Imaging
• Virtually all patients with Legionnaires’ disease have abnormal chest radiographs showing pulmonary infiltrates at the time of clinical presentation.
• Likewise, abscesses can occur in immunosuppressed hosts. The progression of infiltrates and pleural effusion on chest radiography despite appropriate antibiotic therapy within the first week is common, and radiographic improvement lags behind clinical improvement by several days. Complete clearing of infiltrates requires 1–4 months
• Treatment
• Retrospective uncontrolled studies have shown that complications of pneumonia are fewer and clinical response is more rapid in patients receiving quinolines than in those receiving macrolides.
• For critically ill patients, the authors use
  combination regimens of azithromycin, a quinolone, and/or rifampin. This practice is empirical and is not supported by comparative studies. A longer course of therapy (3 weeks) may be appropriate for immunosuppressed patients and those with advanced disease. For azithromycin, with its long half-life, a 5- to 10-day course is sufficient.
• Legionellosis is a nationally notifiable disease in the United States that is monitored through two surveillance systems at the national level. With improved diagnosis and reporting, public health experts can better understand the true burden of legionellosis.
• References:
• Harrison's Principles of IM, 19e
• CDC www.cdc.gov
• Legionnaires' disease Lancet 2015
  

• Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, Morganella, Providencia, Cronobacter, and Edwardsiella, Salmonella, Shigella, and Yersinia. 

1. B-lactamase
2. Broad-spectrum β-lactamases 
3. Extended-spectrum β-lactamases (ESBL) 
4. AmpC β-lactamases
5. Carbapenemases 

• Ampicillin and first- and second-generation cephalosporins have little or no activity. 
• Extensive use of third-generation cephalosporins can induce or select for variants with stable derepression of AmpC β-lactamase, which confers resistance to these agents as well as monobactams (e.g., aztreonam) and—in many cases—β-lactam/β-lactamase inhibitor combinations. 
• Resistance may emerge during therapy; in one study, this phenomenon was documented in 20% of clinical isolates. 
• De novo resistance should be considered when clinical deterioration follows initial improvement, and third-generation cephalosporins should be avoided in the treatment of serious Enterobacter infections. 
• Cefepime is stable in the presence of AmpC β-lactamases; thus, it is a suitable option for treatment of Enterobacter infections so long as no coexistent ESBL is present. Detection of ESBLs in Enterobacter is difficult because of the presence of AmpC β-lactamase; nonetheless, their prevalence (particularly in E. cloacae) is known to be variable worldwide but is generally increasing and is now 5–50% overall. 
• This increase is ­evidenced by NHSN data, which documented resistance to third- and fourth-generation cephalosporins in 37.4% of CLABSI Enterobacter isolates in the United States; 
• Fortunately, carbapenems, amikacin, and tigecycline have generally retained excellent activity (90–99% susceptibility) and fluoroquinolones have good activity (85–95% susceptibility). Once susceptibility data become available, it is critical to de-escalate the antimicrobial regimen whenever possible.
• Harrison's Principles of Internal Medicine, 19e