MENINGOCOCCAL INFECTIONS
• Etiology and Microbiology Neisseria meningitidis is a catalase- and oxidase-positive, gram-negative aerobic diplococcus with a polysaccha-ride capsule that colonizes humans only.
– Of the 13 identified serogroups, only 5—A, B, C, Y, and W135—account for the majority of cases of invasive disease.
– Serogroups A and W135 cause recurrent epidemics in sub-Saharan Africa. Serogroup B can cause hyperendemic disease, and serogroups C and Y cause sporadic disease and small outbreaks.
• Epidemiology Up to 500,000 cases of meningococcal disease occur worldwide each year, with a mortality rate of ~10%.
– Most commonly, meningococci asymptomatically colonize the nasopharynx; such asymptomatic nasopharyngeal carriage is detected in >25% of healthy adolescents and adults.
– Patterns of meningococcal disease include epidemics, outbreaks (e.g., in colleges, refugee camps), hyperendemic disease, and sporadic or endemic cases.
– Although most countries have predominantly sporadic cases (0.3–5 cases per 100,000 population), epidemics in sub-Saharan Africa can have rates as high as 1000 cases per 100,000 population.
– Rates of meningococcal disease are highest among infants, with a second peak in adolescents and young adults (15–25 years of age).
– Other risk factors for meningococcal disease include complement deficiency (C5–C9), close contact with carriers, exposure to tobacco smoke, and a recent URI caused by a virus or Mycoplasma species.
• Pathogenesis Meningococci colonizing the upper respiratory tract invade the bloodstream through the mucosa only rarely, usually within a few days after an invasive strain is acquired.
– The capsule is an important virulence factor, providing resistance to phagocytosis and helping prevent desiccation during transmission between hosts.
– Severity of disease is related to the degree of endotoxemia and the magnitude of the inflammatory response.
– Endothelial injury leads to increased vascular permeability and hypovolemia, resulting in vasoconstriction and ultimately in decreased cardiac output.
– Intravascular thrombosis caused by activation of procoagulant pathways and down-regulation of anticoagulant pathways results in the characteristic purpura fulminans often seen in meningococcemia.
• Clinical Manifestations The most common clinical syndromes are meningitis and meningococcal septicemia, with disease usually developing within 4 days of organism acquisition.
– A nonblanching rash (petechial or purpuric) develops in >80% of cases; early in the illness, the rash is often absent or may be indistinguishable from viral rashes.
– Meningococcal meningitis alone (without septicemia) accounts for 30–50% of cases.
• This meningitis is indistinguishable from other forms of bacterial meningitis unless there is an associated petechial or purpuric rash.
• Classic signs of meningitis (e.g., headache, neck stiffness, photophobia) are often absent or difficult to discern in infants and young children.
– Meningococcal septicemia alone accounts for ~20% of cases and initially may present as an influenza-like illness (e.g., fever, headache, myalgias, vomiting, abdominal pain).
• May progress to shock (e.g., tachycardia, poor peripheral perfusion, oliguria), decreased level of consciousness due to decreased cerebral perfusion, spontaneous hemorrhage (pulmonary, gastric, or cerebral), and ultimately multiorgan failure and death.
• Poor prognostic factors include an absence of meningismus, hypotension, relatively low temperature (<38°C), leukopenia, and thrombocytopenia.
– Chronic meningococcemia presents as repeated episodes of petechial rash associated with fever, joint pain, features of arthritis, and splenomegaly that may progress to acute meningococcal septicemia if untreated.
• Chronic meningococcemia is rarely recognized.
• This condition is occasionally associated with complement deficiencies or inadequate sulfonamide therapy.
– Postmeningococcal reactive disease is an immune complex–mediated disease that occurs 4–10 days after onset of meningococcal disease.
• Manifestations can include a maculopapular or vasculitic rash (2% of cases), arthritis (≤8% of cases), iritis (1% of cases), or serositis. These features resolve spontaneously without sequelae.
• Less common clinical manifestations include pneumonia, pyogenic arthritis, osteomyelitis, purulent pericarditis, endophthalmitis, conjunctivitis, or primary peritonitis.
• Diagnosis Although meningococcal infections are often diagnosed on clinical grounds, blood cultures are positive in ~75% of cases and should be performed to confirm the diagnosis and to facilitate public health investigations.
– In the setting of fever and petechial rash, elevations in the WBC count and inflammatory marker levels suggest meningococcal disease.
– With antibiotic pretreatment, blood cultures are generally negative; in contrast, PCR analysis of whole-blood samples is effective for several days after initiation of antibiotics and increases the diagnostic yield by >40%.
– Unless contraindicated on clinical grounds, LP should be performed in cases of suspected meningococcal meningitis.
• Gram’s staining of CSF is ~80% sensitive, and CSF culture is 90% sensitive. Latex agglutination testing of CSF is insensitive and should be avoided.
• LP should be avoided in pts with meningococcal septicemia, as positioning for the procedure may adversely affect circulatory status.
TREATMENT Meningococcal Infections
• Initial therapy should focus on urgent clinical issues (e.g., hypovolemic shock, increased intracranial pressure, airway patency) and administration of antibiotic therapy.
• Empirical antibiotic therapy for suspected meningococcal disease consists of a third-generation cephalosporin such as ceftriaxone [75–100 mg/kg per day (maximum, 4 g/d) in one or two divided IV doses] or cefotaxime [200 mg/kg per day (maximum, 8 g/d) in four divided IV doses] to provide coverage both for meningococci and for other, potentially penicillin-resistant organisms that may produce an indistinguishable clinical syndrome.
• Meningococcal meningitis and meningococcal septicemia are conventionally treated for 7 days.
– A single dose of ceftriaxone has been used successfully in resource-poor settings.
– Treatment for meningococcal disease at other foci (e.g., pneumonia, arthritis) is usually continued until clinical and laboratory evidence of infection has resolved.
• Little evidence supports other adjunctive therapies (e.g., antibody to lipopolysaccharide, recombinant bactericidal/permeability-increasing protein, activated protein C) in relevant pt populations; these therapies are not currently recommended.
• Prognosis Despite the availability of antibiotics and other intensive medical interventions, ~10% of pts die.
– Necrosis of purpuric lesions leads to scarring and potential need for skin grafting in ~10% of cases.
– Amputations are required in ~2% of cases.
• Prevention Polysaccharide-based and conjugate vaccines exist for primary prevention; secondary cases can be prevented with antibiotic prophylaxis.
– Meningococcal polysaccharide vaccines are currently formulated as bivalent (serogroups A and C) or quadrivalent (serogroups A, C, Y, and W135) and provide adults with immunity of 2–10 years’ duration. Because the B polysaccharide is the same as a polysaccharide expressed in fetuses and is therefore recognized as self, serogroup B strains have not been targeted by polysaccharide vaccines.
– A variety of meningococcal conjugate vaccines have been developed for administration to children. A quadrivalent formulation (sero-groups A, C, Y, and W135) is most common in the United States.
– Close contacts (i.e., household and kissing contacts) of pts with meningococcal disease should receive prophylaxis with ciprofloxacin, ofloxacin, or ceftriaxone to eradicate nasopharyngeal colonization by N. meningitidis.
• Rifampin fails to eradicate carriage in 15–20% of cases, and emerging resistance has been reported.
• Pts with meningococcal disease who receive treatment with an antibiotic that does not clear colonization (e.g., penicillin) should also be given a prophylactic agent at the end of therapy.
LISTERIAL INFECTIONS
• Etiology and Microbiology Listeria monocytogenes is a food-borne pathogen that can cause serious infections, particularly in pregnant women and immunocompromised individuals.
– The organism is a facultatively anaerobic, nonsporulating, gram-positive rod that demonstrates motility when cultured at low temperatures.
– Listeria is commonly found in processed and unprocessed foods such as soft cheeses, delicatessen meats, hot dogs, milk, and cold salads.
– After ingestion of food that contains a high bacterial burden, virulence factors expressed by Listeria allow internalization into cells, intracellular growth, and cell-to-cell spread.
• Epidemiology
– Recent annual incidences in the United States range from 2 to 9 cases per 1 million population.
– There is no human-to-human transmission (other than vertical transmission from mother to fetus) or waterborne infection.
• Clinical Manifestations Listeria causes several clinical syndromes, of which meningitis and septicemia are most common.
– Gastroenteritis: Can develop within 48 h after ingestion of contaminated foods containing a large bacterial inoculum.
• Listeriosis should be considered in outbreaks of gastroenteritis when cultures for other likely pathogens are negative.
• Sporadic cases appear to be uncommon.
– Bacteremia: Pts present with fever, chills, myalgias, and arthralgias. Endocarditis is uncommon and is associated with fatality rates of 35–50%.
– Meningitis: Listeria causes ~5–10% of cases of community-acquired meningitis in adults in the United States, with case–fatality rates of 15–26%.
• Listerial meningitis differs from meningitis of other bacterial etiologies in that its presentation is often subacute and the CSF profile usually reveals <1000 WBCs/μL with a less marked neutrophil predominance.
• Low glucose levels and a positive Gram’s stain are seen in ~30–40% of cases.
– Meningoencephalitis and focal CNS infection: Listeria can directly invade the brain parenchyma and cause cerebritis or focal abscess.
• Of CNS infections, ~10% are macroscopic abscesses, which are sometimes misdiagnosed as tumors.
• Brainstem invasion can cause severe rhombencephalitis, with asymmetric cranial nerve defects, cerebellar signs, and hemiparetic/hemisensory defects.
– Infection in pregnant women and neonates: Listeriosis is a serious infection in pregnancy.
• Pregnant women are usually bacteremic and present with a nonspecific febrile illness that includes myalgias/arthralgias, backache, and headache; CNS involvement is rare. Infected women usually do well after delivery.
• Infection develops in 70–90% of fetuses from infected women; almost 50% of infected fetuses die. This risk can be reduced with prepartum treatment.
• Overwhelming listerial fetal infection—granulomatosis infantiseptica—is characterized by miliary microabscesses and granulomas, most often in the skin, liver, and spleen.
• Late-onset neonatal disease develops ~10–30 days after delivery by mothers with asymptomatic infection.
• Diagnosis Timely diagnosis requires that the illness be considered in groups at risk: pregnant women, elderly pts, neonates, immunocom-promised pts, and pts with chronic underlying medical conditions (e.g., alcoholism, diabetes).
– Listeriosis is diagnosed when the organism is cultured from a usually sterile site, such as blood, CSF, or amniotic fluid.
– Listeriae may be confused with “diphtheroids” or pneumococci in gram-stained CSF or may be gram-variable and confused with Haemophilus spp.
– Serologic tests and PCR assays are not clinically useful at present.
TREATMENT Listerial Infections
• Ampicillin (2 g IV q4h) is the drug of choice for the treatment of listerial infections; penicillin is also highly active.
– Most experts recommend gentamicin (1.0–1.7 mg/kg IV q8h) for synergy.
– For penicillin-allergic pts, trimethoprim-sulfamethoxazole (15–20 mg of TMP/kg IV daily in divided doses q6–8h) should be given. Cephalosporins are not effective.
– Neonates should receive ampicillin and gentamicin, dosed by weight.
• The duration of therapy depends on the syndrome: 2 weeks for bacteremia, 3 weeks for meningitis, 6–8 weeks for brain abscess/encephalitis, and 4–6 weeks for endocarditis. Early-onset neonatal disease can be severe and requires >2 weeks of treatment.
• Prognosis With prompt therapy, many pts recover fully.
– However, permanent neurologic sequelae are common in pts with brain abscess or rhombencephalitis.
– Of live-born treated neonates in one series, 60% recovered fully, 24% died, and 13% were left with neurologic or other complications.
• Prevention Pregnant women and other persons at risk for listeriosis should avoid soft cheeses and should avoid or thoroughly reheat ready-to-eat and delicatessen foods, even though the absolute risk posed by these foods is relatively low.
For a more detailed discussion, see Pollard AJ: Meningococcal Infections, Chap. 143, p. 1211; and Hohmann EL, Portnoy DA: Listeria monocytogenes Infections, Chap. 139, p. 1194, in HPIM-18.