Hospital Infection Control

Gram negative bacteria - Neisseria meningitides

What are the key principles of preventing gram negative bacteria - Neisseria meningitides?

Occupational exposure

  • Occupationally acquire meningococcal disease outside of the laboratory is rarely reported, perhaps in part because of rapid use of PEP.

  • To decrease the risk for infectious disease transmission to health-care personnel, the Healthcare Infection Control Practices Advisory Committee recommends use of empiric infection-control precautions based on the patient's apparent clinical syndrome when the diagnosis is unknown and recommendsuse of droplet precautions (surgical masks) for contact with patients with suspected or confirmed menigococcal disease

  • Respiratory isolation (droplet precaution) of the patient is recommended for 24 hours after starting chemotherapy

  • Meningococcal disease is a nationally notifiable disease

  • Health-care facilities should review their local health authority reporting procedures to ensure timely reporting of notifiable disease, such as N. meningitidis, and employers should provide infection-control training and Post Exposure Prophylaxis (PEP) to potentially exposed workers. Employers also should conduct timely and thorough investigations to identify and evaluate workers potentially exposed to a patient suspected to have meningococcal disease

  • Case information should be reported to CDC through the National Notifiable Diseases Surveillance System (NNDSS), through the National Electronic Telecommunications System for Surveillance (NETSS), or the National Electronic Disease Surveillance System (NEDSS) within 14 days of the initial report to the state or local health department

  • Employers should provide adequate infection-control training to staff member, PEP to exposed workers, and report notifiable disease promptly.

Carriage

  • N. meningitidis colonizes mucosal surfaces of nasopharynx and is transmitted through direct contact with large droplet respiratory secretions from the patients or asymptomatic carriers. At any time, 5%-10 % of the population can be carriers of N. meningitidis, but some strains are more virulent than others.

  • Humans are the only natural reservoir. The Neisseria meningitidis organisms are gram negative, aerobic diplococcic that can attach to the surface of mucosal cells of the nasopharynx.

  • Colonization may be transient, intermittent, or long-term, and the prevalence may increase in the presence of conditions such as concomitant upper respiratory infection, crowded living conditions, and smoking.

  • Colonization induces an immunologic response to N. meningitidis so that by young adulthood the majority of people in the United States have measurable antibody to the pathogenic serogroups of N. meningitids (A, B, C, Y, and W-135)

What are the conclusions of clinical trials and meta-analyses regarding gram negative bacteria - Neisseria meningitides?

Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis in older children and young adults in the United States.

Antimicrobial chemoprophylaxis of close contacts of persons who have sporadic meningococcal disease is the primary means for prevention of meningococcal disease in the United States. Secondary cases are rare as a result of effective chemoprophylaxis.

Risk of secondary disease among close contacts is highest during the first few days after the onset of disease, which requires that chemoprophylaxis be administered as soon as possible. If given more than 14 days after the onset of disease, chemoprophylaxis is probably of limited or no benefit. Oropharyngeal cultures are not useful in determining the need for chemoprophylaxis and may unnecessarily delay the use of effective preventive measures.

High Risk: Chemoprophylaxis Recommended

  1. Household member

  2. Child-care center contacts or nursery school during 7 days before onset of illness

  3. Direct exposure to index patient's secretions(e.g., through kissing or through sharing tooth brushing or eating utensils,

  4. Mouth to mouth resuscitation, unprotected contact during endotracheal intubation, or endotracheal tube management during 7 days before onset of illness

  5. Frequently slept or ate in the same dwelling as index patient during 7 days before onset of illness

  6. For travelers, antimicrobial chemoprophyalaxis should be considered for any passenger who had direct contact with respiratory secretions from an index-patient or for anyone seated directly next to an index-patient on a prolonged flight (i.e., one lasting >8 hours

Low risk: chemoprophylaxis not recommended

  1. Casual contact: no history or direct exposure to index patient's oral secretions

  2. Indirect contact: only contact with a high risk contact, no direct contact with the index patient

  3. Health care professionals without direct exposure to patient's oral secretions

Table I summarizes recommended chemoprophylaxis regimens for high-risk individuals.

Table I.

Recommended chemoprophylaxis regimens for high-risk contacts and persons with invasive meningococcal disease
Drug Efficacy Side Effects Resistance Dose Comments
Rifampin 75-90 % Colored secretionsInteractions with BCP decreased to 25 %, anticoagulation, anti-seizure medications 10 % 300mg PO BID X 2 Days Contraindicated in pregnancy
Ceftriaxone 97% Pain at the injection site (dilute with 1 % lidocaine) none reported <15 ys old: 125 mgif >15 ys 250 mg IM Safe in pregnancy and children
Ciprofloxacin 93 % none reported none reported 500 mg PO x 1 Contraindicated in childrenContraindicated in pregnancy
Azithromycin [43] 93 % 33 % vertigo none reported 500mg PO x 1 Approved for children

There are 2 meningococcal vaccines licensed in the United States for use in children and adult against serotyes A,C,Y, and W 135, the MCV4 and the MPSV4

For group B, polysaccharide vaccines are not yet developed, due to antigenic mimicry with polysaccaride in human neurologic tissues. No vaccine is available for group B in the United States. There is an outer membrane protein vaccine available in some countries, but research studies concluded that, although the vaccine conferred protection against group B meningococcal disease, the effect was insufficient to justify a public vaccination program

The MPSV4

  • The MPSV4 is a polysaccharide vaccine that was licensed in 1981 for use in children 2 years of age or older and has been recommended by the American Academy of Pediatrics for use only for people at increased risk of meningococcal disease.

  • The MPSV4 is administered subcutaneously as a single 0.5 mL dose and can be given concurrently with other vaccines but at different anatomic sites.

  • Usefulness of the polysaccharide vaccine is limited because it does not confer long lasting immunity and does not cause a sustainable reduction of nasopharyngeal carriage of N. meningitidis, and therefore does not interrupt transmission sufficiently to elicit herd immunity.

The MCV4

  • The MCV4 was licensed since 2005 for use in children 11 years of age to 55 years of age

  • Conjugating polysaccharide to a protein carrier that contains T-cell epitopes response at re-exposure, a substantial primary response in infants, and possibly in reduction in the frequency of N. meningitids carriage, protecting unvaccinated persons through herd immunity.

This can also be given concurrently with other recommended vaccines. This is administered intramuscularly as a single 0.5 ML dose.

Routine vaccination of children 2 to 10 years of age is not recommended.

The Advisory Committee on Immunization Practices (ACIP) has made the following recommendations on vaccination with MCV4 and MPSV4

  • The ACIP recommends vaccination for children aged 2 to years who are at increased risk for meningococcal disease

  • Use of MCV4 is preferred among persons aged 11 to 55 years. If MCV4 is unavailable, MPSV4 is an acceptable alternative.

  • As of June of 2001, a total of 37 states had adopted a legislation requiring colleges to provide information on risks of meningococcal diseases either to matriculating students or to students residing on campus and 16 states had mandated vaccination for certain students, unless a vaccination waiver is provided

The following populations are at risk for meningococcal disease:

  • College freshmen living in dormitories;

  • Microbiologists who are routinely exposed to N. meningitidis;

  • Military recruits;

  • Persons who travel to or reside in countries in which N. meningitidisis hyperendemic or epidemic;

  • Persons who have terminal complement component deficiencies; and persons who have functional or anatomic asplenia.

  • Individuals who have HIV type 1 infection are likely at increased risk for meningococcal infection, and vaccination should be considered in this group.

Vaccination is not recommended for those older than 55 years who are not identified as being at risk for meningococcal disease.

Table II summarizes menigococcal conjugate vaccine recommendations.

Table II.

Summary of meningococcal conjugate vaccine recommendations, by risk group Advisory Committee on Immunization Practices (ACIP) 2010
Risk group Primary series Booster dose
Age 11-18 ys 1 dose preferably at age 11 or 12 ys At age 16 ys if primary dose at age 11 or 12 ys
At age 16 through 18 years if primary dose at age 13 through 15 years
No booster needed if primary dose on or after age 16
HIV infected persons 2 doses, 2 months apart At age 16 years if primary dose at age 11 or 12 years
At age 16 through 18 years if primary dose at age 13 through 15 years
No booster needed if primary dose on or after age 16 years
Persons aged 2 through 55 years withComplement deficiency of functional or anatomical asplenia++ 2 doses, 2 months apart Every 5 years
At the earliest opportunity if a 1- dose primary series administered, then every 5 years
Persons aged 2 through 55 years with prolonged increase risk of exposure+ 1 dose Persons aged 2 through 6 years: after 3 years
Persons aged 7 years or older: after 5 years*

Caution

There have been reported cases of Guillain-Barre within 2-5 weeks after receipt of the conjugate vaccine. The overall rate appears to be within the expected background incidence of Guillain-Barre syndrome (1 to 2 cases per 100,000 population), but the timing is of concern and has prompted a warning included in the package insert of the MCV4 vaccine (Menactra)

The FDA and the CDC consider evidence insufficient to establish a casual association or warrant a change in the vaccine recommendations at this time.

However, the syndrome does not appear to able a concern in relation to the polysaccharide vaccine and some physicians may prefer to use polysaccharide vaccine when options exists

Identification of an outbreak

An outbreak of meingococcal disease is a public health crisis that calls for a rapid, coordinated public health response.

Changes that suggest an outbreak is evolving include:

  • Clustering of cases within an age or social group;

  • Shift in disease from children under five years to older children and adolescents;

  • Phenotypic and genetic similarity among the strains causing disease.

For a primary attack rate to be calculated, all confirmed cases of the same serogroup should be summed; secondary cases should be excluded and each set of co-primary cases counted as one case. Because attack rates are calculated both to characterize the risk for disease among the general population and to determine whether overall rates have increased, related cases (secondary and co-primary) should not be included. From an epidemiologic perspective, secondary and co-primary cases can be considered as representing single epidose of disease with direct spread to one or more close contact(s),which is consistent with endemic disease

If three or more cases have occurred in either an organization or a community-based outbreak during <3 months (starting at the time of the first confirmed or probable case), a primary attack rate should be calculated. Because of the limited number of cases typically involved and the seasonal patterns of meningococcal disease (more cases occur during fall than other times of the year), rate calculations should not be annualized. The following formula is used to calculate attack rates:

Attack rate per 100,000 = [(number of primary confirmed or probable cases during a 3-month period)/ (number of population at risk )] x 100,000.

Genotyping date can allow identification of an outbreak strain and help to better define the extent of the outbreak. If strains from a group of patients are unrelated by genotyping, the group of cases most likely does not represent an outbreak. Because molecular subtyping testing might not be readily available or accessible, initiation of outbreak control efforts should not be delayed until genotyping results are available.

What are the consequences of ignoring gram negative bacteria - Neisseria meningitides?

Each year, an estimated 2,400-3,000 case of meningococcal disease occurs in the United States, a rate of 0.8-1.3/100,000 population.

N. meningitidis is one of the leading causes of bacteremic meningitis in the United States.

Despite the continued antibiotic susceptibility of meningococcus to multiple widely available antibiotics, including penicillin, the case-fatality ratio for meningococcal disease is 10%-14%.

Neisseria meningitidis can be classified into 13 serogroups based on the immunologic reactivity of their capsular polysaccharides. Serogroups B, C and Y each cause approximately one third of meningococcal disease cases in the United States. The proportion of cases caused by each serogroup varies by age; serogroup B causes over 50 % of cases in infants younger than 1 year of age, while segrogroups C,Y, and W135 cause 75 % of meningococcal disease in those 11 years and older.

In the United States, >98 % of cases of meningococcal disease are sporadic; however, since 1991, the frequency of localized outbreaks has increased.

Type A is the most common cause within the meningitis belt of Sub-Saharan Africa (a region of savanna that extends from Ethiopia in the east to Senegal in the west), accounting for an estimated 80-85 % of all cases. This disease frequently occurs in epidemics during the hot and dry weather (December to March).

Persons who have deficiencies in the terminal common complement pathway (C3, C5-C9) and those with asplenia are at increased for acquiring meningococcal disease. Antecedent viral infection, household crowding, chronic underlying illness, and both active and passive smoking also are associated with increased risk for meningococcal disease.

During outbreaks, bar or nightclub patronage and alcohol use also have been associated with higher risk for meningococcal disease.

Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis. Several factors make meningococcal disease a matter of public health importance. First it is a communicable disease associated with notable morbidity and mortality. Second, isolated meningococcal cases and outbreaks often causes serious medical and social stress in communities and are associated with increased costs, both economic and social. Finally, each case of meningococcal disease requires a public health response.

Breaches in infection control, notification delays, and lack of worker exposure assessment and post exposure chemoprophylaxis (PEP) can contribute to secondary cases.

Employers should provide adequate infection-control training to staff member, PEP to exposed workers, and report notifiable disease promptly.

What other information supports the conclusions of studies on gram negative bacteria - Neisseria meningitides, e.g., case-control studies and case series?

A prospective surveillance study with nested case control study of US college students with meningococcal infection from September 1, 1998, to August 31, 1999 showed that freshmen living in dormitories had the highest incidence rate at 5.1 per 100,000 compared to 1.4 per 100,000 for the general population. Of the 79-case patients for whom information was available, 54 (68%) had illness due to vaccine-preventable meningococcal serogroups supporting the data from the Advisory Committee on Immunization Practices (ACIP).

A large retrospective study was performed to summarize the evidence for the role of antibiotics in preventing further cases of meningococcal disease through chemoprophylaxis given to the index patient, household contacts and children in day care settings after a single case. The main outcome was to measure subsequent cases of meningococcal disease 1-30 days after onset of disease in the index patient. The conclusion was that the risk of meningococcal disease in household contacts could be reduced by an estimated 89 % if they take antibiotics known to eradicate meningococcal carriage. Chemoprophylaxis should be recommended for the index patient and all household contacts.

Summary of current controversies.

Nasopharyngeal carriage

There are no recommendations for eradicating nasopharyngeal carriage in the community outside of an outbreak or a patient with invasive meningococcal disease. There are three problems with attempting to eliminate nasopharyngeal carriage in the community:

  • Spontaneous loss and acquisition of carriage is common. This was illustrated in a study in military recruits in which 34% experienced one or more change in carrier status over time

  • Recurrent colonization may occur after prophylaxis. In a community-wide prophylaxis program in a semi-closed kibbutz population in Israel, the colonization rate of group B meningococcus dropped from 4.6% at baseline to 0% at 3 weeks; it then rose to 0/5% at 6 months and 3.9% (similar to the baseline level) at one year

  • Antimicrobial prophylaxis has no proven clinical efficacy outside of an outbreak. The meta-analysis cited above included trials in healthy carries. Clinical efficacy of eradication could not be assessed since there were no cases of disease following antibiotics or placebo

Some national policies also recommended chemoprophylaxis to the index patient before discharge from hospital, on the premise that the pathogenic strain may otherwise be reintroduced by the index patient into the household. However, contradictory findings regarding carriage of the pathogenic meningococcal strain after full antibiotic treatment of the index patient are reflected in different recommendations. For example, policy in Denmark, Norway, and Sweden does not recommend prophylaxis for the index patient, whereas it is recommended in the United Kingdom, Canada, the United States, Spain and Germany.

In the United States, chemoprophylaxis is recommended to the index patient if systemic antimicrobial therapy of meningococcal disease with agents other than ceftriaxone or other third-generation cephalosporins were used given that it might not reliably eradicate nasopharyngeal carriage of N. meningitidis.

Mass chemoprophylaxis

Despite heavy community pressure to "do something" immediately in response to a death from meningococcal disease, mass chemoprophylaxis in those who have not been in close contact with an infected persons is unwarranted and is not recommended.

Administration of antibiotics to substantial populations is not recommended to control large outbreaks of disease.

Disadvantages of mass chemoprophylaxis include cost of the drug and administration, difficulty of ensuring simultaneous administration of drugs to substantial populations, drug side effects, and emergence of resistant organisms. In addition, multiple sources and prolonged risk for exposure make this approach impractical and unlikely to succeed. In the majority of outbreak settings, these disadvantages outweigh the possible benefit in disease prevention. However, in outbreaks involving limited populations (e.g., an outbreak in a single school), administration of chemoprophylaxis might be considered, especially in serogroup B outbreaks, for which available vaccines are not effective. When making a decision about initiating mass chemoprophylaxis in these settings, public health officials should consider not only the potential for prevention of new cases but also the logistics, cost, and potential for developing antimicrobial resistance.

However, in limited settings (e.g., a single school) in which cases of infection continue to occur, broad chemoprophylaxis may be considered. In such settings, all targeted persons should receive chemoprophylaxis at the same time in order to avoid "ping-pong" reinfection.

Source control

In the United States, measures that have not been recommended for control of meningococcal disease outbreaks include restricting travel to areas with an outbreak, closing schools or universities, or canceling sporting or social events.

What is the impact of gram negative bacteria - Neisseria meningitides and the need for control, relative to infections at other sites or from other specific pathogens?

Invasive infections caused by Neisseria meningitis are a serious public health problem worldwide and have a heavy economic impact. The incidence of invasive disease due to Neisseria meningitids is highly variable according to geographical area and serogroup distribution.

The occurrence of a death form meningococcal disease is devastating to the family and the community of the person who died and elicits a strong demand for preventive measure from clinicians and the public health sector.

Preventive strategies include antimicrobial chemophrohylaxis for close contacts of patients with invasive meningococcal disease, and in certain circumstances, immunization of the community with meningococcal vaccine.

Summary of research relevant to gram negative bacteria - Neisseria meningitides.

See Table III.

Table III.

Summary of research relevant to gram negative bacteria - Neisseria meningitides
Study Intervention/Evaluation Findings
    Bruce MG.JAMA August, 2001     Risk Factors for Meningococcal Disease in College Students Freshmen who live in dormitories have an independent, elevated risk of meningococcal disease compared with other college students. Use of the currently available quadrivalent polysaccharide vaccine among college students could substantially decrease their risk of meningococcal disease.
Zalmanovici Trestioreanu A, August 2010 Antibiotics for preventing meningococcal infectionsProphylaxis to close contacts of index patients Included 24 studies; 19 including 2531 randomized participants and five including 4354 cluster-randomized participants.Conclusions: using Rifampin during an outbreak may lead to the circulation of resistant isolates. Use of ciprofloxacin, ceftriaxone, or penicillin should be considered.
    Cohn AC,Clin Inf Dise     Changes in Neisseria meningitidis disease epidemiology in the United States, 1998-2007: implications for prevention of meningococcal disease The annual incidence decreased 64.1 % , from 0.92 cases per 100,000 population in 1998 to 0.33 cases per 100,000 in 2007 after the introduction of the MCV4 vaccine.
    Sudeep KarveHealth Outcomes in Research Medicine     Costs of Sequelae Associated with Invasive Meningococcal Disease: Findings from a US Managed Care Population Predicted health care costs among patients with complicated IMD were 3 times higher compared with patients with uncomplicated IMD that should be considered when economic evaluations of meningococcal vaccination programs are made
    Iser BP, PubMedAugust 2011     Outbreak of Neisseria meningitidis C in workers at a large food processing plant in Brazil: challenges of controlling disease spread to the larger community In 8 out of 16 MD cases studied, serogroup C ST 103 complex was identified. Five (31%) cases had neurological findings and five (31%) died. Mass vaccination stopped propagation in the plant but not in the larger community
CDCMMWR Morb MortWkly RepFeb, 2008     Emergence of fluoroquinolone-resistant Neisseria Meningitidis- Minnesota and North Dakota, 2007-2008 There were a cluster of three cases of fluorquinolone-resistant meningococcal disease first time reported in the US in the border area of North Dakota and Minnesota during January 2007-January 2008. Recommendations were made by the CDC that ciprofloxacin should not be used for chemoprophylaxis in that region.
CDCMob & Mortality Wkly Report (MMWR) Occupational Transmission of Neisseira meningitidis, California, 2009 Case report of an index patient followed by two secondary cases of meningococal disease that occurred after breaches in infection control, notification delays, and lack of worker exposure assessment and post-exposure prophylaxis
Christensen H;Lancet Infect Dis 2010 Meningococcal carriage by age: a systematic review and meta-analysis. Carriage prevalence increased through childhood from 4-5 % in infants to peak of 23.7 % in 19 year old and subsequently decreased in adulthood to 7-8 % in 50 ys old.
    Brugdage JFClin Infec Dis. 2002     Meningococcal disease among United States military service members in relation to routine uses of vaccines with different serogrou-specific components, 1964-1998 In the US military, meningococcal disease rates decreased by approximately 94 % from 1984 to 1998. After the initiation of routine immunization in 1971 crude rates decreased sharply and have remained low.
Kristiansen BE,BMJ 1998 Which contacts of patients with meningococcal disease carry the pathogenic strain of Neisseria meningitidis Household contacts had an increased frequency of carriage of the pathogenic strain compared to less close contacts (12.4 vs 1.9%)
Brooks R,Clin Infec Dis2006 Increased case fatality rate associated with outbreaks of Neisseria meningitidis infection , compared with sporadic meningococcal disease in the United States , 1994-2002 Oubreaks remain an important but infrequent public health, representing <2 % of all cases of meningococcal disease. However, given the increased case-fatality rate found among outbreak-related cases of N. meningitidis infection, additional investigation of factors that favor the transmission and virulence of outbreak-related strains is warranted
PurcellBMJ, April,2004 Effectiveness of antibiotics in preventing meningococcal disease after a case: a systematic review The risk of meningococcal disease in household contacts of a patient can be reduced by an estimated 89% if they take antibiotics known to eradicate meningococcal carriage. Chemoprophylaxis should be recommended for the index patient and all household contacts.

Controversies in detail.

Many of the assumed advantages of the conjugate vaccine (long-term immunity, decreased nasopharyngeal carriage, and her immunity) are based on experience with other conjugated polysaccharide vaccines and require confirmation. Because 62 % of the cases of meningococcal disease in the United States occur in children younger than 11 years of age, a comprehensive approach to preventing meningococcal disease will need to address children younger than 11 years. Conjugated polysaccharide vaccines against H. influenza type b and certain pneumococcal serogroups have been shown to be effective in inducing the immunity in children as young as 6 months of age and in lessening the transmission of these pathogens to nonimmunized populations. Preliminary studies suggest that the conjugated meningococcal vaccines elicit protective immune responses in infants and young children.

However, the lack of an effective vaccine for serogroup B meningococcus (the cause of more than 50% of cases among infants and young children) limits the potential effect of immunization strategies in infants and young children. A theoretical concern is that a reduction in the transmission of certain serogroups not covered by the vaccine (especially serogroup B).

What national and international guidelines exist related to gram negative bacteria - Neisseria meningitides?

In the United States the Center for the Disease Control (CDC) works on the prevention and Control of Meningococcal Disease and follows the recommendations of the Advisory Committee on Immunization Practices (ACIP).

Neisseria meningitidis is a reportable disease; the Department of Health (DOH) contributes to prevent outbreaks in the community.

Internationally, the World Health Organization (WHO) regularly provides a technical support at the field level to countries facing epidemics.

Since 1999, a Europe-wide surveillance system, the European Union Invasive Bacterial Infection Surveillance (EU-IBIS) program (integrated into the activities of the European CDC[ECDC] since 2007) has coordinated and integrated surveillance in EU member states to develop a Europe-wide detailed picture of time trends in invasive disease.

What other consensus group statements exist and what do key leaders advise?

Large scale epidemics still occur with deadly frequency in Africa, parts of Asia, South America, and the countries of the former Soviet Union.

These epidemics are most commonly caused by N. meningitidis serogroup A and occasionally by serogroup C. The World Health Organization (WHO) has endorsed a surveillance strategy to predict epidemics early and initiate vaccination drives with a threshold of 15 cases per 100,000 averaged over two weeks.

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