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InternalMed_Harrison. M. catarrhalis rapidly acquired Δ-lactamases during the 1970s and 1980s; antimicrobial susceptibility patterns have remained relatively stable since that time, with >90% of strains now producing Δ-lactamase and thus resistant to amoxicillin. Otitis media in children and exacerbations of COPD in adults are generally managed empirically with antimicrobial agents that are active against S. pneumoniae, H. influenzae, and M. catarrhalis. Most strains of M. catarrhalis are susceptible to amoxicillin/clavulanic acid, extended-spectrum cephalosporins, newer macrolides (azithromycin, clarithromycin), trimethoprimsulfamethoxazole, and fluoroquinolones. Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria Tamar F. Barlam, Dennis L. Kasper THE HACEK GROUP 183e


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InternalMed_Harrison. Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria Tamar F. Barlam, Dennis L. Kasper THE HACEK GROUP 183e HACEK organisms are a group of fastidious, slow-growing, gram-negative bacteria whose growth requires an atmosphere of carbon dioxide. Species belonging to this group include several Haemophilus species, Aggregatibacter (formerly Actinobacillus) species, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. HACEK bacteria normally reside in the oral cavity and have been associated with local infections in the mouth. They are also known to cause severe systemic infections—most often bacterial endocarditis, which can develop on either native or prosthetic valves (Chap. 155).


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InternalMed_Harrison. In large series, 0.8–6% of cases of infective endocarditis are attributable to HACEK organisms, most often Aggregatibacter species, Haemophilus species, and C. hominis. Invasive infection typically occurs in patients with a history of cardiac valvular disease, often in the setting of a recent dental procedure or nasopharyngeal infection. The aortic and mitral valves are most commonly affected. Compared with non-HACEK endocarditis, HACEK endocarditis occurs in younger patients and is more frequently associated with embolic, vascular, and immunologic manifestations but less commonly associated with congestive heart failure. The clinical course of HACEK endocarditis tends to be subacute, particularly with Aggregatibacter or Cardiobacterium. However, K. kingae endocarditis may have a more aggressive presentation. Systemic embolization is common. The overall prevalence of major emboli associated with HACEK endocarditis ranges from 28% to 71% in different series. On echocardiography,


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InternalMed_Harrison. aggressive presentation. Systemic embolization is common. The overall prevalence of major emboli associated with HACEK endocarditis ranges from 28% to 71% in different series. On echocardiography, valvular vegetations are seen in up to 85% of patients. Aggregatibacter and Haemophilus species cause mitral valve vegetations most often; Cardiobacterium is associated with aortic valve vegetations. The microbiology laboratory should be alerted when a HACEK organism is being considered; however, most cultures that ultimately yield a HACEK organism become positive within the first week, especially with improved culture systems such as BACTEC. In addition, polymerase chain reaction (PCR) techniques (e.g., of cardiac valves) and other tools, such as matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry performed directly on agar colonies, are facilitating the diagnosis of HACEK infections. Because of the organisms’ slow growth, antimicrobial testing may be


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InternalMed_Harrison. of flight (MALDI-TOF) mass spectrometry performed directly on agar colonies, are facilitating the diagnosis of HACEK infections. Because of the organisms’ slow growth, antimicrobial testing may be difficult, and β-lactamase production may not be detected. Resistance is most commonly noted in Haemophilus and Aggregatibacter species. E-test methodology may increase the accuracy of susceptibility testing. The overall prognosis in HACEK endocarditis is excellent and significantly better than that in endocarditis caused by non-HACEK pathogens.


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InternalMed_Harrison. Haemophilus Species Haemophilus parainfluenzae is the most common species isolated from cases of HACEK endocarditis. Of patients with HACEK endocarditis due to Haemophilus species, 60% have been ill for <2 months before presentation, and 19–50% develop congestive heart failure. Mortality rates as high as 30–50% were reported in older series; however, more recent studies have documented mortality rates of <5%. H. parainfluenzae has been isolated from other infections, such as meningitis; brain, dental, pelvic, and liver abscess; pneumonia; urinary tract infection; and septicemia.


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InternalMed_Harrison. Aggregatibacter Species The species of Aggregatibacter that most frequently cause infective endocarditis are A. actinomycetemcomitans, A. (formerly Haemophilus) aphrophilus, and A. paraphrophilus. Aggregatibacter is associated with prosthetic valve endocarditis more often than are Haemophilus species. A. actinomycetemcomitans can be isolated from soft tissue infections and abscesses in association with 183e-1 Actinomyces israelii. Typically, patients who develop endocarditis with Aggregatibacter have periodontal disease or have recently undergone dental procedures in the setting of underlying cardiac valvular damage. The disease is insidious; patients may be sick for several months before diagnosis. Frequent complications include embolic phenomena, congestive heart failure, and renal failure. A. actinomycetemcomitans has been isolated from patients with brain abscess, meningitis, endophthalmitis, parotitis, osteomyelitis, urinary tract infection, pneumonia, and empyema, among other


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InternalMed_Harrison. A. actinomycetemcomitans has been isolated from patients with brain abscess, meningitis, endophthalmitis, parotitis, osteomyelitis, urinary tract infection, pneumonia, and empyema, among other infections, while A. aphrophilus is often associated with bone and joint infection.


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InternalMed_Harrison. Cardiobacterium hominis C. hominis primarily causes endocarditis in patients with underlying valvular heart disease or with prosthetic valves. This organism most frequently affects the aortic valve. Many patients have signs and symptoms of long-standing infection before diagnosis, with evidence of arterial embolization, vasculitis, cerebrovascular accidents, immune complex glomerulonephritis, or arthritis at presentation. Embolization, mycotic aneurysms, and congestive heart failure are common complications. A second species, C. valvarum, has now been described in association with endocarditis.


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InternalMed_Harrison. Eikenella corrodens E. corrodens is most frequently recovered from sites of infection in conjunction with other bacterial species. Clinical sources of E. corrodens include sites of human bite wounds (clenchedfist injuries), endocarditis, soft tissue infections, osteomyelitis, head and neck infections, respiratory infections, chorioamnionitis, gynecologic infections associated with intrauterine devices, meningitis, brain abscesses, and visceral abscesses. This organism is the least common cause of HACEK endocarditis.


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InternalMed_Harrison. Kingella kingae Because of improved microbiologic methodology and molecular methods such as real-time PCR, the isolation of K. kingae is increasingly common. Inoculation of clinical specimens (e.g., synovial fluid) into aerobic blood culture bottles enhances recovery of this organism. More than half of cases of K. kingae infection are bone and joint infections; the majority of the remaining infections are infective endocarditis and bacteremia. PCR studies of joint fluid can identify K. kingae in culture-negative cases. Some studies now demonstrate that K. kingae has surpassed Staphylococcus aureus as the leading cause of septic arthritis in children. Invasive K. kingae infections with bacteremia are associated with upper respiratory tract infections and stomatitis in 80% of cases. Rates of oropharyngeal colonization with


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InternalMed_Harrison. K. kingae are highest in the first 3 years of life (detected in ~10% of children), coinciding with an increased incidence of skeletal infections due to this organism. K. kingae bacteremia can present with a petechial rash similar to that seen in Neisseria meningitidis sepsis. Infective endocarditis, unlike other infections with K. kingae, occurs in older children and adults. The majority of patients have preexisting valvular disease. There is a high incidence of complications, including arterial emboli, cerebrovascular accidents, tricuspid insufficiency, and congestive heart failure with cardiovascular collapse. (Table 183e-1) Ceftriaxone (2 g/d) is first-line therapy for HACEK endocarditis. Data on the use of levofloxacin (500–750 mg/d) for HACEK endocarditis remain limited, but this drug can be considered an alternative for treatment of patients intolerant of β-lactam therapy. Of note, Eikenella is resistant to clindamycin, metronidazole, and aminoglycosides.


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InternalMed_Harrison. Native-valve endocarditis should be treated for 4 weeks with antibiotics, whereas prosthetic-valve endocarditis requires 6 weeks of therapy. The cure rates for HACEK prosthetic-valve endocarditis appear to be high. Unlike prosthetic-valve endocarditis caused by other gram-negative organisms, HACEK endocarditis is often cured with antibiotic treatment alone—i.e., without surgical intervention. CHAPTER 183e Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria Haemophilus spp. Ceftriaxone (2 g/d) Ampicillin/sulbactam (3 g of ampicillin q6h) Aggregatibacter actinomycetemcomitans, A. aphrophilus, A. paraphrophilus, other species units q4h) or ampicillin (2 g q4h) Ampicillin/sulbactam resistance has been described in Haemophilus and Aggregatibacter spp. Data on use of levofloxacin for endocarditis therapy are limited. Fluoroquinolones are not recommended for treatment of patients <18 years of age.


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InternalMed_Harrison. Data on use of levofloxacin for endocarditis therapy are limited. Fluoroquinolones are not recommended for treatment of patients <18 years of age. Penicillin or ampicillin can be used if the organism is susceptible. However, because of the slow growth of HACEK bacteria, antimicrobial testing may be difficult, and β-lactamase production may not be detected.


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InternalMed_Harrison. Achromobacter xylosoxidans Achromobacter (previously Alcaligenes) xylosoxidans is probably part of the endogenous intestinal flora and has been isolated from a variety of water sources, including well water, IV fluids, and humidifiers. Immunocompromised hosts, including patients with cancer and postchemotherapy neutropenia, cirrhosis, chronic renal failure, and cystic fibrosis, are at increased risk. Nosocomial outbreaks and pseudo-outbreaks of A. xylosoxidans infection have been attributed to contaminated fluids, and clinical illness has been associated with isolates from many sites, including blood (often in the setting of intravascular devices). Community-acquired A. xylosoxidans bacteremia usually occurs in the setting of pneumonia. Metastatic skin lesions are present in one-fifth of cases. The reported mortality rate is as high as 67%—a figure similar to rates for other bacteremic gram-negative pneumonias.


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InternalMed_Harrison. carbapenems, and aminoglycosides, but resistance has been described to all those agents. Because Aeromonas can produce various β-lactamases, including carbapenemases, susceptibility testing must be used to guide therapy. Antibiotic prophylaxis (e.g., with ciprofloxacin) is indicated when medicinal leeches are used. Capnocytophaga Species This genus of fastidious, fusiform, gram-negative coccobacilli is facultatively anaerobic and requires an atmosphere enriched in carbon dioxide for optimal growth. C. ochracea, C. gingivalis, C. haemolytica, and C. sputigena have been associated with sepsis in immunocompromised hosts, particularly neutropenic patients with oral ulcerations. These species have been isolated from many other sites as well, usually as part of a polymicrobial infection. Most Capnocytophaga infections are contiguous with the oropharynx (e.g., periodontal disease, respiratory tract infections, cervical abscesses, and endophthalmitis).


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InternalMed_Harrison. (Table 183e-2) Treatment is based on in vitro susceptibility testing of all clinically relevant isolates; multidrug resistance is common. Meropenem, tigecycline, and colistin are typically the most active agents. Aeromonas Species More than 85% of Aeromonas infections are caused by A. hydrophila, A. caviae, and A. veronii biovar sobria. Aeromonas proliferates in potable water, freshwater, and soil. It remains controversial whether Aeromonas is a cause of bacterial gastroenteritis; asymptomatic colonization of the intestinal tract with Aeromonas occurs frequently. However, rare cases of hemolytic-uremic syndrome following bloody diarrhea have been shown to be secondary to the presence of Aeromonas.


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InternalMed_Harrison. Aeromonas causes sepsis and bacteremia in infants with multiple medical problems and in immunocompromised hosts, particularly those with cancer or hepatobiliary disease. A. caviae is associated with health care–related bacteremia. Aeromonas infection and sepsis can occur in patients with trauma (including severe trauma with myonecrosis) and in burn patients exposed to Aeromonas by environmental (freshwater or soil) contamination of their wounds. Reported mortality rates range from 25% among immunocompromised adults with sepsis to >90% among patients with myonecrosis. Aeromonas can produce ecthyma gangrenosum (hemorrhagic vesicles surrounded by a rim of erythema with central necrosis and ulceration; see Fig. 25e-35) resembling the lesions seen in Pseudomonas aeruginosa infection. This organism causes nosocomial infections related to catheters, surgical incisions, or use of leeches. Other manifestations include necrotizing fasciitis, meningitis, peritonitis, pneumonia, and ocular


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InternalMed_Harrison. organism causes nosocomial infections related to catheters, surgical incisions, or use of leeches. Other manifestations include necrotizing fasciitis, meningitis, peritonitis, pneumonia, and ocular infections.


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InternalMed_Harrison. (Table 183e-2) Aeromonas species are generally susceptible to fluoroquinolones (e.g., ciprofloxacin at a dosage of 500 mg every 12 h PO or 400 mg every 12 h IV), thirdand fourth-generation cephalosporins, Aeromonas spp. Elizabethkingia/ Chryseobacterium spp. Shewanella spp. Capnocytophaga spp. Meropenem, Treatment should tigecycline, colistin be based on in vitro susceptibility testing; multidrug resistance is common among these organisms. Fluoroquinolones (e.g., ciprofloxacin), thirdand fourth-generation cephalosporins, carbapenems, aminoglycosides Fluoroquinolones, trimethoprimsulfamethoxazole, piperacillin/tazobactam Fluoroquinolones, thirdand fourth-generation cephalosporins, carbapenems Fluoroquinolones, thirdand fourth-generation cephalosporins, β-lactam/βlactamase inhibitors, carbapenems, aminoglycosides Ampicillin/sulbactam Penicillin should be used if the isolate is known to be susceptible.


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InternalMed_Harrison. Ampicillin/sulbactam Penicillin should be used if the isolate is known to be susceptible. ceftriaxone used if the isolate is known to be susceptible. P. multocida is also susceptible to tetracyclines and fluoroquinolones. C. canimorsus and C. cynodegmi are endogenous to the canine mouth (Chap. 167e). Patients infected with these species frequently have a history of dog bites or of canine exposure without scratches or bites. Asplenia, glucocorticoid therapy, and alcohol abuse are predisposing conditions that can be associated with severe sepsis with shock and disseminated intravascular coagulation. Patients typically have a petechial rash that can progress from purpuric lesions to gangrene. Meningitis, endocarditis, cellulitis, osteomyelitis, and septic arthritis also have been associated with these organisms.


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InternalMed_Harrison. (Table 183e-2) Because of increasing β-lactamase production, a penicillin derivative plus a β-lactamase inhibitor—such as ampicillin/ sulbactam (1.5–3.0 g of ampicillin every 6 h)—is currently recommended for empirical treatment of infections caused by Capnocytophaga species. If the isolate is known to be susceptible, infections with C. canimorsus should be treated with penicillin (12– 18 million units every 4 h). Capnocytophaga is also susceptible to clindamycin (600–900 mg every 6–8 h). This regimen or ampicillin/ sulbactam should be given prophylactically to asplenic patients who have sustained dog-bite injuries.


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InternalMed_Harrison. Elizabethkingia/Chryseobacterium Species Elizabethkingia meningoseptica (formerly Chryseobacterium meningosepticum) is an important cause of nosocomial infections, including outbreaks due to contaminated fluids (e.g., disinfectants and aerosolized antibiotics) and sporadic infections due to indwelling devices, feeding tubes, and other fluid-associated apparatuses. Nosocomial E. meningoseptica infection usually involves neonates or patients with underlying immunosuppression (e.g., related to malignancy or diabetes). E. meningoseptica has been reported to cause meningitis (primarily in neonates), pneumonia, sepsis, endocarditis, bacteremia, and soft tissue infections. Most published reports have originated from Taiwan. Chryseobacterium indologenes has caused bacteremia, sepsis, and pneumonia, typically in immunocompromised patients with indwelling devices.


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InternalMed_Harrison. (Table 183e-2) These organisms are often susceptible to fluoroquinolones and trimethoprim-sulfamethoxazole. They may be susceptible to β-lactam/β-lactamase inhibitor combinations such as piperacillin/ tazobactam but can possess extended-spectrum β-lactamases and metallo-β-lactamases. Susceptibility testing should be performed.


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InternalMed_Harrison. Pasteurella multocida P. multocida is a bipolar-staining, gram-negative coccobacillus that colonizes the respiratory and gastrointestinal tracts of domestic animals; oropharyngeal colonization rates are 70–90% in cats and 50–65% in dogs. P. multocida can be transmitted to humans 183e-3 through bites or scratches, via the respiratory tract from contact with contaminated dust or infectious droplets, or via deposition of the organism on injured skin or mucosal surfaces during licking. Most human infections affect skin and soft tissue; almost two-thirds of these infections are caused by cats. Patients at the extremes of age or with serious underlying disorders (e.g., cirrhosis, diabetes) are at increased risk for systemic manifestations, including meningitis, peritonitis, osteomyelitis and septic arthritis, endocarditis, and septic shock, but cases have also occurred in healthy individuals of all ages. If inhaled,


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InternalMed_Harrison. P. multocida can cause acute respiratory tract infection, particularly in patients with underlying sinus and pulmonary disease. P. multocida is susceptible to penicillin, ampicillin, ampicillin/sulbactam, secondand third-generation cephalosporins, tetracyclines, and fluoroquinolones. β-lactamase-producing strains have been reported. Rhizobium (formerly Agrobacterium) radiobacter has usually been associated with infection in the presence of medical devices, including intravascular catheter–related infections, prosthetic-joint and prosthetic-valve infections, and peritonitis caused by dialysis catheters. Cases of endophthalmitis after cataract surgery also have been described. Most R. radiobacter infections occur in immunocompromised hosts, especially individuals with malignancy or HIV infection. Strains are usually susceptible to fluoroquinolones, thirdand fourth-generation cephalosporins, and carbapenems (Table 183e-2).


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InternalMed_Harrison. Shewanella putrefaciens and S. algae are ubiquitous organisms found primarily in seawater. Devitalized tissues can become colonized with Shewanella and serve as a nidus for systemic infection. Shewanella species cause skin and soft tissue infections, chronic ulcers of the lower extremities, ear infections, biliary tract infections, pneumonia, necrotizing fasciitis, bacteremia, and sepsis. A fulminant course is associated with cirrhosis, diabetes mellitus, malignancy, or other severe underlying conditions. Organisms are often susceptible to fluoroquinolones, thirdand fourth-generation cephalosporins, β-lactam/β-lactamase inhibitors, carbapenems, and aminoglycosides (Table 183e-2).


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InternalMed_Harrison. Chromobacterium violaceum has been responsible for life-threatening infections with severe sepsis and metastatic abscesses, particularly in children with defective neutrophil function (e.g., those with chronic granulomatous disease). Ochrobactrum anthropi causes infections related to central venous catheters in compromised hosts; other invasive infections have been described. Other organisms implicated in human infections include Weeksella species; various CDC groups, such as Ve-1 and Ve-2; Flavimonas species; Sphingobacterium species; and Oligella urethralis. The reader is advised to consult subspecialty texts and references for further guidance on these organisms. CHAPTER 183e Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria Victor L. Yu, M. Luisa Pedro-Botet, Yusen E. Lin


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InternalMed_Harrison. CHAPTER 183e Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria Victor L. Yu, M. Luisa Pedro-Botet, Yusen E. Lin Legionellosis refers to the two clinical syndromes caused by bacteria of the genus Legionella. Pontiac fever is an acute, febrile, self-limited illness that has been serologically linked to Legionella species, whereas Legionnaires’ disease is the designation for pneumonia caused by these species. Legionnaires’ disease was first recognized in 1976, when an outbreak of pneumonia took place at a Philadelphia hotel during an American Legion convention. The family Legionellaceae comprises more than 50 species with more than 70 serogroups. The species L. pneumophila causes 80–90% of human infections and includes at least 16 serogroups; serogroups 1, 4, and 6 are most commonly implicated in human infections. To date, 18 species other than L. pneumophila have been associated with human infections, among which L. micdadei (Pittsburgh pneumonia agent),


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InternalMed_Harrison. L. bozemanii, L. dumoffii, and L. longbeachae are the most common. Members of the Legionellaceae are aerobic gram-negative bacilli that do not grow on routine microbiologic media. Buffered charcoal yeast extract (BCYE) agar is the medium used to grow Legionella.


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InternalMed_Harrison. The natural habitats for L. pneumophila are aquatic bodies, including lakes and streams. L. longbeachae has been isolated from natural soil. Commercial potting soil has been suggested as the reservoir for L. longbeachae infections in Australia and New Zealand. Legionella can survive under a wide range of environmental conditions; for example, the organisms can live for years in refrigerated water samples. Natural bodies of water contain only small numbers of legionellae. However, once the organisms enter human-constructed aquatic reservoirs (such as drinking-water systems), they can grow and proliferate. Factors known to enhance colonization by and amplification of legionellae include warm temperatures (25°–42°C) and the presence of scale and sediment. L. pneumophila can form micro-colonies within biofilms; its eradication from drinking-water systems requires disinfectants that can penetrate the biofilm. The presence of symbiotic microorganisms, including algae, amebas, ciliated


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InternalMed_Harrison. within biofilms; its eradication from drinking-water systems requires disinfectants that can penetrate the biofilm. The presence of symbiotic microorganisms, including algae, amebas, ciliated protozoa, and other water-dwelling bacteria, promotes the growth of Legionella. The organisms can invade and multiply within free-living protozoa.


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InternalMed_Harrison. Heavy rainfall and flooding can result in the entry of high numbers of legionellae into water-distribution systems, leading to an upsurge of cases. Large buildings over three stories high are commonly colonized with Legionella. Sporadic community-acquired Legionnaires’ disease has been linked to colonization of hotels, office buildings, factories, and even private homes. Drinking-water systems in hospitals and extended-care facilities have been the source for health care–associated Legionnaires’ disease.


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InternalMed_Harrison. In contrast, cooling towers and evaporative condensers have been overestimated as sources of Legionella causing human illness. Early investigations that implicated cooling towers antedated the discovery that the organism could also exist in drinking water. In many outbreaks attributed to cooling towers, cases of Legionnaires’ disease continued to occur despite disinfection of the towers; drinking water was found to be the actual source. Koch’s postulates have never been fulfilled for Legionella links to cooling tower–associated outbreaks as they have been for hospital-acquired Legionnaires’ disease. Nevertheless, cooling towers have, in rare instances, been implicated in community-acquired outbreaks, including an outbreak in Murcia, Spain. As mentioned above, L. longbeachae infections have been linked to potting soil, but the mode of transmission remains to be clarified.


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InternalMed_Harrison. Multiple modes of transmission of Legionella to humans exist, including aerosolization, aspiration, and direct instillation into the lungs during respiratory tract manipulations. Aspiration is now known to be the predominant mode of transmission, but it is unclear whether Legionella enters the lungs via oropharyngeal colonization or directly via the drinking of contaminated water. Oropharyngeal colonization with Legionella has been demonstrated in patients undergoing transplantation. Nasogastric tubes have been linked to hospital-acquired Legionnaires’ disease; microaspiration of contaminated water was the hypothesized mode of transmission. Surgery with general anesthesia is a known risk factor that is consistent with aspiration. Especially compelling is the reported 30% incidence of postoperative Legionnaires’ disease among patients undergoing head and neck surgery at a hospital with a contaminated water supply; aspiration is a recognized postoperative complication in such cases. One


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InternalMed_Harrison. Legionnaires’ disease among patients undergoing head and neck surgery at a hospital with a contaminated water supply; aspiration is a recognized postoperative complication in such cases. One observational study showed that patients with hospital-acquired Legionnaires’ disease underwent endotracheal intubation significantly more often and for a significantly longer duration than patients with hospital-acquired pneumonias of other etiologies.


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InternalMed_Harrison. Aerosolization of Legionella by devices filled with tap water, including whirlpools, nebulizers, and humidifiers, has been linked to cases in patients. An ultrasonic mist machine in the produce section of a grocery store has been the source in community outbreaks. Pontiac fever has been linked to Legionella-containing aerosols from water-using machinery, a cooling tower, air conditioners, and whirlpools.


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InternalMed_Harrison. Community-Acquired Pneumonia The incidence of Legionnaires’ disease depends on the degree of contamination of the aquatic reservoir, the immune status of the persons exposed to water from that reservoir, the intensity of exposure, and the availability of specialized laboratory tests on which the correct diagnosis can be based. Numerous prospective studies have ranked 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.) On the basis of a multihospital study of community-acquired pneumonia in Ohio, the Centers for Disease Control and Prevention (CDC) estimated that only 3% of community-acquired cases of Legionnaires’ disease are diagnosed as such. Observational studies of community-acquired pneumonia showed that Legionnaires’ disease was largely unrecognized unless Legionella


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InternalMed_Harrison. cases of Legionnaires’ disease are diagnosed as such. Observational studies of community-acquired pneumonia showed that Legionnaires’ disease was largely unrecognized unless Legionella diagnostic testing was routinely applied to all patients with pneumonia; such studies in Spain and Germany resulted 1015 in detection of increased numbers of cases throughout Europe. It is likely that observational studies in Taiwan and Australia will have a similar result, with more cases identified throughout Asia as the index of suspicion rises.


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InternalMed_Harrison. Hospital-Acquired Pneumonia Legionella is responsible for 10–50% of cases of nosocomial pneumonia when a hospital’s water system is colonized with the organism. The incidence of hospital-acquired Legionnaires’ disease depends on the degree of contamination of drinking water, as defined by the rate of positivity of distal water sites; in contrast, the use of quantitative criteria of the number of colony-forming units per milliliter has proven useless.


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InternalMed_Harrison. Proactive culture of the hospital water supply has increased the detection of hospital-acquired Legionnaires’ disease and simul taneously allowed expeditious diagnosis resulting in early administration of antibiotic therapy. In the early years after its recognition, Legionnaires’ disease was documented primarily in the United States. As diagnostic modalities (especially the urinary antigen test) became more widely used, cases were documented in European hospitals. Likewise, following the enactment of public health guidelines in Taiwan, cases attributable to hospital tap water were found in Taiwanese hospitals. Risk factors for Legionnaires’ disease include cigarette smoking, chronic lung disease, advanced age, prior hospitalization with discharge within 10 days before onset of pneumonia symptoms, and immunosuppression. Immunosuppressive conditions that predispose to Legionnaires’ disease include transplantation, HIV infection, and treatment with glucocorticoids or tumor necrosis


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InternalMed_Harrison. symptoms, and immunosuppression. Immunosuppressive conditions that predispose to Legionnaires’ disease include transplantation, HIV infection, and treatment with glucocorticoids or tumor necrosis factor α antagonists. However, in a large prospective study of community-acquired pneumonia, 28% of patients with Legionnaires’ disease did not have these classic risk factors. Hospital-acquired cases are now being recognized among neonates and immunosuppressed children.


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InternalMed_Harrison. Pneumonia in Transplant Recipients Transplant recipients appear to be at unusually high risk of Legionella pneumonia. This elevated risk may be due to diagnostic bias, given the extensive workup for opportunistic pathogens with pneumonic symptoms as well as the long-standing immunosuppression in this population of patients. Legionnaires’ disease usually occurs in the 3 months after transplantation. Cavitation is seen on chest radiograph more frequently in transplant recipients, and mortality rates are higher. Pontiac Fever Pontiac fever occurs in epidemics. The high attack rate (>90%) reflects airborne transmission.


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InternalMed_Harrison. Pontiac Fever Pontiac fever occurs in epidemics. The high attack rate (>90%) reflects airborne transmission. Legionella enters the lungs through aspiration or direct inhalation. 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,


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InternalMed_Harrison. L. pneumophila evades 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. The humoral immune system is active against Legionella. Type-specific IgM and IgG antibodies are measurable within weeks of infection. In vitro, antibodies promote killing of Legionella by phagocytes (neutrophils, monocytes, and alveolar macrophages). Immunized animals 1016 develop a specific antibody response, with subsequent resistance to Legionella challenge. However, antibodies neither enhance lysis by complement nor inhibit intracellular multiplication


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InternalMed_Harrison. animals 1016 develop a specific antibody response, with subsequent resistance to Legionella challenge. However, antibodies neither enhance lysis by complement nor inhibit intracellular multiplication within phagocytes. The genome of L. pneumophila has been sequenced. A broad range of membrane transporters within the genome are thought to optimize the use of nutrients in water and soil. Some L. pneumophila strains are clearly more virulent than others, although the precise factors mediating virulence remain uncertain. For example, although multiple strains may colonize water-distribution systems, only a few cause disease in patients exposed to water from these systems. At least one surface epitope of L. pneumophila serogroup 1 is associated with virulence. Monoclonal antibody subtype mAb2 has been linked to virulence. L. pneumophila serogroup 6 is more commonly involved in hospital-acquired Legionnaires’ disease and is especially likely to be associated with a poor outcome.


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InternalMed_Harrison. CLINICAL AND LABORATORY FEATURES Pontiac Fever Pontiac fever is an acute, self-limiting, flu-like illness with an incubation period of 24–48 h. Pneumonia does not develop. Malaise, fatigue, and myalgias are the most common symptoms, occurring in 97% of cases. Fever (usually with chills) develops in 80–90% of cases and headache in 80%. Other symptoms (seen in fewer than 50% of cases) include arthralgias, nausea, cough, abdominal pain, and diarrhea. Modest leukocytosis with a neutrophilic predominance is sometimes detected. Complete recovery occurs within a few days; antibiotic therapy is unnecessary. A few patients may experience lassitude for some weeks after recovery. The diagnosis is established by antibody seroconversion. Pontiac fever due to L. longbeachae has been reported in individuals exposed to potting soil.


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InternalMed_Harrison. Legionnaires’ Disease (Pneumonia) 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. The course and prognosis of Legionella pneumonia more 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.


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InternalMed_Harrison. The incubation period for Legionnaires’ disease is usually 2–10 days, although slightly longer incubation periods have been documented. Fever is almost universal. In one observational study, 20% of patients had temperatures in excess of 40°C (104°F). 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. CLInICAL CLuES SuggESTIvE of LEgIonnAIRES’ DISEASE Numerous neutrophils but no organisms revealed by Gram’s staining of respiratory secretions Failure to respond to β-lactam drugs (penicillins or cephalosporins) and aminoglycoside antibiotics Occurrence of illness in an environment in which the potable water supply is known to be contaminated with Legionella Onset of symptoms within 10 days after discharge from the hospital (hospital-acquired legionellosis manifesting after discharge or transfer)


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InternalMed_Harrison. Onset of symptoms within 10 days after discharge from the hospital (hospital-acquired legionellosis manifesting after discharge or transfer) Although the clinical manifestations often considered classic for Legionnaires’ disease may suggest the diagnosis (Table 184-1), prospective comparative studies have shown that clinical manifestations are generally nonspecific and that Legionnaires’ disease is not readily distinguishable from pneumonia of other etiologies. 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.


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InternalMed_Harrison. Sporadic cases of Legionnaires’ disease appear to be more severe than outbreak-associated and hospital-acquired cases, presumably because their diagnosis is delayed. Results of the German CAPNETZ Study showed that, among cases of community-acquired Legionella pneumonia, ambulatory patients were as common as hospitalized patients. Extrapulmonary Legionellosis Because the portal of entry for Legionella is the lung in virtually all cases, extrapulmonary manifestations usually result from bloodborne dissemination from the lung. Legionella has been identified in lymph nodes, spleen, liver, or kidneys in autopsied cases. Sinusitis, peritonitis, pyelonephritis, skin and soft tissue infection, septic arthritis, and pancreatitis have developed predominantly in immunosuppressed patients. The most severe sequela, neurologic dysfunction, is rare but can be debilitating. The most common neurologic deficits in the long term—ataxia and speech difficulties—result from cerebellar dysfunction.


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InternalMed_Harrison. We speculate that cardiac abnormalities in patients without pneumonia are caused by Legionella-contaminated water entering through an intravenous site, chest tube, or surgical wound, with subsequent seeding of a prosthetic valve, the myocardium, or the pericardium. This scenario is supported by cases occurring at Stanford University Hospital in which sternal wound infections and prosthetic valve endocarditis due to L. pneumophila were observed. The source was a sink in the postoperative surgical recovery ward.


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InternalMed_Harrison. Chest Radiography Virtually all patients with Legionnaires’ disease have abnormal chest radiographs showing pulmonary infiltrates at the time of clinical presentation. In a few cases of hospital-acquired disease, fever and respiratory tract symptoms have preceded the radiographic appearance of the infiltrate. Radiologic findings are nonspecific. Pleural effusion is evident in 28–63% of patients on hospital admission. In immunosuppressed patients, especially those receiving glucocorticoids, distinctive rounded nodular opacities may be seen; these lesions may expand and cavitate (Fig. 184-1). 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. Computed tomography (CT) is more sensitive than chest radiography,


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InternalMed_Harrison. and radiographic improvement lags behind clinical improvement by several days. Complete clearing of infiltrates requires 1–4 months. Computed tomography (CT) is more sensitive than chest radiography, may show more extensive disease, and should be performed if fever persists during treatment with presumably effective antibiotics (Fig. 184-2).


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InternalMed_Harrison. FIGURE 184-1 Chest radiographic findings in a 52-year-old man who presented with pneumonia subsequently diagnosed as Legionnaires’ disease. The patient was a cigarette smoker with chronic obstructive pulmonary disease and alcoholic cardiomyopathy; he had received glucocor-ticoids. Legionella pneumophila was identified by direct fluorescent antibody staining and culture of sputum. Left: Baseline chest radiograph show-ing long-standing cardiomegaly. Center: Admission chest radiograph showing new rounded opacities. Right: Chest radiograph taken 3 days after admission, during treatment with erythromycin.


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InternalMed_Harrison. Given the nonspecific clinical manifestations of Legionnaires’ disease and the high mortality rates for untreated Legionnaires’ disease, Legionella testing—especially the Legionella urinary antigen test—is recommended for all patients with pneumonia, including patients with ambulatory pneumonia and hospitalized children. Legionella cultures should be made more widely available because the urinary antigen test can diagnose only L. pneumophila serogroup 1. Hospitals in which the drinking water is known to be colonized with Legionella species should have Legionella cultures routinely available.


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InternalMed_Harrison. The diagnosis of Legionnaires’ disease requires special microbiologic tests (Table 184-2). The sensitivity of bronchoscopy specimens is similar to that of sputum samples for culture on selective media; if sputum is not available, bronchoscopy specimens may yield the organism. Bronchoalveolar lavage fluid gives higher yields than bronchial wash specimens. Thoracentesis should be performed if pleural effusion is found, and the fluid should be evaluated by direct fluorescent antibody (DFA) staining, culture, and the antigen assay designed for use with urine. Stains Gram’s staining of material from normally sterile sites, such as pleural fluid or lung tissue, occasionally suggests the diagnosis; efforts to detect Legionella in sputum by Gram’s staining typically reveal numerous leukocytes but no organisms. When they are visualized, the organisms appear as small, pleomorphic, faint, gram-negative bacilli.


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InternalMed_Harrison. L. micdadei organisms can be detected as weakly or partially acid-fast bacilli in clinical specimens. The DFA stain is rapid and highly specific but is less sensitive than culture because large numbers of organisms are required for microscopic visualization. This test is more likely to be positive in advanced than in early disease.


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InternalMed_Harrison. Culture The definitive method for diagnosis of Legionella infection is isolation of the organism from respiratory secretions, although culture for 3–5 days is required. Antibiotics added to the medium suppress the growth of competing flora from nonsterile sites, and dyes color the colonies and assist in identification. The use of multiple selective BCYE media is necessary for maximal sensitivity. When culture plates are overgrown with other microflora, pretreatment of the specimen with acid or heat can markedly improve the yield. L. pneumophila is often isolated from sputum that is not grossly or microscopically purulent; sputum containing more than 25 epithelial cells per high-power field (a finding that classically suggests contamination) may still yield L. pneumophila.


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InternalMed_Harrison. L. pneumophila. Antibody Detection Antibody testing of both acuteand convalescent-phase sera is necessary. A fourfold rise in titer is diagnostic; 12 weeks are often required for the detection of an antibody response. A single titer of 1:128 in a patient with pneumonia constitutes circumstantial evidence for Legionnaires’ disease. The CDC uses a titer of 1:256 as presumptive evidence for Legionnaires’ disease. Serology is of use primarily in epidemiologic studies. The specificity of serology for Legionella species other than L. pneumophila is uncertain; there is cross-reactivity within Legionella species and with some gram-negative bacilli. Serology is used as the criterion for the diagnosis of Pontiac fever.


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InternalMed_Harrison. Urinary Antigen The assay for Legionella soluble antigen in urine is second only to culture in terms of sensitivity and is highly specific. A rapid immunochromatographic assay is commercially available (BinaxNOW; Alere, Waltham, MA). This assay is relatively inexpensive and easy to perform. Its drawback is that the urinary antigen test is reliable only for L. pneumophila serogroup 1, which causes ~80% of Legionella infections. Cross-reactivity with other L. pneumophila serogroups and other Legionella species has been detected in up to 22% of urine samples from patients with culture-proven cases. Antigen in urine is detectable 3 days after the onset of clinical disease and disappears over 2 months; positivity can be prolonged when patients receive glucocorticoids. The test is not affected by antibiotic administration.


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InternalMed_Harrison. Molecular Methods DFA stains can identify a number of Legionella species. Both polyclonal and monoclonal antibody stains are commercially available. Polymerase chain reaction (PCR) with DNA probes is being applied in-house in selected hospitals but is not yet commercially available. PCR has proven somewhat useful in the identification of Legionella from environmental water specimens. Epidemiologic links cannot easily be made with PCR because the infecting pathogen is not available for molecular subtyping. Procalcitonin can be used as an indicator of severity of illness in patients in ICUs. Clinical response to antibiotics can be monitored by procalcitonin levels. Because Legionella is an intracellular pathogen, antibiotics that can attain high intracellular concentrations are most likely to be effective. The dosages for various drugs used in the treatment of Legionella infection are listed in Table 184-3.


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InternalMed_Harrison. The macrolides (especially azithromycin) and the respiratory quinolones are now the antibiotics of choice and are effective as mono-therapy. Compared with erythromycin, the newer macrolides have superior in vitro activity, display greater intracellular activity, reach higher concentrations in respiratory secretions and lung tissue, and have fewer adverse effects. The pharmacokinetics of the newer macrolides and quinolones also allow onceor twice-daily dosing. Quinolones are the preferred antibiotics for transplant recipients because both macrolides and rifampin interact pharmacologically with cyclosporine and tacrolimus. Retrospective uncontrolled studies have shown that complications of pneumonia are fewer and clinical response is more rapid in patients receiving quinolones than in those receiving macrolides. Initial therapy should be given by the


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InternalMed_Harrison. FIGURE 184-2 Computed tomography (CT) scans of a 49-year-old woman with no underlying conditions who presented with community-acquired pneumonia. CT revealed multilobar infiltrates, some of which were not as prominent on chest x-ray. Cultures of both the patient’s sputum and her home water supply yielded Legionella pneumophila serogroup 1. (Images courtesy of Dr. Wen-Chien Ko, National Cheng Kung University Hospital, Tainan, Taiwan.) Test Sensitivity, % Specificity, % aUse of multiple selective media with dyes. bReliable only for L. pneumophila serogroup 1. cIgG and IgM testing of both acuteand convalescent-phase sera. A single titer of ≥1:256 is considered presumptive, whereas a fourfold rise in titer between the acute and convalescent phases is considered definitive. Titers peak at 3 months. IV route. A clinical response usually occurs within 3–5 days, after which oral therapy can be substituted. The total duration of therapy in the immunocompetent host is 10–14 days.


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InternalMed_Harrison. IV route. A clinical response usually occurs within 3–5 days, after which oral therapy can be substituted. The total duration of therapy in the immunocompetent host is 10–14 days. Alternative agents include tetracycline and its analogues doxycycline and minocycline. Tigecycline is active in vitro, but clinical experience with this drug is minimal. Anecdotal reports have described both successes and failures with trimethoprim-sulfamethoxazole, imipenem, and clindamycin.


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InternalMed_Harrison. 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. Rifampin is highly active in vitro and in cell models. Its interaction with other medications and its side effect of reversible hyperbilirubinemia can be minimized by limiting the duration of therapy to 3–5 days. 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 5to 10-day course is sufficient. Pontiac fever requires only symptom-based treatment, not antimicrobial therapy. Mortality rates for Legionnaires’ disease vary with the patient’s underlying disease, the patient’s immune status, the severity of pneumonia, and the timing of administration of appropriate antimicrobial therapy.


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InternalMed_Harrison. Trimethoprim-sulfamethoxazole 160/800 mg IV q8h 160/800 mg PO q12h Rifampind 300–600 mg PO or IV q12h aDosages are derived from clinical experience. bThe authors recommend doubling the first dose. cThe IV formulation is not available in some countries. dRifampin should be used only in combination with a macrolide or a quinolone. Mortality rates are highest (80%) among immunosuppressed patients who do not receive appropriate antimicrobial therapy early in the course of illness. With timely antibiotic treatment, mortality rates from community-acquired Legionnaires’ disease among immunocompetent patients range from 0 to 11%; without treatment, the figure may be as high as 31%. In a study of survivors of an outbreak of community-acquired Legionnaires’ disease, sequelae of fatigue, neurologic symptoms, and weakness were found in 63–75% of patients 17 months after receipt of antibiotics.


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InternalMed_Harrison. Routine environmental culture of hospital water supplies for Legionella is recommended as an approach to the prevention of hospital-acquired Legionnaires’ disease. Guidelines mandating this proactive approach have been adopted throughout Europe and in several U.S. states. The presence of Legionella in the water supply mandates the use of specialized laboratory tests (especially culture on selective media and the urinary antigen test) for patients with hospital-acquired pneumonia. A 30% cutoff for the presence of Legionella in water from multiple hospital sites prompts an increased index of suspicion. When the 30% cutoff point is exceeded, diagnostic tests for Legionella need to be applied in all cases of hospital-acquired pneumonia, and measures directed at eliminating the organism from the water supply should be considered. Quantitative criteria at a given water site (colony-forming units [CFU]/mL) have proven unreliable and inconsistent in the prediction of disease.


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InternalMed_Harrison. Studies have shown that neither a high degree of outward cleanliness of the water system nor routine application of maintenance measures decreases the frequency or intensity of Legionella contamination. Thus, engineering guidelines and building codes, although routinely advocated as preventive measures, have little impact on the presence of Legionella. Environmental cultures for Legionella from cold-water taps, hot-water taps, the hot-water recirculating line, and water-storage tanks will reveal the source of hospital-acquired infections. Disinfection of the hospital drinking-water system is an effective preventive measure for hospital-acquired cases of Legionnaires’ diseases because this system is the reservoir for Legionella. In geographic areas where the climate is semitropical, cold-water lines may be colonized by Legionella.


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InternalMed_Harrison. Copper-silver ionization is a reliable method for eradication of Legionella. Unlike the efficacy of chlorine dioxide decontamination and chlorination, that of ionization is not affected by high water temperature. Ionization systems are easy to install, and the ions are odorless, with minimal adverse effects. The efficacy of copper-silver ionization has been documented in hospitals worldwide. A comprehensive review of 10 published studies concluded that copper-silver ionization is effective for Legionella control as long as ion levels are monitored. If cold-water colonization by Legionella is the source of an outbreak, chlorine dioxide and monochloramine offer advantages. Chlorine dioxide, often the least expensive option, penetrates biofilms better and is less corrosive than chlorine. The major disadvantage of chlorine dioxide is the need to maintain an effective residual throughout the drinking-water system, especially in the hot-water system. Eradication of Legionella by chlorine


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InternalMed_Harrison. major disadvantage of chlorine dioxide is the need to maintain an effective residual throughout the drinking-water system, especially in the hot-water system. Eradication of Legionella by chlorine dioxide may require several months—a drawback in outbreak situations. Monochloramine is a promising approach in disinfection. Hyperchlorination is no longer recommended because of its expense, carcinogenicity, corrosive effects on piping, and unreliable efficacy.


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InternalMed_Harrison. Point-of-use disposable water filters (0.2 μm) may be an economical and effective option in high-risk areas (e.g., ICUs and transplantation units). These filters can be used in an outbreak situation for a limited period. Ineffective yet expensive methods that are often promulgated include removal of stagnation (“dead legs”) in the water-distribution system and replacement or disinfection/cleaning of distal outlets. Infection control personnel should oversee the selection of disinfection technology and should apply evidence-based criteria when making their choice. Managers of health care facilities should not be given the primary responsibility for selection and subsequent monitoring of measures to eliminate and control Legionella.


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InternalMed_Harrison. Pertussis and Other Bordetella Infections Karina A. Top, Scott A. Halperin Pertussis is an acute infection of the respiratory tract caused by Bordetella pertussis. The name pertussis means “violent cough,” which aptly describes the most consistent and prominent feature of the ill-185 ness. The inspiratory sound made at the end of an episode of paroxys mal coughing gives rise to the common name for the illness, “whoop ing cough.” However, this feature is variable: it is uncommon among infants ≤6 months of age and is frequently absent in older children and adults. The Chinese name for pertussis is “the 100-day cough,” which accurately describes the clinical course of the illness. The identification of B. pertussis was first reported by Bordet and Gengou in 1906, and vaccines were produced over the following two decades. Of the 10 identified species in the genus Bordetella, only four are of major medical significance. B. pertussis infects only humans and is the


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InternalMed_Harrison. B. pertussis produces a wide array of toxins and biologically active 1021 products that are important in its pathogenesis and in immunity. Most of these virulence factors are under the control of a single genetic locus that regulates their production, resulting in antigenic modulation and phase variation. Although these processes occur both in vitro and in vivo, their importance in the pathobiology of the organism is unknown; they may play a role in intracellular persistence and person-to-person spread. The organism’s most important virulence factor is pertussis toxin, which is composed of a B oligomer–binding subunit and an enzymatically active A protomer that ADP-ribosylates get cells, producing a variety of biologic effects. Pertussis toxin has important mitogenic activity, affects the circulation of lymphocytes, and serves as an adhesin for bacterial binding to respiratory ciliated cells. Other important virulence factors and adhesins are filamentous hemagglutinin, a component of


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InternalMed_Harrison. circulation of lymphocytes, and serves as an adhesin for bacterial binding to respiratory ciliated cells. Other important virulence factors and adhesins are filamentous hemagglutinin, a component of the cell wall, and pertactin, an outer- membrane protein. Fimbriae, bacterial appendages that play a role in bacterial attachment, are the major antigens against which agglu tinating antibodies are directed. These agglutinating antibodies have historically been the primary means of serotyping B. pertussis strains.


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InternalMed_Harrison. Other virulence factors include tracheal cytotoxin, which causes respi ratory epithelial damage; adenylate cyclase toxin, which impairs host most important Bordetella species causing human disease. B. paraper tussis causes an illness in humans that is similar to pertussis but is typiimmune-cell function; dermonecrotic toxin, which may contribute to respiratory mucosal damage; and lipooligosaccharide, which has propcally milder; co-infections with B. parapertussis and B. pertussis have erties similar to those of other gram-negative bacterial endotoxins.


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InternalMed_Harrison. been documented. With improved polymerase chain reaction (PCR) diagnostic methodology, up to 20% of patients with a pertussis-like syndrome have been found to be infected with B. holmesii, formerly thought to be an unusual cause of bacteremia. B. bronchiseptica is an important pathogen of domestic animals that causes kennel cough in dogs, atrophic rhinitis and pneumonia in pigs, and pneumonia in cats. Both respiratory infection and opportunistic infection due to B. bronchiseptica are occasionally reported in humans. B. petrii, B. hinzii, and B. ansorpii have been isolated from patients who are immunocompromised. Bordetella species are gram-negative pleomorphic aerobic bacilli that share common genotypic characteristics. B. pertussis and B.


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InternalMed_Harrison. Bordetella species are gram-negative pleomorphic aerobic bacilli that share common genotypic characteristics. B. pertussis and B. parapertussis are the most similar of the species, but B. parapertussis does not express the gene coding for pertussis toxin. B. pertussis is a slow-growing fastidious organism that requires selective medium and forms small, glistening, bifurcated colonies. Suspicious colonies are presumptively identified as B. pertussis by direct fluorescent antibody testing or by agglutination with species-specific antiserum. B. pertussis is further differentiated from other Bordetella species by biochemical and motility characteristics.


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InternalMed_Harrison. Pertussis is a highly communicable disease, with attack rates of within households in well-immunized populations. The infection has a worldwide distribution, with cyclical outbreaks every 3–5 years (a pattern that has persisted despite widespread immunization). Pertussis occurs in all months; however, in North America, its activity peaks in summer and autumn. In developing countries, pertussis remains an important cause of infant morbidity and death. The reported incidence of pertussis worldwide has decreased as a result of improved vaccine coverage (Fig. 185-1). However, coverage rates are still <50% in many developing nations; the World Health Organization (WHO) estimates that 90% of the burden of pertussis is in developing regions. In addition, overreporting of immunization coverage and underreporting of disease result in substantial underestimation of the global burden of pertussis. The WHO estimates that there were 195,000 deaths from pertussis among children in 2008.


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InternalMed_Harrison. Pertussis and Other Bordetella Infections 0 500,000 1,000,000 1,500,000 2,000,000 2,500,000 Number of cases 0 10 20 30 40 50 60 70 80 90 100 Immunization coverage (%)Number of cases Official coverage WHO/UNICEF estimates Pertussis global annual reported cases and DTP3 coverage, 1980–2012 FIGuRE 185-1 Global annual reported cases of pertussis and rate of coverage with DTP3 (diphtheria toxoid, tetanus toxoid, and pertussis vaccine; 3 doses), 1980–2012. (© World Health Organization, 2013. All rights reserved. From www.who.int/immunization/monitoring_ surveillance/burden/vpd/surveillance_type/passive/Pertussis_coverage.JPG. Source: WHO/IVB database, 2013.) Number of reported cases FIGuRE 185-2 Reported cases of pertussis by year—United States, 1976–2012. (From the Centers for Disease Control and Prevention, www.cdc.gov/pertussis/surv-reporting/cases-by-year.html. Accessed December 17, 2013.)


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InternalMed_Harrison. Before the institution of widespread immunization programs in the developed world, pertussis was one of the most common infectious causes of morbidity and death. In the United States before the 1940s, between 115,000 and 270,000 cases of pertussis were reported annually, with an average yearly rate of 150 cases per 100,000 population. With universal childhood immunization, the number of reported cases fell by >95%, and mortality rates decreased even more dramatically. Only 1010 cases of pertussis were reported in 1976 (Fig. 185-2). After that historic low, rates of pertussis slowly increased. In recent years, pertussis epidemics have been reported with increasing frequency worldwide. The United States experienced widespread outbreaks of pertussis in 2005, 2010, and 2012 at levels not seen in 40–50 years (>40,000 reported cases in 2012).


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InternalMed_Harrison. Although thought of as a disease of childhood, pertussis can affect people of all ages and is increasingly being identified as a cause of prolonged coughing illness in adolescents and adults. In unimmunized populations, pertussis incidence peaks during the preschool years, and well over half of children have the disease before reaching adulthood. In highly immunized populations such as those in North America, the peak incidence is among infants <1 year of age who have not completed the three-dose primary immunization series. An increase in pertussis incidence among adolescents and adults began in the late 1990s and led to the introduction of an adolescent booster across North America by 2006. While the disease burden among adolescents has started to decrease, children 7–10 years of age have recently emerged as a high-risk group. In major outbreaks in 2010 and 2012, the incidence of pertussis among children 10 years of age, most of whom were fully immunized, was as high as that among


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InternalMed_Harrison. recently emerged as a high-risk group. In major outbreaks in 2010 and 2012, the incidence of pertussis among children 10 years of age, most of whom were fully immunized, was as high as that among infants <6 months of age. Although adults contribute a smaller proportion of reported cases of pertussis than do children and adolescents, this difference may be related to a greater degree of underrecognition and underreporting. A number of studies of prolonged coughing illness suggest that B. pertussis may be the etiologic agent in 12–30% of adults with cough that does not improve within 2 weeks. In one study of the efficacy of an acellular pertussis vaccine in adolescents and adults, the incidence of pertussis in the placebo group was 3.7–4.5 cases per 1000 person-years. Although this prospective cohort study yielded a lower estimate than the studies of cough illness, its results still translate to 600,000–800,000 cases of pertussis annually among adults in the United States.


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InternalMed_Harrison. Severe morbidity and high mortality rates, however, are restricted almost entirely to infants. In Canada, there were 16 deaths from pertussis between 1991 and 2001; all those who died were infants ≤6 months of age. Similarly, in the United States between 1993 and 2004, all pertussis deaths and 86% of hospitalizations for pertussis involved infants ≤3 months of age. Although school-age children are the source of infection for most households, adults are the likely source for cases in high-risk infants and may serve as the reservoir of infection between epidemic years.


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InternalMed_Harrison. Infection with B. pertussis is initiated by attachment of the organism to the ciliated epithelial cells of the nasopharynx. Attachment is mediated by surface adhesins (e.g., pertactin and filamentous hemagglutinin), which bind to the integrin family of cell-surface proteins, probably in conjunction with pertussis toxin. The role of fimbriae in adhesion and in maintenance of infection has not been fully delineated. At the site of attachment, the organism multiplies, producing a variety of other toxins that cause local mucosal damage (tracheal cytotoxin, dermonecrotic toxin). Impairment of host defense by B. pertussis is mediated by pertussis toxin and adenylate cyclase toxin. There is local cellular invasion, with intracellular bacterial persistence; however, systemic dissemination does not occur. Systemic manifestations (lymphocytosis) result from the effects of the toxins.


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InternalMed_Harrison. The pathogenesis of the clinical manifestations of pertussis is poorly understood. It is not known what causes the hallmark paroxysmal cough. A pivotal role for pertussis toxin has been proposed. Proponents of this position point to the efficacy of preventing clinical symptoms with a vaccine containing only pertussis toxoid. Detractors counter that pertussis toxin is not the critical factor because paroxysmal cough also occurs in patients infected with B. parapertussis, which does not produce pertussis toxin. It is thought that neurologic events in pertussis, such as seizures and encephalopathy, are due to hypoxia from coughing paroxysms or apnea rather than to the effects of specific bacterial products. B. pertussis pneumonia, which occurs in up to 10% of infants with pertussis, is usually a diffuse bilateral primary infection. In older children and adults with pertussis, pneumonia is often due to secondary bacterial infection with streptococci or staphylococci. Deaths from pertussis


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InternalMed_Harrison. a diffuse bilateral primary infection. In older children and adults with pertussis, pneumonia is often due to secondary bacterial infection with streptococci or staphylococci. Deaths from pertussis among young infants are frequently associated with very high levels of leukocytosis and pulmonary hypertension.


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InternalMed_Harrison. Both humoral and cell-mediated immunity are thought to be important in pertussis. Antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae are all protective in animal models. Pertussis agglutinins were correlated with protection in early studies of whole-cell pertussis vaccines. Serologic correlates of protection conferred by acellular pertussis vaccines have not been established, although antibody to pertactin, fimbriae, and (to a lesser degree) pertussis toxin correlated best with protection in two efficacy trials. The duration of immunity after whole-cell pertussis vaccination is short-lived, with little protection remaining after 10–12 years. Recent studies have demonstrated early waning of immunity—i.e., within 2–4 years after the fifth dose of acellular pertussis vaccine in children who received acellular pertussis vaccine for their primary series in infancy. These data suggest that boosters may be needed more frequently than every 10 years, as


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InternalMed_Harrison. pertussis vaccine in children who received acellular pertussis vaccine for their primary series in infancy. These data suggest that boosters may be needed more frequently than every 10 years, as previously thought. Although immunity after natural infection was thought to be lifelong, seroepidemiologic evidence demonstrates that it clearly is not and that subsequent episodes of clinical pertussis are prevented by intermittent subclinical infection.


InternalMed_Harrison

InternalMed_Harrison. Pertussis is a prolonged coughing illness with clinical manifestations that vary by age (Table 185-1). Although not uncommon among adolescents and adults, classic pertussis is most often seen in preschool and school-age children. After an incubation period averaging 7–10 days, an illness develops that is indistinguishable from the common cold and is characterized by coryza, lacrimation, mild cough, low-grade fever, and malaise. After 1–2 weeks, this catarrhal phase evolves into the paroxysmal phase: the cough becomes more frequent and spasmodic with repetitive bursts of 5–10 coughs, often within a single expiration. Posttussive vomiting is frequent, with a mucous plug occasionally expelled at the end of an episode. The episode may be terminated by an audible whoop, which occurs upon rapid inspiration against a closed glottis at the end of a paroxysm. During a spasm, there may be impressive neck-vein distension, bulging eyes, tongue


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InternalMed_Harrison. TABLE 185-1 CLInICAL FEATuREs OF PERTussIs, By AgE gROuP And dIAgnOsTIC sTATus Percentage of Patients protrusion, and cyanosis. Paroxysms may be precipitated by noise, eating, or physical contact. Between attacks, the patient’s appearance is normal but increasing fatigue is evident. The frequency of paroxysmal episodes varies widely, from several per hour to 5–10 per day. Episodes are often worse at night and interfere with sleep. Weight loss is not uncommon as a result of the illness’s interference with eating. Most complications occur during the paroxysmal stage. Fever is uncommon and suggests bacterial superinfection. After 2–4 weeks, the coughing episodes become less frequent and less severe—changes heralding the onset of the convalescent phase. This phase can last 1–3 months and is characterized by gradual resolution of coughing episodes. For 6–12 months, intercurrent viral infections may be associated with a recrudescence of paroxysmal cough.


InternalMed_Harrison

InternalMed_Harrison. Not all individuals who develop pertussis have classic disease. The clinical manifestations in adolescents and adults are more often atypical. In a German study of pertussis in adults, more than two-thirds had paroxysmal cough and more than one-third had whoop. Adult illness in North America differs from this experience: the cough may be severe and prolonged but is less frequently paroxysmal, and a whoop is uncommon. Vomiting with cough is the best predictor of pertussis as the cause of prolonged cough in adults. Other predictive features are a cough at night, sweating episodes between paroxysms of coughing, and exposure to other individuals with a prolonged coughing illness.


InternalMed_Harrison

InternalMed_Harrison. Complications are frequently associated with pertussis and are more common among infants than among older children or adults. Subconjunctival hemorrhages, abdominal and inguinal hernias, pneumothoraces, and facial and truncal petechiae can result from increased intrathoracic pressure generated by severe fits of coughing. Weight loss can follow decreased caloric intake. In a series of more than 1100 children <2 years of age who were hospitalized with pertussis, 27.1% had apnea, 9.4% had pneumonia, 2.6% had seizures, and 0.4% had encephalopathy; 10 children (0.9%) died. Pneumonia is reported in <5% of adolescents and adults and increases in frequency after 50 years of age. In contrast to the primary B. pertussis pneumonia that develops in infants, pneumonia in adolescents and adults with pertussis is usually caused by a secondary infection with encapsulated organisms such as Streptococcus pneumoniae or Haemophilus influenzae. Pneumothorax, severe weight loss, inguinal hernia, rib


InternalMed_Harrison

InternalMed_Harrison. pertussis is usually caused by a secondary infection with encapsulated organisms such as Streptococcus pneumoniae or Haemophilus influenzae. Pneumothorax, severe weight loss, inguinal hernia, rib fracture, carotid artery aneurysm, and cough syncope have all been reported in adolescents and adults with pertussis.


InternalMed_Harrison

InternalMed_Harrison. If the classic symptoms of pertussis are present, clinical diagnosis is not difficult. However, particularly in older children and adults, it is difficult to differentiate infections caused by B. pertussis and B. parapertussis from other respiratory tract infections on clinical grounds. Therefore, laboratory confirmation should be attempted in all cases. Lymphocytosis (an absolute lymphocyte count of >108–109/L) is common among young children, in whom it is unusual with other infections, but not among adolescents and adults. Culture of nasopharyngeal secretions remains the gold standard of diagnosis, although DNA detection by PCR has replaced culture in many laboratories because 1023 of increased sensitivity and quicker results. Appropriate PCR methodology must include primers to differentiate among B. pertussis, B. parapertussis, and B. holmesii. The best specimen is collected by nasopharyngeal aspiration, in which a fine flexible plastic catheter attached to a 10-mL syringe is


InternalMed_Harrison

InternalMed_Harrison. among B. pertussis, B. parapertussis, and B. holmesii. The best specimen is collected by nasopharyngeal aspiration, in which a fine flexible plastic catheter attached to a 10-mL syringe is passed into the nasopharynx and withdrawn while gentle suction is applied. Since B. pertussis is highly sensitive to drying, secretions for culture should be inoculated without delay onto appropriate medium (Bordet-Gengou or Regan-Lowe), or the catheter should be flushed with a phosphate-buffered saline solution for culture and/or PCR. An alternative to the aspirate is a Dacron or rayon nasopharyngeal swab; again, inoculation of culture plates should be immediate or an appropriate transport medium (e.g., Regan-Lowe charcoal medium) should be used. Results of PCR can be available within hours; cultures become positive by day 5 of incubation. B. pertussis and B. parapertussis can be differentiated by agglutination with specific antisera or by direct immunofluorescence.


InternalMed_Harrison

InternalMed_Harrison. Nasopharyngeal cultures in untreated pertussis remain positive for a mean of 3 weeks after the onset of illness; these cultures become negative within 5 days of the institution of appropriate antimicrobial therapy. The duration of a positive PCR in untreated pertussis or after therapy is not known but exceeds that of positive cultures. Since much of the period during which the organism can be recovered from the nasopharynx falls into the catarrhal phase, when the etiology of the infection is not suspected, there is only a small window of opportunity for culture-proven diagnosis. Cultures from infants and young children are more frequently positive than those from older children and adults; this difference may reflect earlier presentation of the former age group for medical care. Direct fluorescent antibody tests of nasopharyngeal secretions for direct diagnosis may still be available in some laboratories but should not be used because of poor sensitivity and specificity.


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InternalMed_Harrison. Direct fluorescent antibody tests of nasopharyngeal secretions for direct diagnosis may still be available in some laboratories but should not be used because of poor sensitivity and specificity. Pseudo-outbreaks of pertussis have been reported as a result of false-positive PCR results. Greater standardization of PCR methodology can alleviate this problem.


InternalMed_Harrison

InternalMed_Harrison. As a result of the difficulties with laboratory diagnosis of pertussis in adolescents, adults, and patients who have been symptomatic for >4 weeks, increasing attention is being given to serologic diagnosis. Enzyme immunoassays detecting IgA and IgG antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae have been developed and assessed for reproducibility. Twoor fourfold increases in antibody titer are suggestive of pertussis, although cross-reactivity of some antigens (such as filamentous hemagglutinin and pertactin) among Bordetella species makes it difficult to depend diagnostically on seroconversion involving a single type of antibody. Late presentation for medical care and prior immunization also complicate serologic diagnosis because the first sample obtained may in fact be a convalescent-phase specimen. Criteria for serologic diagnosis based on comparison of results for a single serum specimen with established population values are gaining acceptance,


InternalMed_Harrison

InternalMed_Harrison. may in fact be a convalescent-phase specimen. Criteria for serologic diagnosis based on comparison of results for a single serum specimen with established population values are gaining acceptance, and serologic measurement of antibody to pertussis toxin is becoming more widely standardized and available for diagnostic purposes, particularly in outbreak settings and for surveillance.


InternalMed_Harrison

InternalMed_Harrison. A child presenting with paroxysmal cough, posttussive vomiting, and whoop is likely to have an infection caused by B. pertussis or B. parapertussis; lymphocytosis increases the likelihood of a B. pertussis etiology. Viruses such as respiratory syncytial virus and adenovirus have been isolated from patients with clinical pertussis but probably represent co-infection. In adolescents and adults, who often do not have paroxysmal cough or whoop, the differential diagnosis of a prolonged coughing illness is more extensive. Pertussis should be suspected when any patient has a cough that does not improve within 14 days, a paroxysmal cough of any duration, a cough followed by vomiting (adolescents and adults), or any respiratory symptoms after contact with a laboratory-confirmed case of pertussis. Other etiologies to consider include infections caused by Mycoplasma pneumoniae, Chlamydia pneumoniae, adenovirus, influenza virus, and other respiratory viruses. Use of angiotensin-converting


InternalMed_Harrison

InternalMed_Harrison. Drug Adult Daily Dose Frequency Duration, Days Comments Erythromycin estolate 1–2 g 3 divided doses 7–14 Frequent gastrointestinal side effects Clarithromycin 500 mg 2 divided doses 7 — Azithromycin 500 mg on day 1, 250 mg 1 daily dose 5 — subsequently Trimethoprim-160 mg of trimethoprim, 800 mg of 2 divided doses 14 For patients allergic to macrolides; data on enzyme (ACE) inhibitors, reactive airway disease, and gastroesophageal reflux disease are well-described noninfectious causes of prolonged cough in adults. The purpose of antibiotic therapy for pertussis is to eradicate the infecting bacteria from the nasopharynx; therapy does not substantially alter the clinical course unless given early in the catarrhal phase. Macrolide antibiotics are the drugs of choice for treatment of pertussis (Table 185-2); macrolide-resistant B. pertussis strains have been reported but are rare. Trimethoprim-sulfamethoxazole is recommended as an alternative for individuals allergic to macrolides.


InternalMed_Harrison

InternalMed_Harrison. Young infants have the highest rates of complication and death from pertussis; therefore, most infants (and older children with severe disease) should be hospitalized. A quiet environment may decrease the stimulation that can trigger paroxysmal episodes. Use of β-adrenergic agonists and/or glucocorticoids has been advocated by some authorities but has not been proven to be effective. Cough suppressants are not effective and play no role in the management of pertussis. Hospitalized patients with pertussis should be placed in respiratory isolation, with the use of precautions appropriate for pathogens spread by large respiratory droplets. Isolation should continue for 5 days after initiation of macrolide therapy or, in untreated patients, for 3 weeks (i.e., until nasopharyngeal cultures are consistently negative).


InternalMed_Harrison

InternalMed_Harrison. PREVENTION Chemoprophylaxis Because the risk of transmission of B. pertussis within households is high, chemoprophylaxis is widely recommended for household contacts of pertussis cases. The effectiveness of chemoprophylaxis, although unproven, is supported by several epidemiologic studies of institutional and community outbreaks. In the only randomized placebo-controlled study, erythromycin estolate (50 mg/kg per day in three divided doses; maximum dose, 1 g/d) was effective in reducing the incidence of bacteriologically confirmed pertussis by 67%; however, there was no decrease in the incidence of clinical disease. Despite these disappointing results, many authorities continue to recommend chemoprophylaxis, particularly in households with members at high risk of severe disease (children <1 year of age, pregnant women). Data are not available on use of the newer macrolides for chemoprophylaxis, but these drugs are commonly used because of their increased tolerability and their


InternalMed_Harrison

InternalMed_Harrison. <1 year of age, pregnant women). Data are not available on use of the newer macrolides for chemoprophylaxis, but these drugs are commonly used because of their increased tolerability and their effectiveness.


InternalMed_Harrison

InternalMed_Harrison. Immunization (See also Chap. 148) The mainstay of pertussis prevention is active immunization. Pertussis vaccine became widely used in North America after 1940; the reported number of pertussis cases subsequently fell by >90%. Whole-cell pertussis vaccines are prepared through the heating, chemical inactivation, and purification of whole


InternalMed_Harrison

InternalMed_Harrison. B. pertussis organisms. Despite their efficacy (average estimate, 85%; range for different products, 30–100%), whole-cell pertussis vaccines are associated with adverse events—both common (fever; injection-site pain, erythema, and swelling; irritability) and uncommon (febrile seizures, hypotonic hyporesponsive episodes). Alleged associations of whole-cell pertussis vaccine with encephalopathy, sudden infant death syndrome, and autism, although not substantiated, have spawned an active anti-immunization lobby. The development of acellular pertussis vaccines, which are effective and less reactogenic, has greatly alleviated concerns about the inclusion of pertussis vaccine in the combined infant immunization series.


InternalMed_Harrison

InternalMed_Harrison. Although whole-cell vaccines are still used extensively in developing regions of the world, acellular pertussis vaccines are used exclusively for childhood immunization in much of the developed world. In North America, acellular pertussis vaccines for children are given as a three-dose primary series at 2, 4, and 6 months of age, with a reinforcing dose at 15–18 months of age and a booster dose at 4–6 years of age.


InternalMed_Harrison

InternalMed_Harrison. Although a wide variety of acellular pertussis vaccines were developed, only a few are still widely marketed; all contain pertussis toxoid and filamentous hemagglutinin. One acellular pertussis vaccine also contains pertactin, and another contains pertactin and two types of fimbriae. In light of phase 3 efficacy studies, most experts have concluded that two-component acellular pertussis vaccines are more effective than monocomponent vaccines and that the addition of pertactin increases efficacy still more. The further addition of fimbriae appears to enhance protective efficacy against milder disease. In two studies, protection conferred by pertussis vaccines correlated best with the production of antibody to pertactin, fimbriae, and pertussis toxin.


InternalMed_Harrison

InternalMed_Harrison. Adult formulations of acellular pertussis vaccines have been shown to be safe, immunogenic, and efficacious in clinical trials in adolescents and adults and are now recommended for routine immunization of these groups in several countries, including the United States. In this country, adolescents should receive a dose of the adult-formulation diphtheria–tetanus–acellular pertussis vaccine at the preadolescence physician’s visit, and all unvaccinated adults should receive a single dose of this combined vaccine. In addition, in the United States, pertussis immunization is specifically recommended for health care workers and for women during each pregnancy to increase passive transfer of maternal antibodies to the fetus. Pertussis vaccine coverage among


InternalMed_Harrison

InternalMed_Harrison. U.S. adolescents was 78.2% in 2011, but coverage among adults is low (2.1% as of 2007). Further improvements in adult vaccine coverage may permit better control of pertussis across the age spectrum, with collateral protection of infants too young to be immunized. However, more effective vaccines with longer-lasting protection will ultimately be needed to control this disease. diseases Caused by gram-negative Enteric Bacilli Thomas A. Russo, James R. Johnson GENERAL FEATuRES AND PRINCIPLES Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, 186


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InternalMed_Harrison. diseases Caused by gram-negative Enteric Bacilli Thomas A. Russo, James R. Johnson GENERAL FEATuRES AND PRINCIPLES Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, 186 Morganella, Providencia, Cronobacter, and Edwardsiella are gram-negative enteric bacilli that are members of the family Enterobacteriaceae. Salmonella, Shigella, and Yersinia, also in the family Enterobacteriaceae, are discussed in Chaps. 190, 191, and 196, respectively. These pathogens cause a wide variety of infections involving diverse anatomic sites in both healthy and compromised hosts. Increasing antimicrobial resistance in this group has put them at the forefront of an evolving public health crisis. In addition, new infectious syndromes have emerged. Therefore, a thorough knowledge of clinical presentations and appropriate therapeutic choices is necessary for optimal outcomes.


InternalMed_Harrison

InternalMed_Harrison. E. coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, Morganella, Providencia, Cronobacter, and Edwardsiella are components of the normal animal and human colonic micro biota and/or the microbiota of a variety of environmental habitats, including long-term-care facilities (LTCFs) and hospitals. As a result, except for certain pathotypes of intestinal pathogenic E. coli, these genera are global pathogens. The incidence of infection due to these agents is increasing because of the combination of an aging population and increasing antimicrobial resistance. In healthy humans, E. coli is the predominant species of gram-negative bacilli (GNB) in the colonic flora; Klebsiella and Proteus are less prevalent. GNB (primarily E. coli, Klebsiella, and Proteus) only transiently colonize the oropharynx and skin of healthy individuals. In contrast, in LTCFs and hospital settings, a variety of GNB emerge as the dominant microbiota of both mucosal and skin surfaces, particularly in


InternalMed_Harrison

InternalMed_Harrison. the oropharynx and skin of healthy individuals. In contrast, in LTCFs and hospital settings, a variety of GNB emerge as the dominant microbiota of both mucosal and skin surfaces, particularly in association with antimicrobial use, severe illness, and extended length of stay. LTCFs are emerging as an important reservoir for resistant GNB. This colonization may lead to subsequent infection; for example, oropharyngeal colonization may lead to pneumonia. Interestingly, the use of ampicillin or amoxicillin was associated with an increased risk of subsequent infection due to the hypervirulent variant of Klebsiella pneumoniae in Taiwan; this association suggests that changes in the quantity or prevalence of colonizing bacteria may be important. Serratia and Enterobacter infection may be acquired through a variety of infusates (e.g., medications, blood products). Edwardsiella infections are acquired through freshwater and marine environment exposures and are most common in Southeast Asia.


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InternalMed_Harrison. Enteric GNB possess an extracytoplasmic outer membrane, which consists of a lipid bilayer with associated proteins, lipoproteins, and polysaccharides (capsule, lipopolysaccharide). The outer membrane 1025 interfaces with the external environment, including the human host. A variety of components of the outer membrane are critical determinants in pathogenesis (e.g., capsule) and antimicrobial resistance (e.g., permeability barrier, efflux pumps). Multiple bacterial virulence factors are required for the pathogenesis of infections caused by GNB. Possession of specialized virulence genes defines pathogens and enables them to infect the host efficiently. Hosts and their cognate pathogens have been co-adapting throughout evolutionary history. During the host-pathogen “chess match” over time, various and redundant strategies have emerged in both the pathogens and their hosts (Table 186-1).


InternalMed_Harrison

InternalMed_Harrison. Intestinal pathogenic mechanisms are discussed below. The members of the Enterobacteriaceae family that cause extraintestinal infections are primarily extracellular pathogens and therefore share certain pathogenic features. Innate immunity (including the activities of complement, antimicrobial peptides, and professional phagocytes) and humoral immunity are the principal host defense components. Both susceptibility to and severity of infection are increased with dysfunction or deficiencies of these components. By contrast, the virulence traits of intestinal pathogenic E. coli—i.e., the distinctive strains that can cause diarrheal disease—are for the most part different from those of extraintestinal pathogenic E. coli (ExPEC) and other GNB that cause extraintestinal infections. This distinction reflects site-specific differences in host environments and defense mechanisms.


InternalMed_Harrison

InternalMed_Harrison. A given strain usually possesses multiple adhesins for binding to a variety of host cells (e.g., in E. coli: type 1, S, and F1C fimbriae; P pili). Nutrient acquisition (e.g., of iron via siderophores) requires many genes that are necessary but not sufficient for pathogenesis. The ability to resist the bactericidal activity of complement and phagocytes in the absence of antibody (e.g., as conferred by capsule or O antigen of lipopolysaccharide) is one of the defining traits of an extracellular pathogen. Tissue damage (e.g., as mediated by hemolysin in the case of E. coli) may facilitate spread within the host. Without doubt, many important virulence genes await identification (Chap. 145e).


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InternalMed_Harrison. The ability to induce septic shock is another defining feature of these genera. GNB are the most common causes of this potentially lethal syndrome. Pathogen-associated molecular pattern molecules (PAMPs; e.g., the lipid A moiety of lipopolysaccharide) stimulate a proinflammatory host response via pattern recognition receptors (e.g., Toll-like or C-type lectin receptors) that activate host defense signaling pathways; if overly exuberant, this response results in shock (Chap. 325). Direct bacterial damage of host tissue (e.g., by toxins) or collateral damage from the host response can result in the release of damage-associated molecular pattern molecules (DAMPs; e.g., HMGB1) that can propagate a detrimental proinflammatory host response.


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InternalMed_Harrison. Many antigenic variants (serotypes) exist in most genera of GNB. For example, E. coli has more than 150 O-specific antigens and more than 80 capsular antigens. This antigenic variability, which permits immune evasion and allows recurrent infection by different strains of the same species, has impeded vaccine development (Chap. 148). InTERACTIOns OF ExTRAInTEsTInAL PATHOgEnIC ESCHERICHIA COLI wITH THE HuMAn HOsT: A PARAdIgM FOR ExTRACELLuLAR, ExTRAInTEsTInAL gRAM-nEgATIvE BACTERIAL PATHOgEns


InternalMed_Harrison

InternalMed_Harrison. E. coli can cause either intestinal or extraintestinal infection, depending on the particular pathotype, and Edwardsiella tarda can cause both intestinal and extraintestinal infection. Klebsiella primarily causes extraintestinal infection, but hemorrhagic colitis has been associated with a toxin-producing variant of Klebsiella oxytoca. Depending on both the host and the pathogen, nearly every organ or body cavity can be infected with GNB. E. coli and—to a lesser degree—Klebsiella account for most extraintestinal infections due to GNB and are the most virulent pathogens within this group; this virulence is demonstrated by the ability of E. coli and Klebsiella pneumoniae (primarily the hypervirulent variant) to cause severe infections in healthy, ambulatory hosts from the community. However, the other genera are also important, especially among LTCF residents and hospitalized patients, in large part because of the intrinsic or acquired antimicrobial resistance of these organisms and the


InternalMed_Harrison

InternalMed_Harrison. the other genera are also important, especially among LTCF residents and hospitalized patients, in large part because of the intrinsic or acquired antimicrobial resistance of these organisms and the increasing number of individuals with compromised host defenses. The mortality rate is substantial in many GNB infections and correlates with the severity of illness. Especially problematic are pneumonia and bacteremia (arising from any source), particularly when complicated by organ failure (severe sepsis) and/or shock, for which the associated mortality rates are 20–50%.


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InternalMed_Harrison. Isolation of GNB from sterile sites almost always implies infection, whereas their isolation from nonsterile sites, particularly from open soft-tissue wounds and the respiratory tract, requires clinical correlation to differentiate colonization from infection. Tentative laboratory identification based on lactose fermentation and indole production (described for each genus below), which usually is possible before final identification of the organism and determination of its antimicrobial susceptibilities, may help to guide empirical antimicrobial therapy.