Educational Objectives

The goals of this program are  to improve the prevention of infectious diseases by use of vaccines and the manage­ment of methicillin-resistant Staphylococcus aureus (MRSA) infections. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe risk factors and give immunization recommendations for infectious diseases ranging from human papillomavirus to influenza.

2.   Assess the need for immunizations in individual health care providers.

3.   Explain the molecular mechanisms behind treatment resistance in Staphylcoccus aureus.

4.   Distinguish resistance patterns of hospital-acquired MRSA from those of community-acquired MRSA.

5.   Manage MRSA infections of varying severity using the appropriate antibiotics and strategies.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee re­ported nothing to disclose. In his lecture, Dr. Kroger presents information that is related to off-label or investigational use of a therapy, product, or device. The planning committee reported nothing to disclose.

Acknowledgments

Dr. Kroger was recorded at the 32nd Annual Eastern Shore Medical Symposium, held June 22-26, 2009, in Rehoboth Beach, DE, and jointly sponsored by Jefferson Medical College, Philadelphia, PA, and the University of Delaware. Dr. Cinti was re­corded at 27th Advances in the Management of Infectious Diseases: Winter Update, presented March 5-7, 2009, on Captiva Is­land, FL, by the University of Michigan Medical School. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Infectious Diseases: Update on Prevention and Management

Adult Immunization 2009

Andrew T. Kroger, MD, MPH, Medical Officer, Education, Information, and Partnership Branch, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC), At­lanta, GA

Human Papillomavirus (HPV)

Overview: causal agent of cervical cancer; >100 HPV types  —  60 cause cutaneous warts in hands and feet; 40 con­sidered mucosal (cause genital infection); 20 of 40 mucosal high-risk  —  type 16 and 18 most common and respon­sible for low/high grade cervical abnormalities (precursor to cervical and other anogenital cancers); 20 of 40 low-risk (type 6, 11)  —  responsible for low-grade cervical abnormalities, 90% of genital warts, and recurrent respiratory papillomas in larynx; HPV prevalence  —  20 million people infected; incidence  —  6.2 million infections annually; 50% of sexually active people acquire genital HPV infection (occurs soon after sexual debut); infection most com­mon at transformation zone (more exposed in immature cervix)

Vaccine: inactivated; recommend 3 doses (0, 2, and 6 mo); studies  —  show 100% efficacy when given before sexual debut (efficacy lower in exposed individuals); disease can occur after vaccination of people already infected with virus; dosing intervals  —  4 wk between doses 1 and 2; 12-wk interval between dose 2 and 3 (minimum); no maxi­mum interval; document histories; can be administered with other age-appropriate vaccines; compressed schedule  —  16-wk interval  between dose 1 and 3; no data to support efficacy; prefer 24-wk interval minimum; <16-wk interval  —dose considered invalid; catch-up schedule  —  combined with other childhood immunizations; HPV vaccine series started at <27 yr of age should be completed; vaccine (eg, Gardasil)  —  for types 16, 18, 6, and 11 (cause 70% of cervical cancers); administer to infected patients to cover remaining strains

Pertussis

Adult tetanus-diphtheria-acellular-pertussis (Tdap) vaccine: 1-time dose in all age groups for which vaccine li­censed; lacking efficacy data on patients >64 yr of age; 1-time dose replaces dose of tetanus and diphtheria (Td) vaccine; indicated as booster following primary series of pertussis-containing vaccine; lack record of infant diph­theria, tetanus, and pertussis disease (DTaP) vaccine  —  recommend full primary series of tetanus toxoid-contain­ing vaccine (2 Td and 1 Tdap); Tdap as booster dose  —  administer at 10-yr interval from last tetanus toxoid-containing vaccine dose in adults; for adolescents, 5 yr from last dose; overly frequent administration of vaccine can lead to local reaction (minor); split doses  —  cause increase in local Arthus reaction; not recommended; 2-yr in­terval considered safe

Pertussis: can be fatal in infants; mortality study (2004-2006)  —84% of deaths occurred at <3 mo of age; individuals at risk for acquiring and transmitting pertussis to infants should receive Tdap dose as soon as possible (no need to wait interval from previous dose of Td vaccine); higher-risk individuals  —clinicians, people involved in pertussis outbreak, people living with infants, and women in postpartum period

Tdap in pregnancy: CDC recommends deferring dose in pregnancy; American Academy of Pediatrics (AAP) rec­ommendation differs from that of CDC and Advisory Committee on Immunization Practices (ACIP); recommend deferral  —  risk for pertussis considered same for pregnant and nonpregnant women; concern about unknown effect of maternal Tdap on fetal immune system; 1949 study  —  infants born to mothers who received tetanus toxoid-con­taining vaccine in pregnancy had decreased response to first dose of DTaP vaccine; infants recovered with second dose;  Tdap not contraindicated in pregnancy, but because of these data, CDC recommends deferral of vaccine in pregnancy; Td necessary if pregnant woman wounded

Influenza Season (2009-2010)

Overview: 15% to 20% people infected annually; highest risk  — ³50 yr of age; ³65 yr of age at highest risk for com­plications, including death; infants 0 to 2 yr of age  —  hospitalization rates equal to those of elderly; recommenda­tions (19 to 49 yr of age)  —  include patients with chronic heart disease, chronic lung disease, diabetes, residents of nursing homes, household contacts of those at high risk, and health care workers

Seasonal vaccine: 2 types (type A and B); of type A, 2 subtypes (H1N1 and H3N2) in this year's vaccines; inacti­vated subunit  —  intramuscular (IM); trivalent; split virus (not whole; cannot cause disease); 2 wk for vaccine to take effect; duration of immunity £1 yr; live attenuated vaccine  —  intranasal spray; trivalent; same 3 strains; dura­tion of immunity £1 yr; 1 dose per season for patients ³9 yr of age; novel H1N1 influenza (swine flu)  —  late-season increase in number of specimens; vaccine in clinical trials; emphasize preventive measures (eg, cover cough, hand hygiene, social distancing, antivirals)

Pneumococcal Disease

Risk factors and recommendations: goal  —  prevent invasive disease (eg, bacteremia, meningitis); highest risk  —  age ³65 yr; other risk factors  —  asthma; cigarette smoking; persons  ³2 yr with anatomic or functional asplenia, HIV infection, environments or settings with increased risk (eg, day care centers); if risk factor present  —  recommend 1 dose of vaccine for adult; adult <65 yr of age with specific risk factor (eg, immunocompromised, chronic renal disease)  —  second dose  5 yr later; all others at younger ages  —  1 dose;  second dose at 65 yr of age

Vaccine Recommendations for Health Care Providers (HCPs)

Hepatitis B: for vaccinated HCPs  —  no serologic test required before entry into health care system; vaccinated, un­tested, antibody to hepatitis B surface antigen (HBsAg)-negative HCPs  —assume person failed to respond to first series, administer second series and test after sixth dose, or give 1 dose and test after 4 to 6 wk; if antibody test pos­itive, stop; if negative, complete second series and test again (1-2 mo after last dose); persistent nonresponse to vaccine  —  <5% of vaccinated do not develop anti-HBsAg after 6 doses (called "hyporesponders"); check antigen status (may be positive); if later exposed, treat as nonresponder with postexposure prophylaxis; certain situations warrant repeat testing in (eg, immunocompromised, dialysis)

Measles-mumps-rubella (MMR): recommended for all adults born after 1956; for some HCPs (born 1956 or ear­lier); ACIP may recommend for all HCPs who cannot provide documentation; recommend facilities "strongly con­sider" HCPs born before 1957 receive 1 dose of MMR vaccine; 2006 mumps outbreak on college campuses  —  8% of cases occurred in health care settings; recommendation for all HCPs involved in outbreak to receive second dose

Varicella: challenging to determine susceptibility vs immunity; dosing schedule  —  2 doses (12 mo and 4-6 yr of age); recommended for susceptible adults (1-mo interval); criteria for immunity  —documentation of age-appropriate vac­cination, laboratory evidence of immunity or confirmation of disease; born in United States before 1980; HCP di­agnosis of varicella or zoster; HCPs  —  if born before 1980, vaccine still recommended (if no other criteria met); hemorrhagic varicella (and other conditions)  —  can reach 30% in population of immunocompromised patients

Herpes zoster:  localized and unilateral; associated with aging and anything that reduces immunocompetence; life­time risk 30%; complications  —  postherpetic neuralgia; pain that lasts after rash clears ( £1 yr) and occurs in 20% of shingles cases; vaccine  —  live vaccine; indicated for prevention of zoster and postherpetic neuralgia; recom­mended for patients ³60 yr of age; indicated for persons with current varicella immunity based on disease; not spe­cifically recommended for patients who received varicella vaccine; history of zoster not considered; 1 dose, 0.6 mL subcutaneous injection; use of zoster vaccine  —  assume all patients ³ 60 yr of age had chickenpox disease (vari­cella; no need to screen); for HCPs  —  testing helpful in some circumstances; tests effective for detecting immunity (not cell-mediated) based on past disease

Community-Acquired Methicillin-Resistant Staphylococcus Aureus (CA-MRSA)

Sandro K. Cinti, MD, Associate Professor, Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, and Staff, University of Michigan Hospitals and Health Centers and Veterans Affairs Health System, Ann Arbor

Rates of infection: increased rate of skin and soft tissue infections since 1997 (strong association with CA-MRSA); Gonzales Pediatrics 2005  —  14 children with Staphylococcus aureus sepsis (2002-2004); 13 of 14 bacteremic; no vegetations; 11 of 14 required intubation; 3 children (previously healthy) died; 8 with blunt trauma; 12 had CA-MRSA and Panton-Valentine leukocidin (PVL; gene may be associated with increased virulence)

Epidemiology: S aureus often sequela of influenza; 64% of pediatric S aureus-associated influenza deaths MRSA; MRSA  —at Texas Childrens hospital, 76% of S aureus infections acquired in community (51% in San Francisco; 4%-50% in Minnesota); clusters  —  55% to 80% methicillin resistance in S aureus infections; common in sports teams (eg, football, wrestling); predisposition among American Indians; college football team 2005  —  10% of team (6 linemen) developed CA-MRSA; 7 of 11 had abscesses or boils; MRSA associated with more abscess formation and eschar than other cellulitis; strong association with lifestyle (eg, shared towels, soap, living space); MRSA in­fections often recur

Resistance mechanisms: penicillin  —  hospital acquired (HA) resistance to penicillin occurred in <10 yr (took longer in community); methicillin  —  resistance almost immediate, due to mecA gene; mecA gene  —  encodes penicillin-binding protein with decreased affinity for b-lactams; mobile genetic element (can be transferred); CA strains resis­tant to macrolides and clindamycin

MRSA overview: 1970s  —  increase in hospitals; late 1990s  —peak in community cases; hospital and community strains differ; disease burden of HA  —  >125,000 cases of MRSA infection per year in United States; increased mor­tality (relative risk 2.15); attributable mortality of MRSA infection  —  7.5%; 9500 deaths annually from HA form); median increase in length of stay after infection »8 days); costs  —  median $2488 per patient; $314 million annually

Vancomycin-resistant S aureus (VRSA): few strains and cases; continues to circulate and periodically appears; re­sistance mechanism  —  vanA gene encodes ligase that synthesizes D-ala-D-lac instead of D-ala-D-ala; conjugate transfer of vanA gene from vancomycin-resistant enterococci (VRE) to MRSA to produce VRSA; antibiotics  —  linezolid, daptomycin; overused; starting to see resistance

Nosocomial MRSA: usually associated with antibiotic use; causes  —  intravenous (IV) catheter or surgical site infec­tion; ventilator-associated pneumonias; often resistant to other antibiotics

CA-MRSA overview: CDC definition  —  positive MRSA culture (in outpatient or within 48 hr of admission); no pre­vious history of MRSA; no history of surgery or admission to hospital, nursing home, or dialysis unit within past year, no indwelling catheters or devices; source  —  organism obtained small cassette from unknown source; ap­peared simultaneously on several continents; all isolates have SCCmec type IV cassette (HA form has types I, II, and III) and PVL gene which may cause selective advantage; HA- vs CA- MRSA  —  HA strains resistant to multiple antibiotics; CA strains sensitive to trimethoprim-sulfamethoxazole (TMP-SMZ; eg, Bactrim) clindamycin, doxycy­cline and fluoroquinolones; some CA strains resistant to erythromycin; clinical characteristics  —  77% have skin and soft tissue infections (eg, abscesses, cellulitis); 6% invasive (eg, bacteremia, septic arthritis, osteomyelitis); 2% cause pneumonia; necrotizing fasciitis; underlying conditions include IV drug use, previous infection, diabetes, and HIV infection; spider bites  —  brown recluse spider causes large necrotic lesions similar to CA-MRSA presentation

Virulence of CA-MRSA vs CA methicillin-susceptible S aureus (MSSA): MSSA  —  possibly becoming more viru­lent (due to PVL gene); study of United States army soldiers  —  38% colonized with MRSA developed soft tissue infections (vs 3% with MSSA); PVL gene present in 67% of CA-MRSA isolates (including all wound isolates)

PVL toxin: causes lysis of neutrophils and monocytes; associated with more severe complications, eg, necrotizing pneumonias; higher recurrence rate with PVL; associated with community outbreaks; present in CA-MRSA (strains USA400, USA300); not typically found in CA-MSSA strains; PVL and pulmonary disease (PD)  —  CA-MRSA more likely associated with PD than CA-MSSA; PVL gene-positive S aureus more often associated with PD than PVL gene-negative S aureus (65% vs 9%); more easily transmitted to close contacts; exact mechanisms of increased virulence not known; PVL not present in strains that cause  —  HA pneumonia, endocarditis, sternal wound infections, urinary tract infections, toxic shock syndrome, superficial folliculitis, and impetigo

Risk factors for CA-MRSA: history of MRSA infection or colonization in patient or close contact; increased preva­lence in local community or patient population; recurrent skin disease; crowded living conditions (eg, military bar­racks, homeless shelters); history of incarceration; participation in contact sports; skin or soft tissue infection with poor response to b-lactam antibiotics; recent and/or frequent antibiotic use; injection drug use; American Indians and Pacific Islanders, urban pediatric populations, and homosexual men; 2 to 3 antibiotics within 1 yr  —  odds ratio (OR) 2.46; >4 antibiotics  —  OR 6.24; highest risk  —  use of quinolones and macrolides

Managing MRSA

Disease severity: mild  —  incision and drainage alone may be sufficient; for afebrile, previously healthy person, can give TMP-SMZ, clindamycin, or doxycycline; moderate  —  if febrile but previously healthy, consider hospitaliza­tion and treatment with vancomycin (in patients who look ill); empiric therapy includes vancomycin (can also use TMP-SMZ or clindamycin); avoid doxycycline in more severe cases; avoid linezolid as first-line therapy; adjust therapy based on culture an