94 DISEASES CAUSED BY OTHER GRAM-NEGATIVE BACTERIA
Harrison’s Manual of Medicine
DISEASES CAUSED BY OTHER GRAM-NEGATIVE BACTERIA
Bartonella henselae and Bartonella quintana
Other Gram-Negative Rods Associated with Animal Injuries
EPIDEMIOLOGY Brucellosis is a zoonosis caused by four species of aerobic gram-negative bacilli. Brucella melitensis, the most common cause, is acquired from goats, sheep, and camels. B. suis is acquired from hogs, B. abortus from cattle, and B. canis from dogs. Humans become infected by exposure to animal tissues (e.g., slaughterhouse workers, butchers) or by ingestion of untreated milk or milk products or raw meat.
CLINICAL MANIFESTATIONS The acute illness generally presents after a 7- to 21-d incubation period, although the incubation period may be as long as several months. The most common signs and symptoms are fever, chills, fatigue, anorexia, weight loss, and sweats. Other common manifestations include headaches, myalgias, low back pain, constipation, sore throat, and dry cough. Localized infections may occur as well, including osteomyelitis (especially of the lumbosacral vertebrae), arthritis, splenic abscess, epididymoorchitis, CNS infection, and endocarditis. Finally, brucellosis may present chronically, with generalized ill health for >1 year after its onset.
DIAGNOSIS Most cases are diagnosed on the basis of potential exposure, compatible clinical features, and elevated levels of Brucella agglutinins (usually detected by a standard tube agglutination test). In nonendemic areas a titer of ³1:160 is considered positive; in endemic areas a titer of 1:320 or 1:640 is significant, and IgM assays are positive in early infection. The most definitive evidence of infection is isolation of the organism from blood or bone marrow, optimally with special culture techniques. Cultures may take up to 6 weeks to become positive but ultimately are positive in 50–70% of cases. Samples in which the presence of Brucella is suspected should be so labeled to alert the laboratory to use special culture techniques and to be aware of the hazard posed by this material to laboratory personnel.
Optimal treatment consists of doxycycline (100 mg bid) plus an aminoglycoside—i.e., gentamicin (3–5 mg/kg IV qd in 3 divided doses), streptomycin (1 g IM qd in pts <45 years old, 500–750 mg IM qd in pts ³45 years old), or netilmicin (2 mg/kg IV or IM q12h)—for 4 weeks followed by a combination of doxycycline and rifampin (600–900 mg PO qd) for 4–8 weeks. Young children and pregnant women may be treated with trimethoprim-sulfamethoxazole (TMP-SMZ; 2 or 3 single-strength tablets q12h) and rifampin for 8–12 weeks. Repeat blood cultures and IgG measurements should be performed every 3–6 months for 2 years.
EPIDEMIOLOGY Francisella tularensis is a bipolar-staining, pleomorphic bacillus that is transmitted to humans by insect bites, skin contact, inhalation, or ingestion of material from multiple species of wild animals. In the U.S., transmission takes place primarily through skin contact with infected wild rabbits or by tick or deerfly bite. Tularemia is common in Arkansas, Oklahoma, and Missouri; these three states account for >50% of U.S. cases. Cases have been reported with increasing frequency from Scandinavia, eastern Europe, and Siberia.
CLINICAL MANIFESTATIONS Tularemia presents as several different clinical syndromes, most of which are associated with fever, chills, headache, and myalgias, after a 2- to 10-d incubation period. Ulceroglandular tularemia (75–85% of cases) follows skin inoculation of F. tularensis; a papule forms and evolves into a punched-out-appearing ulcer with a necrotic base. Large, tender regional lymph nodes develop. Oculoglandular disease develops after inoculation into the eye and presents as purulent conjunctivitis and regional lymphadenopathy. Pulmonary tularemia, which has a high mortality rate and may complicate other forms of the disease or follow inhalation of the organism, presents as nonproductive cough and bilateral patchy infiltrates. The typhoidal form, which is now thought to be rare in the U.S., presents as fever without skin lesions or adenopathy.
DIAGNOSIS Diagnosis is based on serologic agglutination tests. A fourfold rise in titer over 2–3 weeks is diagnostic of acute infection. A single titer of ³1:160 constitutes presumptive evidence of infection. Gram’s staining of material usually yields negative results; special stains and indirect fluorescent antibody may be revealing, although false-positives due to Legionella spp. have been reported. Culture and isolation of F. tularensis are difficult, pose a major risk to laboratory personnel, and should be attempted only in laboratories with adequate isolation techniques and experienced personnel.
The treatment of choice is streptomycin (7.5–10 mg/kg IM q12h) for 7–10 d; in severe infections, 15 mg/kg q12h may be used for the first 48–72 h. Gentamicin (1.7 mg/kg IV or IM q8h) also may be used. Chloramphenicol and tetracycline have been used to treat tularemia, with good initial response rates but unacceptable relapse rates.
EPIDEMIOLOGY Yersinia pestis, a gram-negative coccobacillus, causes sporadic cases of human disease and is transmitted by the bite of the rodent flea, predominantly in the southwestern U.S. Plague occurs sporadically both in rural areas throughout the world and in a few urban areas of southern Asia. Less commonly, plague is contracted via airborne droplets. In its pulmonic form, plague can be transmitted from person to person.
CLINICAL MANIFESTATIONS Bubonic plague is characterized by rapid onset of fever, myalgias, arthralgias, and painful lymphadenopathy (the bubo) after a 2- to 6-d incubation period. Insect contact often is not recalled, but an eschar, papule, pustule, scab, or ulcer may indicate the point of inoculation. If left untreated, bubonic plague may progress to sepsis, hypotension, DIC, and death within 2–10 d. Secondary pneumonia develops in 10–20% of pts, characteristically with initially diffuse interstitial pneumonitis in which sputum production is scant. Primary Y. pestis pneumonia develops after an incubation period of 1–4 d, with acute onset of fever, chills, myalgia, headache, cough, and dyspnea (often accompanied by hemoptysis); CXR shows involvement of a single lobe progressing to multilobar involvement. The illness is fulminant, and death occurs within 2–6 d in the absence of treatment. Meningitis is a serious but unusual manifestation of plague.
DIAGNOSIS Since plague is unusual in the U.S., a high index of clinical suspicion and a thorough epidemiologic history are required for timely diagnosis and prompt institution of specific therapy. The laboratory diagnosis is usually based on stains and cultures of blood, sputum, an aspirated bubo, or CSF. Stains reveal characteristic bipolar “safety-pin” forms. Culture is usually positive but requires 48–72 h. Serology may serve to confirm cases.
The drug of choice for plague is streptomycin (1 g IM q12h for 10 d). Gentamicin (1.0–1.7 mg/kg IV q8h) and tetracycline (500 mg PO or IV q6h) are alternatives. Pts with pneumonic plague should be placed in respiratory isolation, and contacts should receive prophylactic tetracycline (250–500 mg PO qid). Death is almost always due to a delay in treatment.
Bartonella henselae and Bartonella quintana
CLINICAL MANIFESTATIONS Cat-Scratch Disease Cat-scratch disease follows a primary skin inoculation by the lick, scratch, or bite of a cat. B. henselae, a tiny gram-negative rod, is now thought to be the only causative agent of cat-scratch disease. Frequently, a skin lesion (papule or pustule) develops after 3–5 d at the primary site of inoculation. Tender lymphadenopathy occurs after 1–2 weeks (often after resolution of the skin lesion) and persists for 3–6 weeks or longer. Dissemination of infection is rare in immunocompetent hosts and causes meningoencephalitis, osteomyelitis, or hepatitis. Conjunctival infection with preauricular lymphadenopathy is referred to as Parinaud’s oculoglandular syndrome.
Trench Fever Trench fever is a febrile illness that has recently reemerged in homeless persons (in whom infection has been caused by B. quintana) and persons bitten by ticks (B. henselae). Fever, headache, and aseptic meningitis are common symptoms. Bacteremia can persist for weeks.
Bacillary Angiomatosis In immunocompromised hosts, especially those with HIV infection, B. henselae may disseminate to involve virtually any organ system, causing a lobular proliferation of new blood vessels. On the skin, this condition is recognized as cutaneous bacillary angiomatosis (also called epithelioid angiomatosis). Characteristically, the lesions are red or purple, resembling Kaposi’s sarcoma; they develop anywhere on the skin or mucous membranes. Disseminated bacillary angiomatosis may involve the liver, spleen, bone marrow, lymph nodes, and/or CNS. Dissemination causes persistent fever, abdominal pain, weight loss, and malaise. B. henselae is associated with peliosis of the liver or spleen, which may cause abdominal pain and the appearance of nodular lesions on CT or MRI of the organ. B. quintana is associated with osseous and SC infection.
DIAGNOSIS B. henselae and B. quintana may be identified in tissue by Warthin-Starry silver stain. In addition, in cases involving immunocompromised hosts, the bacteria may be isolated from cultures of blood and other sites, although lengthy incubation (2–4 h) is required. Polymerase chain reaction testing of clinical specimens may be considered for definitive identification of Bartonella spp. Serology is positive in 70–90% of pts with cat-scratch disease.
Cat-scratch disease is generally self-limited and resolves spontaneously. However, pts with dissemination should be treated with azithromycin (500 mg PO on day 1, 250 mg PO on days 2–5); ciprofloxacin and doxycycline may also be used. Cutaneous bacillary angiomatosis usually responds to treatment with erythromycin (500 mg PO qid) or doxycycline (100 mg PO bid) for 3 weeks; relapse may require prolonged therapy. Disseminated disease is treated with erythromycin (2 g IV qd) for a prolonged course (3 weeks to 2 months), with a switch to oral therapy after clinical improvement.
EPIDEMIOLOGY B. bacilliformis is a tiny gram-negative bacillus that causes Oroya fever and, in its chronic form, skin lesions called verruga peruana. The vector of these diseases is the sandfly found in the river valleys of the Andes Mountains of Peru, Ecuador, and Colombia.
CLINICAL MANIFESTATIONS Oroya fever is characterized by fever, chills, malaise, headache, altered mentation, and muscle and joint pains that may begin insidiously or acutely ~3 weeks after the bite of the sandfly vector. Profound anemia results from parasitization of erythrocytes, which are then phagocytosed and destroyed by the host. Red or purple cutaneous lesions called verrugas—either tiny or large and pedunculated—may develop during the convalescent phase.
Oroya fever is usually treated with chloramphenicol, although it also responds to tetracyclines, penicillin, or streptomycin. Intercurrent Salmonella infections are common.
OTHER GRAM-NEGATIVE RODS ASSOCIATED WITH ANIMAL INJURIES
This small gram-negative coccobacillus is transmitted by bites or scratches from animals, particularly cats and dogs. Infections are characterized by the rapid development of intense inflammation and purulent drainage. There is a high risk of deep tissue infections, including osteomyelitis, tendon sheath involvement, or septic arthritis. Treatment consists of ampicillin/sulbactam (1.5–3.0 g IV q6h), amoxicillin/clavulanic acid (500/125 mg PO tid), or—in the penicillin- allergic pt—TMP-SMZ (160/800 mg PO or IV q12h).
This fusiform gram-negative rod is associated with septicemia following dog bites, particularly in alcoholics, splenectomized pts, or pts taking steroids on a chronic basis. The incubation period averages 5 d. Pts present with fever that is sometimes accompanied by meningitis or endocarditis. In splenectomized pts, DIC, gangrene, adrenal hemorrhage, pulmonary hemorrhage, and fulminant sepsis may occur. The organism may be identified on Gram’s or Wright’s stain of buffy coat of blood from splenectomized individuals. Treatment of C. canimorsus sepsis consists of penicillin G (2–3 million U IV q4h for 14 d). Alternatives for use in the penicillin-allergic pt include clindamycin, third-generation cephalosporins, and fluoroquinolones.
For a more detailed discussion, see Madoff LC: Infectious Complications of Bites and Burns, Chap. 127, p. 817; Madkour MM, Kasper DL: Brucellosis, Chap. 160, p. 986; Jacobs RF: Tularemia, Chap. 161, p. 990; Campbell GL, Dennis DT: Plague and Other Yersinia Infections, Chap. 162, p. 993; and Tompkins LS: Bartonella Infections, Including Cat-Scratch Disease, Chap. 163, p. 1001, in HPIM-15.