Bacterial Sinusitis. Presenter Disclosure Information. Learning Objectives. Topics. Background. Infectious Diseases 2:30 3:30pm

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1 Infectious Diseases 2:30 3:30pm Infectious Disease Updates in Primary Care SPEAKER Neil Skolnik, MD Presenter Disclosure Infmation The following relationships exist related to this presentation: Neil Skolnik, MD, is consultant f and receives speaking/teaching honaria from AstraZeneca. He is also a consultant and receives speaking/teaching honaria f Purdue, and is a consultant f Boehringer Ingelheim and Succampo. Off-Label/Investigational Discussion In accdance with pmicme policy, faculty have been asked to disclose discussion of unlabeled unapproved use(s) of drugs devices during the course of their presentations. Topics Learning Objectives Sinusitis Genital herpes Testing f latent tuberculosis infection HIV and hypercholesterolemia MRSA decontamination Apply current clinical guidelines to the diagnosis and treatment of acute bacterial sinusitis Differentiate the diagnosis of latent tuberculosis infection from that of active tuberculosis Apply current evidence and guidelines to the clinical management of genital herpes Background Bacterial Sinusitis The excessive use of antibiotics in ambulaty practice has contributed to the emergence and spread of antibiotic-resistant bacteria. Proper selection of who and when to treat is imptant. Issues to balance: Patient discomft Patient expectations 1

2 Case 1 45-year-old man comes to the office with four days of nasal discharge and cough, requesting antibiotics f sinusitis. What criteria help you distinguish viral from bacterial sinus infections? Acute Bacterial Rhinosinusitis (ABRS): Diagnosis Based on Clinical Criteria Presence of one of the following : Persistent symptoms signs compatible with acute rhinosinusitis lasting f >10 days without any evidence of clinical improvement Onset with severe symptoms signs of high fever (>102 F) and purulent nasal discharge facial pain lasting f at least 3 4 consecutive days at the beginning of illness Onset with wsening symptoms signs characterized by new onset of fever, headache, increase in nasal discharge following a typical viral URI that lasted 5 6 days and were initially improving (ie, double-sickening ) URI = upper respiraty infection Chow AW, et al. IDSA Clinical Practice Guideline f Acute Bacterial Rhinosinusitis in Children and Adults. Clin Inf Dis. 2012;54(8):e ABRS Diagnosis - Conclusions Clinical diagnosis is best Little benefit of any imaging study in the diagnosis of acute sinusitis Reserve imaging studies f unusual severity recurrent chronic illness When imaging, CT Scan is the study of choice Is Imaging Helpful in Diagnosis of Sinusitis? Chow AW, et al. IDSA Clinical Practice Guideline f Acute Bacterial Rhinosinusitis in Children and Adults. Clin Inf Dis. 2012;54(8):e CT Scans of the Sinuses 31 patients with colds f hours 87% had abnmalities of maxillary sinus After two weeks, CT repeated in 14 patients 79% showed clearing marked improvement IDSA 2012 Recommendations f Treatment of ABRS Bacterial sinusitis should be treated Amoxicillin-clavulanate, rather than amoxicillin alone, is recommended as empiric antimicrobial therapy f ABRS in children and adults IDSA = Infectious Diseases Society of America Gwaltney JM, et al. N Engl J Med. 1994;330: Chow AW, et al. IDSA Clinical Practice Guideline f Acute Bacterial Rhinosinusitis in Children and Adults. Clin Inf Dis. 2012;54(8):e

3 High Dose Amoxicillin-Clavulanate Who Are the High-Risk Patients? 2 g ally twice daily 90 mg/kg/day ally twice daily Adults: 5-7 days Children: days Severe infection (e.g., evidence of systemic toxicity with fever of 39º C [102º F] higher) Threat of suppurative complications Attendance at daycare Recommended f children and adults with ABRS from geographic regions with high endemic rates (>10%) of invasive PNS S. pneumoniae* and high-risk individuals Age < 2 >65 years Recent hospitalization Antibiotic use within the past month * Penicillin-nonsusceptible Streptococcus pneumoniae Chow AW, et al. IDSA Clinical Practice Guideline f Acute Bacterial Rhinosinusitis in Children and Adults. Clin Inf Dis. 2012;54(8):e Chow AW, et al. IDSA Clinical Practice Guideline f Acute Bacterial Rhinosinusitis in Children and Adults. Clin Inf Dis. 2012;54(8):e Treatment f Patients with Penicillin Allergy Adults Doxycycline Respiraty fluoquinolone (levofloxacin moxifloxacin) Children Clindamycin plus third-generation cephalospin (cefixime cefpodoxime) Levofloxacin (if type I hypersensitivity) Chow AW, et al. IDSA Clinical Practice Guideline f Acute Bacterial Rhinosinusitis in Children and Adults. Clin Inf Dis. 2012;54(8):e Second-Line Treatments f ABRS Recommended Respiraty fluoquinolone (levofloxacin moxifloxacin) Doxycycline highly active against respiraty pathogens S. pneumoniae 98% H. influenza 98% M. catarrhalis 99% Third-generation cephalospin (cefixime cefpodoxime) plus clindamycin NOT Recommended Macrolides (clarithromycin and azithromycin) High resistance among S. pneumoniae (30%) TMP/SMX* High resistance S. pneumoniae and H. influenza (30-40%) Second and third-generation al cephalospins Variable resistance to S. pneumoniae Chow AW, et al. IDSA Clinical Practice Guideline f Acute Bacterial Rhinosinusitis in Children and Adults. Clin Inf Dis. 2012;54(8):e Trimethoprim -sulfamethoxazole Adjunctive Therapies f ABRS Intranasal saline irrigation with physiologic hypertonic saline Intranasal cticosteroids, primarily in patients with a histy of allergic rhinitis Herpes Simplex Virus (HSV-2) Infection Chow AW, et al. IDSA Clinical Practice Guideline f Acute Bacterial Rhinosinusitis in Children and Adults. Clin Inf Dis. 2012;54(8):e

4 Case 2 Epidemiology of HSV in the U.S. 39-year-old woman comes to the office after learning that her now previous sexual partner has herpes. She has had no symptoms. She wants to know if she can be tested. Should she be tested f herpes, and if so what test should be done? What is the benefit of testing? If she tests positive f herpes, since she is asymptomatic, do you recommend treatment? Two HSV serotypes HSV-1 and HSV-2 HSV-2 causes majity of cases of recurrent genital herpes in the U.S. Approximately 750,000 1,000,000 new cases each year CDC Sexually Transmitted Diseases Surveillance, Figure Accessed May HSV Transmission Majity of genital herpes infections are transmitted by persons who are unaware they are infected with HSV-2, asymptomatic when transmission occurs Likelihood of transmission declines with increased duration of infection Incubation period after acquisition is 2-12 days (average is 4 days) Efficiency of sexual transmission is greater from men to women than from women to men HSV Pathology The virus remains latent indefinitely Reactivation is precipitated by multiple known and unknown facts and induces viral replication The re-activated virus may cause cutaneous outbreak of herpetic lesions subclinical viral shedding CDC. STD Treatment Guidelines MMWR. 2010; 59(RR-12): CDC. Genital Herpes - CDC Fact Sheet. CDC. STD Treatment Guidelines MMWR. 2010; 59(RR-12): Clinical Manifestations of HSV Genital Shedding Among Symptomatic and Asymptomatic Persons With HSV-2 Infection Asymptomatic Primary Infection Recurrent Infections Most common clinical manifestation Approximately 80% of persons seropositive f HSV-2 antibody have not been diagnosed with genital herpes 498 HSV-2 seropositive, healthy participants Average age: 41 years At least 30 days wth of genital swabs collected Symptomatic 18% Asymptomatic Men Women HSV-2 Genital Lesions 82% 57% 43% Tronstein E, et al. JAMA. 2011;305(14):

5 Viral Shedding in Symptomatic vs Asymptomatic Persons HSV Shedding Summary Percent Percent of Days with Viral Shedding N=498 P< Copies/mL (log 10 ) N=498 Median Amount of Virus Detected P= Among persons with asymptomatic HSV infection, significant viral shedding occurs on ~10% of the time The quantity of virus shed is similar in symptomatic and asymptomatic persons Risk of transmission is high even f seropositive, asymptomatic individuals 0 Symptomatic Asymptomatic 0 Symptomatic Asymptomatic Tronstein E, et al. JAMA. 2011;305(14): Tronstein E, et al. JAMA. 2011;305(14): HSV Diagnosis Clinical diagnosis is insensitive and nonspecific Clinical diagnosis should be confirmed by labaty testing: Virologic tests Type-specific serologic tests Virologic Tests Viral Culture (gold standard) Preferred test if genital ulcers other mucocutaneous lesions are present Highly specific (>99%) Sensitivity depends on stage of lesion; declines rapidly as lesions begin to heal Positive me often in primary infection (80% 90%) than with recurrences (30%) Cultures should be typed Polymerase Chain Reaction (PCR) Me sensitive than viral culture Not FDA-cleared widely available Preferred test f detecting HSV in spinal fluid Type-Specific Serologic Tests Type-specific and nonspecific antibodies to HSV develop during the first several weeks to few months following infection and persist indefinitely. When to Use Recurrent atypical genital symptoms with negative HSV cultures A clinical diagnosis of genital herpes without labaty confirmation A sex partner with herpes As part of a comprehensive evaluation f STDs among persons at high risk f whom infmation may be helpful Management of Genital Herpes: Counseling Natural Histy Concern about transmission to others Asymptomatic viral shedding is common and HSV transmission can occur during asymptomatic periods Frequency of outbreaks varies among individuals, and often decreases over time Prodromal symptoms may precede outbreaks Transmission& Prevention Infm current and future sex partners about genital herpes diagnosis 5

6 Management of Genital Herpes: Antiviral Medications CDC-Recommended Regimens f First Clinical Episode Oral antiviral chemotherapy Most effective if started within 48 hours of symptom onset Partially controls symptoms of herpes Does not eradicate latent virus Does not change natural histy Agents: acyclovir, valacyclovir, famciclovir Topical antiviral treatment is not recommended Acyclovir 400 mg ally 3 times a day Acyclovir 200 mg ally 5 times a day Famciclovir 250 mg ally 3 times a day Valacyclovir 1 g ally twice a day 7-10 days CDC. STD Treatment Guidelines MMWR 2010; 59(RR-12): CDC. STD Treatment Guidelines MMWR 2010; 59(RR-12): Suppressive Therapy Reduces Risk of Transmission of Genital Herpes Recurrent Episodes of Genital Herpes: Episodic vs. Suppressive Treatment 1484 immunocompetent, heterosexual, monogamous couples one with clinically symptomatic genital HSV-2 one susceptible to HSV-2 Randomly assigned to receive either 500 mg of valacyclovir once daily placebo f 8 months Cey L, et al. N Engl J Med. 2004;350: Percent of Days HSV DNA Detected in Samples of Genital Secretions N=1484 immunocompetent, heterosexual, monogamous couples Source Partners with HSV-2 Shedding (%) >0 to <10 10 to <20 20 to <30 Cey L, et al. N Engl J Med. 2004;350: to <40 40 to <50 Time with HSV-2 Shedding (% of Days) 15% 10% 5% 0% Valacyclovir (n=39) Placebo (n=50) P< % Valacyclovir 11% Placebo Partner Acquisition of HSV-2 Percentage of Days Clinically Symptomatic HSV-2 Infection Developed in Seronegative Partners 5.0% Hazard Ratio: % P= % 2.0% 1.0% 0.5% 2.2% 5.0% 4.0% 3.0% 2.0% 1.0% Overall Acquisition of HSV-2 Hazard Ratio: 0.52 P= % 3.6% 0.0% 0.0% Valacyclovir Placebo Valacyclovir Placebo Once-daily valacyclovir significantly reduced viral shedding and risk of genital HSV-2 transmission among heterosexual, HSV-2 discdant couples Cey L, et al. N Engl J Med. 2004;350:

7 CDC-Recommended Regimens f Episodic Therapy Drug Frequency Duration Acyclovir 400 mg ally 3 times a day 5 days Acyclovir 800 mg ally Twice a day 5 days Acyclovir 800 mg ally 3 times a day 2 days Famciclovir 125 mg ally Twice a day 5 days Famciclovir 1000 mg ally Twice a day 1 day Episodic Treatment f Recurrent Genital Herpes Ameliates shtens duration of lesions Requires initiation of therapy within 1 day of lesion onset Provide patient with a supply of drug a prescription and instructions to self-initiate treatment immediately when symptoms begin Valacyclovir 500 mg ally Twice a day 3 days Valacyclovir 1 g ally Once a day 5 days CDC. STD Treatment Guidelines MMWR. 2010; 59(RR-12): CDC. STD Treatment Guidelines MMWR. 2010; 59(RR-12): CDC-Recommended Regimens f Suppressive Therapy Drug Acyclovir 400 mg ally Famciclovir 250 mg ally Valacyclovir 500 mg ally Valacyclovir 1 g ally Frequency Twice a day Twice a day Once a day Once a day May be less effective than other regimens in patients who have very frequent recurrences ( 10 episodes per year). Suppressive Therapy f Recurrent Genital Herpes Reduces frequency of recurrences By 70%-80% in patients with > 6 recurrences per year Also effective in those with less frequent recurrences Reduces but does not eliminate subclinical viral shedding Periodically (eg, once a year), reassess need f continued suppressive therapy CDC. STD Treatment Guidelines MMWR. 2010; 59(RR-12): Kimberlin DW. Antiviral Therapy of HSV 1 and 2, in Arvin A, et al, eds. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; ( ) Johnson C, et al. Lancet. 2012; 379: Episodic vs. Suppressive Treatment Counseling: Decreasing Genital Herpes Transmission Rate Episodic Therapy Effective in shtening duration of recurrent episodes Suppressive Therapy Effective in preventing symptomatic recurrences and decreasing transmission Abstain from sexual activity with uninfected partners when lesions prodrome present Use latex condoms Antiviral suppressive therapy 7

8 Case 3 Latent Tuberculosis Infection (LTBI) vs Active Tuberculosis Patient 23-year-old female new college graduate Never been outside the US Healthy, no medical problems Recent blood don (HIV-) to Red Cross No sick contacts Medical Histy Takes al contraceptive f dysmenrhea Got a PPD f a new teaching job and it was 18 mm Chest x-ray was negative Not interested in treatment if she does not definitely need it What is her diagnosis? What would she require f treatment? Are there other diagnostic options? Differentiating Between Latent TB Infection and Active TB Latent TB Infection Active TB Infection Symptoms No symptoms physical findings suggestive of TB disease May include one me: fever, cough, chest pain, weight loss, night sweats, hemoptysis, fatigue, and decreased appetite TST IGRA Usually positive Usually positive Chest X-Ray Typically nmal Usually abnmal; May be nmal in persons with advanced immunosuppression extrapulmonary disease Respiraty specimens Transmission Treatment CDC. MMWR ;59(RR-5):1-26. If done, specimens are smear and culture negative Cannot spread bacteria to others Consider treatment to prevent active TB Usually smear culture positive; May be negative in persons with extrapulmonary minimal/early pulmonary disease May spread bacteria to others Needs treatment f active TB TST=tuberculin skin test. IGRA=interferon gamma release assays Problems with Tuberculin Skin Testing (TST) Variation in interpretation of test by reader > 5 mm >10 mm >15 mm Need to come back to have it read False positives in patients with BCG histy other mycobacterium Booster (some people need two-step test) Shtage of PPD (Spring 2013)* *CDC. MMWR. 2013;62(16):312. BCG=Bacille Calmette Guerin PPD=purified protein derivative Options f Positive PPD Treatment Re-evaluate with IGRA (interferon gamma release assay) PPD=purified protein derivative Interferon Gamma Release Assay (IGRA) Tests In vitro blood tests that measure T cell release of interferon-gamma following stimulation by antigens unique to Mycobacterium tuberculosis Can not differentiate active from latent infections Should not be used to diagnose active TB Not effected by BCG status Testing does not effect other future testing Can be boosted by TST (should do at time of reading) Diminished by HIV infection BCG=Bacille Calmette Guerin TST=tuberculin skin test 8

9 IGRA Tests 2 tests available QFT-GIT T-Spot Overall sensitivity f latent TB infection 95% T-Spot 90% QFT-GIT 80% TST 80% Overall sensitivity/specificity low in high-risk TB populations Requires blood draw Window of conversion 4-7 weeks Meta-Analysis of TST vs IGRA f Progression from LTBI to Active TB Pooled Analysis of All Studies (N=28) IGRA TST P Value Positive Predictive Value (PPV) 2.7% 1.5% < Negative Predictive Value (NPV) 99.7% 99.4% <0.01 Pooled Analysis of High-Risk TB Populations IGRA TST P Value Positive Predictive Value (PPV) 6.8% 2.4% < Diel R, et al. Chest. July 2012;142:63-75 QFT-GIT Interpretation Interpretation Nil* TB Response Response Mitogen Positive IU/ml and 25% of Nil Any Negative** 8.0 <0.35 IU/ml <25% of Nil 0.5 Indeterminate 8.0 >8.0 <0.35 IU/ml <25% of Nil Any <0.5 Any * The interferon gamma (IFN-γ) concentration in plasma from blood incubated without antigen. The IFN-γ concentration in plasma from blood stimulated with a single cocktail of peptides representing early secrety antigenic target-6 (ESAT-6), culture filtrate protein-10 (CFP-10), and part of TB 7.7 minus Nil. The IFN-γ concentration in plasma from blood stimulated with mitogen minus Nil. Interpretation indicating that Mycobacterium tuberculosis infection is likely. ** Interpretation indicating that M. tuberculosis infection is not likely. Interpretation indicating an uncertain likelihood of M. tuberculosis infection. CDC. MMWR ;59(RR-5):1-26. T Spot Interpretation Interpretation Nil* TB Response Response Mitogen Positive 10 spots 8 spots Any Bderline** 10 spots 5, 6, 7 spots Any Negative 10 spots 4 spots Indeterminate ** >10 spots 10 spots Any <5 spots Any <20 spots * Numnber of spots resulting from incubation of PBMCs in culture media without antigens. The greater number of spots resulting from stimulation of peripheral blood mononuclear cells (PBMCs) with two separate cocktails of peptides representing early secrety antigenic target-6 (ESAT-6) culture filtrate protein-10 (CFP-10) minus Nil. The number of spots resulting from stimulation of PBMCs with mitogen without adjustment f the number of spots resulting from incubation of PBMCs without antigens. Interpretation indicating that Mycobacterium tuberculosis infection is likely. ** Interpretation indicating an uncertain likelihood of M. tuberculosis infection. Interpretation indicating that M. tuberculosis infection is not likely. CDC. MMWR ;59(RR-5):1-26. US IGRA Guidelines Case 4 IGRA Can be used in place of (not in addition to ) TSTs Preferred over TST f Received BCG as vaccine cancer Rx Po chance of followup f TST s read Low pre-test probability TST Preferred over IGRA f children under 5 years CDC. MMWR ;59(RR-5):1-26. When To Do Both When negative test Risk is otherwise high When initial test is positive Risk is overall low Additional positive test would encourage treatment of LTBI Repeating a test might occur with indeterminate test 49-year-old female with HIV on HAART darunavir boosted by ritonavir emtricitabine/tenofovir Obesity; type 2 diabetes; hypertension Does she need a statin? If so, which one? Labs: A1C: 8.9% CMP: nl FBS: 199 mg/dl TC: 169 mg/dl LDL-C: 103 mg/dl TG: 124 mg/dl HDL-C: 41 mg/dl 9

10 Statin Use in Patients with HIV Infection Dyslipidemia is common in HIV npatients Lipodystrophies manifested by peripheral fat wasting and central fat accumulation can develop Dyslipidemia management same as f non-hiv patients Consider altering HIV regimen if using agents with po lipid profiles (eg, lopinavir) with lipid-sparing alternatives Protease inhibit (PI): atazanavir, darunavir Non-nucleoside reverse transcriptase inhibit (NNRTI) integrase inhibit Statins in HIV Atvastatin Pravastatin Simvastatin and Lovastatin Rosuvastatin Effective with lower drug interaction profile Less efficacious but does not go through CYP3A4 system Contraindicated because highly metabolized by CYP3A4 system Might decrease HAART med levels (lopinavir/ritonavir) Pitavastatin Might be a good choice (FDA 2012) Notes: Isolated TG elevation can use all the agents Watch f myopathy and hepatitis Ahmed MH, et al. Expert Opin Pharmacother. 2012;13(13): Case 5 40-year-old man with recurrent MRSA infections Interested in decontamination/ decolonization, if that is possible How do you advise him? Advising Patients on MRSA MRSA can live on surfaces f up to 6 months Hand washing Cover wounds Don t share razs Use disinfectants vs detergents sanitizers on surfaces Check common surfaces Wash clothes/anything that comes in contact with skin Bleach not required Hot water not required Flos/walls not associated with MRSA transmission Liu C, et al. Clin Infect Dis. 2011;52(3):e18-e55. Personal Decolonization Little evidence of lasting effect Healthcare wkers Nasal mupirocin decreased carriage 91% Recolonized in 26% within 4 weeks, 50% at 6 months Topical therapy Mupirocin to ant nares bid f 5-7 days (? resistance) (C-III) Chlhexidine baths (2-4%) washes f 5-10 days (C-III) Diluted bleach baths Oral therapy No evidence of efficacy (A-III) Liu C, et al. Clin Infect Dis. 2011;52(3):e18-e55. Decolonization of asymptomatic family members can be considered (C-III) ICU Decolonization Randomized Trial in 74 ICU s at 43 Hospitals N=74,256 patients Compared Intervention vs Baseline Period Strategy Screening and isolation Targeted decolonization Universal Decolonization Intervention Nasal culture, if + isolated Nasal culture, if + nasal mupirocin and chlhexidine washes All received mupirocin and chlhexidine washes Huan SS, et al. New Engl J Med. 2013;368: MRSA Isolates Hazard Ratios Bloodstream Infections P <0.01 P <