1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Bacterial Infections Slide Set Prepared by the AETC National Resource Center based on recommendations from the CDC, National Institutes of Health, and HIV Medicine Association/Infectious Diseases Society of America

2. May 2013www.aidsetc.org 2 About This Presentation These slides were developed using recommendations published in May 2013. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. – AETC National Resource Center http://www.aidsetc.org

3. Bacterial Infections  Bacterial respiratory infections  Bacterial enteric infections  Bartonellosis  Syphilis

4. Bacterial Infections Bacterial Respiratory Infections

5. www.aidsetc.org Bacterial Respiratory Disease: Epidemiology  Bacterial pneumonia is a common cause of HIV-related morbidity  In HIV-infected persons:  Higher rates of bacterial pneumonia  Higher mortality  Increased incidence of bacteremia (esp. with S pneumoniae)  Can occur at any CD4 count or stage of disease  Recurrent pneumonia (≥2 episodes in 1 year) is an AIDS-defining condition May 2013 5

6. www.aidsetc.org Bacterial Respiratory Disease: Epidemiology (2)  Incidence lower with use of ART  Risk factors include  Low CD4 count (<200 cells/µL)  No or intermittent use of ART  Cigarette smoking  Injection drug use  Chronic viral hepatitis May 2013 6

7. www.aidsetc.org Bacterial Respiratory Disease: Epidemiology (3) Organisms:  S pneumoniae  Drug-resistant strains are increasingly common  H influenzae  P aeruginosa  S aureus, including MRSA  Atypicals (infrequent) May 2013 7

8. www.aidsetc.org Bacterial Respiratory Disease: Clinical Manifestations  Presentation similar to that of HIV uninfected, with acute symptoms (fevers, chills, rigors, chest pain, productive cough, dyspnea)  Subacute illness suggests alternative diagnosis (PCP, TB, chronic fungal disease, etc)  Physical exam: evidence of focal consolidation or pleural effusion  WBC usually elevated, may see left shift May 2013 8

9. www.aidsetc.org Bacterial Respiratory Disease: Clinical Manifestations (2)  Assess disease severity (including signs of sepsis) and arterial oxygenation in all patients  Pneumonia Severity Index (PSI) appears valid for HIV-infected patients May 2013 9

10. www.aidsetc.org Bacterial Respiratory Disease: Diagnosis  Chest X ray:  Commonly shows unilateral, focal, segmental, or lobar consolidation, but may show atypical presentations (multilobar, nodular, reticulonodular) Chest X ray: pneumococcal pneumonia showing right middle lobe consolidation Credit: C. Daley, MD; HIV InSite May 2013 10

11. www.aidsetc.org Bacterial Respiratory Disease: Diagnosis (2)  CAP diagnosis and management guidelines apply to HIV-infected as well as HIV-uninfected patients  Chest X ray: PA and lateral, if possible  Consider the possibility of specific pathogens, eg:  TB: if compatible clinical and X-ray presentation, manage as potential TB, pending test results  PCP: evaluate if clinically indicated (PCP may coexist with bacterial pneumonia)  P aeruginosa: if CD4 ≤50 cells/µL, preexisting lung disease, neutropenia, on corticosteroids, recent hospitalization, or residence in a health care facility  S aureus: if recent influenza or other viral infection, history of injection drug use, or severe bilateral necrotizing pneumonia May 2013 11

12. www.aidsetc.org Bacterial Respiratory Disease: Diagnosis (3)  Microbiologic diagnosis allows targeted treatment of specific pathogen(s)  Test to identify specific pathogens that would significantly alter standard (empirical) management decisions, if their presence is suspected  For patients well enough to be treated as outpatient: routine testing for etiology is optional  For hospitalized patients with suspected CAP: Gram stain and culture of expectorated sputum specimen, 2 blood cultures  Gram stain and culture of expectorated sputum only if good quality specimen as well as good lab performance measures  Endotracheal aspirate sample for intubated patients  Consider bronchoscopy with BAL lavage if differential includes pathogens such as P jiroveci May 2013 12

13. www.aidsetc.org Bacterial Respiratory Disease: Diagnosis (4)  Microbiologic diagnosis  Consider blood cultures for all:  Higher rate of bacteremia in HIV-infected patients with CAP  Higher risk of drug-resistant pneumococcal infection  Blood culture has high specificity but low sensitivity  Consider urinary antigen tests for L pneumophila and S pneumoniae  Consider diagnostic thoracentesis if pleural effusion May 2013 13

14. www.aidsetc.org Bacterial Respiratory Disease: Preventing Exposure  No effective means of reducing exposure to S pneumoniae and H influenzae May 2013 14

15. www.aidsetc.org Bacterial Respiratory Disease: Preventing Disease  Pneumococcal vaccine:  Recommended for all with HIV infection, regardless of CD4 count  23-valent pneumococcal polysaccharide vaccine (PPV23)  Multiple observational studies reported benefits including reduced risk of pneumococcal bacteremia  13-valent pneumococcal conjugate vaccine (PCV13)  Recommended for use in adults with HIV or other immunocompromising conditions  7-valent PCV  High efficacy against vaccine-type invasive pneumococcal disease in one study May 2013 15

16. www.aidsetc.org Bacterial Respiratory Disease: Preventing Disease (2) Pneumococcal vaccination recommendations  No previous pneumococcal vaccination  Preferred:  1 dose PCV13 followed by:  If CD4 ≥200 cells/µL: PPV23 should be given ≥8 weeks after PCV13  If CD4 200 cells/µL  Alternative:  1 dose PPV23  Previous PPV23 vaccination  1 dose of PCV13, to be given ≥1 year after last receipt of PPV23 May 2013 16

17. www.aidsetc.org Bacterial Respiratory Disease: Preventing Disease (3) Pneumococcal vaccination recommendations (2)  Revaccination  Individuals who previously received PPV23  Duration of protective effect of PPV23 is not known  1 dose PPV23 recommended for age 19-64 years if ≥5 years since 1st dose of PPV  Another dose of PPV23 for age ≥65 if ≥5 years since previous PPV23  Single dose of PCV13 should be given if ≥1 year since previous PPV23  Subsequent doses of PPV23 as above  No more than 3 lifetime doses of PPV23 May 2013 17

18. www.aidsetc.org Bacterial Respiratory Disease: Preventing Disease (4)  Influenza vaccine:  Recommended annually during influenza season (bacterial pneumonia may occur as complication of influenza)  Live attenuated vaccine is contraindicated and is not recommended for HIV-infected persons May 2013 18

19. www.aidsetc.org Bacterial Respiratory Disease: Preventing Disease (5)  H influenzae type B vaccine:  Not usually recommended for adults, unless anatomic or functional asplenia (low incidence of infection) May 2013 19

20. www.aidsetc.org Bacterial Respiratory Disease: Preventing Disease (6)  Antiretroviral therapy: reduces risk of bacterial pneumonia  TMP-SMX and macrolides: reduce frequency of bacterial respiratory infections when given as prophylaxis for PCP or MAC, respectively  These should not be prescribed solely to prevent bacterial respiratory infections  Behavioral interventions:  Cessation of smoking, injection drug use, alcohol use May 2013 20

21. www.aidsetc.org Bacterial Respiratory Infections: Treatment  Outpatient versus inpatient treatment:  Severity of disease and CD4 count may both be important  Mortality higher with higher PSI class, with CD4 <200 cells/µL  Some offer hospitalization to all CAP patients with CD4 200 cells/µL  Basic principles of treatment are same as those for HIV uninfected May 2013 21

22. www.aidsetc.org Bacterial Respiratory Infections: Treatment (2)  Target most common pathogens, particularly S pneumoniae and H influenzae  Empiric treatment should be started promptly  Specimens for diagnosis should be collected before antibiotics are given  Modify treatment, if indicated, based on microbiologic and drug susceptibility results  Fluoroquinolones should be used cautiously if TB suspected but not being treated (risk of TB monotherapy)  Empiric macrolide monotherapy cannot be routinely recommended (risk of macrolide-resistant S pneumoniae) May 2013 22

23. www.aidsetc.org Bacterial Respiratory Infections: Treatment (3)  Outpatient treatment (empiric)  Preferred:  Oral beta-lactam + macrolide (azithromycin, clarithromycin)  Preferred beta-lactams: high-dose amoxicillin or amoxicillin- clavulanate  Alternative beta-lactams: cefpodoxime, cefuroxime  Fluoroquinolone, especially if penicillin allergy  Levofloxacin 750 mg PO QD  Moxifloxacin 400 mg PO QD  Alternative: beta-lactam + doxycycline  Duration of therapy: 7-10 days for most; minimum 5 days  Should be afebrile for 48-72 hours, clinically stable May 2013 23

24. www.aidsetc.org Bacterial Respiratory Infections: Treatment (4)  Hospitalized, non-ICU treatment (empiric)  Preferred:  IV beta-lactam + macrolide (azithromycin, clarithromycin)  Preferred beta-lactams: ceftriaxone, cefotaxime, ampicillin- sulbactam  IV f luoroquinolone, especially if penicillin allergy  Levofloxacin 750 mg IV QD  Moxifloxacin 400 mg IV QD  Alternative:  IV beta-lactam + doxycycline  IV penicillin for confirmed pneumococcal pneumonia May 2013 24

25. www.aidsetc.org Bacterial Respiratory Infections: Treatment (5)  Inpatient, ICU (empiric)  Preferred:  IV beta-lactam + IV azithromycin  IV beta-lactam + (levofloxacin 750 mg IV QD or moxifloxacin 400 mg IV QD)  Preferred beta-lactams: ceftriaxone, cefotaxime, ampicillin- sulbactam  Alternative:  Penicillin allergy: aztreonam IV + IV levofloxacin or moxifloxacin as above May 2013 25

26. www.aidsetc.org Bacterial Respiratory Infections: Treatment (6)  Most CAP pathogens can be treated with the recommended regimens  Exceptions: P aeruginosa and S aureus (including community-acquired MRSA)  Empiric coverage may be warranted, if either is suspected  Diagnostic tests (sputum Gram stain and culture) likely to be of high yield May 2013 26

27. www.aidsetc.org Bacterial Respiratory Infections: Treatment (7)  Empiric Pseudomonas treatment  Preferred: antipneumococcal antipseudomonal beta- lactam + (ciprofloxacin 400 mg IV Q8-12H or levofloxacin 750 mg IV QD)  Preferred beta-lactams: piperacillin-tazobactam, cefepime, imipenem, meropenem  Alternative:  Beta-lactam as above + IV aminoglycoside + IV azithromycin  Beta-lactam as above + IV aminoglycoside + (moxifloxacin 400 mg IV QD or levofloxacin 750 mg IV QD)  Penicillin allergy: replace beta-lactam with aztreonam May 2013 27

28. www.aidsetc.org Bacterial Respiratory Infections: Treatment (8)  Empiric S aureus (including community- acquired MRSA) treatment:  Add vancomycin (IV) or linezolid (IV or PO) alone to the antibiotic regimen  For severe necrotizing pneumonia, consider addition of clindamycin to vancomycin (not to linezolid), to minimize bacterial toxin production May 2013 28

29. www.aidsetc.org Bacterial Respiratory Infections: Treatment (9)  When etiology of the pneumonia is identified, modify antimicrobial therapy to target that pathogen  Consider switch from IV to PO therapy: when improved clinically, able to tolerate PO medications, have intact GI function  Clinical stability: temperature 90% or PaO 2 >60 mm Hg May 2013 29

30. www.aidsetc.org Bacterial Respiratory Infections: Starting ART  Initiate ART early in course of bacterial pneumonia  In one randomized study, early ART in setting of OIs (including bacterial infections) decreased AIDS progression and death May 2013 30

31. www.aidsetc.org Bacterial Respiratory Infections: Monitoring and Adverse Events  Clinical response typically seen within 48-72 hours after start of appropriate antimicrobial therapy  Advanced HIV, CD4 7 days)  Patients on ART had shorter time to clinical stability  IRIS has not been described May 2013 31

32. www.aidsetc.org Bacterial Respiratory Infections: Treatment Failure  If worsening symptoms/signs or no improvement, evaluate further for other infectious and noninfectious causes  Consider possibility of TB May 2013 32

33. www.aidsetc.org Bacterial Respiratory Infections: Preventing Recurrence  23-valent pneumococcal vaccine, as above  Influenza vaccine during influenza season  Antibiotic prophylaxis generally not recommended to prevent bacterial respiratory infections (potential for drug resistance and toxicity) May 2013 33

34. www.aidsetc.org Bacterial Respiratory Infections: Considerations in Pregnancy  Diagnosis as in nonpregnant adults (abdominal shielding during radiographic procedures)  Management as in nonpregnant adults, except:  Clarithromycin not recommended as first-line agent (birth defects in animals); azithromycin recommended when macrolide is indicated  Quinolones may be used for serious infections when indicated (no arthropathy or birth defects reported in exposed human fetuses)  Doxycycline not recommended (hepatoxicity, staining of fetal teeth and bones) May 2013 34

35. www.aidsetc.org Bacterial Respiratory Infections: Considerations in Pregnancy (2)  Management:  Beta-lactams: no known teratogenicity or increased toxicity  Aminoglycosides: theoretical risk of fetal renal or eighth nerve damage, but not documented in humans except with streptomycin, kanamycin  Linezolid: limited data; not teratogenic in animal studies May 2013 35

36. www.aidsetc.org Bacterial Respiratory Infections: Considerations in Pregnancy (3)  Increased risk of preterm labor and delivery  If pneumonia after 20 weeks of gestation, monitor for contractions  Pneumococcal and influenza vaccines can be administered  Influenza vaccine recommended for all pregnant women during influenza season  During pregnancy, vaccines should be administered after ART has been initiated, to minimize transient HIV RNA increases that may be caused by vaccine May 2013 36

37. Bacterial Infections Bacterial Enteric Infections

38. November 2014www.aidsetc.org 38 Bacterial Enteric Disease: Epidemiology  Higher incidence of gram-negative enteric infections among HIV-infected patients  Risk greatest if CD4 <200 cells/µL or AIDS  Risk decreased with ART  Most commonly cultured bacteria:  Salmonella  Shigella  Campylobacter  E coli  Clostridium difficile

39. November 2014www.aidsetc.org 39 Bacterial Enteric Disease: Epidemiology (2)  Source usually ingestion of contaminated food or water  Other risks:  Oral-fecal exposure through sexual activity (especially Shigella and Campylobacter)  HIV-related alterations in mucosal immunity or intestinal integrity, gastric acid-blocking medications

40. November 2014www.aidsetc.org 40 Bacterial Enteric Disease: Clinical Manifestations  Three major clinical syndromes  Self-limited gastroenteritis  Diarrheal disease +/- fever, bloody diarrhea, weight loss, possible bacteremia  Bacteremia associated with extraintestinal involvement, with or without GI illness

41. November 2014www.aidsetc.org 41 Bacterial Enteric Disease: Clinical Manifestations (2)  Severe diarrhea: ≥6 loose stools per day, with our without other signs/symptoms  In HIV infection:  Greater risk of more serious illness with greater immunosuppression  Relapses may occur after treatment  Recurrent Salmonella bacteremia is an AIDS- defining illness

42. November 2014www.aidsetc.org 42 Bacterial Enteric Disease: Diagnosis  History: exposures; medication review; diarrhea frequency, volume, presence of blood; associated signs/symptoms (eg, fever)  Physical exam including temperature, assessment of hydration and nutritional status  Stool and blood cultures  Obtain blood cultures in patients with diarrhea and fever  Routine stool culture may not identify non-jejuni non- coli Campylobacter species; request special testing for these if initial evaluation is unrevealing

43. November 2014www.aidsetc.org 43 Bacterial Enteric Disease: Diagnosis (2)  C difficile toxin or PCR  If recent or current antibiotic exposure, cancer chemotherapy, recent hospitalization, residence in long-term care facility, CD4 <200 cells/µL, acid- suppressive medications, moderate-severe community-acquired diarrhea  Endoscopy  If stool studies and blood culture are nondiagnostic, or if treatment for an established diagnosis fails  May diagnose nonbacterial causes (eg, parasites, CMV, MAC, noninfectious causes)  Consider STDs (eg, rectal infections caused by lymphogranuloma venereum or N gonorrhoeae)

44. November 2014www.aidsetc.org 44 Bacterial Enteric Disease: Preventing Exposure Advice to patients:  Handwashing:  After potential contact with feces, pets or other animals, gardening/ contact with soil; before preparing food, eating; before and after sex  For prevention of enteric infection, soap and water preferred over alcohol-based cleansers (these do not kill C difficile spores, are partly active against norovirus and Cryptosporidium)  Sex:  Avoid unprotected sexual practices that might result in oral exposure to feces

45. November 2014www.aidsetc.org 45 Bacterial Enteric Disease: Preventing Disease  Antimicrobial prophylaxis usually not recommended, including for travellers  Risk of adverse reactions, resistant organisms, C difficile infection  Can be considered in rare cases, depending on level of immunosuppression and the region and duration of travel  Fluoroquinolone (FQ) or rifaximin  TMP-SMX may give limited protection (eg, if pregnant or already taking for PCP prophylaxis)

46. November 2014www.aidsetc.org 46 Bacterial Enteric Disease: Treatment  Treatments usually the same as in HIV- uninfected patients  Give oral or IV rehydration if indicated  Advise bland diet and avoidance of fat, dairy, and complex carbohydrates  Effectiveness and safety of probiotics or antimotility agents not adequately studied in HIV- infected patients  Avoid antimotility agents if concern about inflammatory diarrhea

47. November 2014www.aidsetc.org 47 Bacterial Enteric Disease: Treatment (2) Empiric Therapy  CD4 count and clinical status guide initiation and duration of empiric antibiotics, eg:  CD4 count >500 cells/µL with mild symptoms: only rehydration may be needed  CD4 count 200-500 cells/µL and symptoms that compromise quality of life: consider short course of antibiotics  CD4 count <200 cells/µL with severe diarrhea, bloody stool, or fevers/chills: diagnostic evaluation and antibiotics

48. November 2014www.aidsetc.org 48 Bacterial Enteric Disease: Treatment (3) Empiric Therapy (cont.)  Preferred: ciprofloxacin 500-750 mg PO (or 400 mg IV) Q12H  Alternative: ceftriaxone 1 g IV Q24H or cefotaxime 1 g IV Q8H  Adjust therapy based on study results  Traveler’s diarrhea: consider possibility of antibiotic resistance

49. November 2014www.aidsetc.org 49 Bacterial Enteric Disease: Treatment (4) Salmonella spp.  In HIV infection, treatment recommended, because of high risk of bacteremia and mortality in HIV-infected patients  Preferred:  Ciprofloxacin 500-750 mg PO (or 400 mg IV) Q12H  Alternative:  Levofloxacin 750 mg PO or IV Q24H  Moxifloxacin 400 mg PO or IV Q24H  TMP-SMX PO or IV, if susceptible  Ceftriaxone (IV) or cefotaxime (IV), if susceptible

50. November 2014www.aidsetc.org 50 Bacterial Enteric Disease: Treatment (5) Salmonella spp. (cont.)  Optimal duration of therapy not defined  Gastroenteritis without bacteremia  CD4 count ≥200 cells/µL: 7-14 days  CD4 count <200 cells/µL: 2-6 weeks  Gastroenteritis with bacteremia  CD4 count ≥200 cells/µL:14 days, longer if persistent bacteremia or complicated infection  CD4 count <200 cells/µL: 2-6 weeks  If bacteremia, monitor closely for recurrence (eg, bacteremia or localized infection)

51. November 2014www.aidsetc.org 51 Bacterial Enteric Disease: Treatment (6) Shigella spp.  Treatment recommended, to shorten duration and possibly prevent transmission  Preferred:  Ciprofloxacin 500-750 mg PO or 400 mg IV Q12H  Alternative (depending on susceptibilities):  Levofloxacin 750 mg PO or IV Q24H  Moxifloxacin 400 mg PO or IV Q24H  TMP-SMX 106/800 mg PO or IV Q12H  Azithromycin 500 mg PO QD for 5 days (not recommended if bacteremia)

52. November 2014www.aidsetc.org 52 Bacterial Enteric Disease: Treatment (7) Shigella spp. (cont.)  High rate of TMP-SMX resistance in infections acquired outside the U.S.; reports of azithromycin resistance in HIV-infected MSM  Duration of therapy  Gastroenteritis: 7-10 days (5 days for azithromycin)  Bacteremia: ≥14 days  Recurrent infection: up to 6 weeks

53. November 2014www.aidsetc.org 53 Bacterial Enteric Disease: Treatment (8) Campylobacter spp.  Optimal treatment in HIV poorly defined  Culture and susceptibility recommended (increasing resistance to FQ)  Mild disease and CD4 >200 copies/µL: may withhold antibiotics unless symptoms persist beyond several days  Mild-moderate disease  Preferred  Ciprofloxacin 500-750 mg PO or 400 mg IV Q12H  Azithromycin 500 mg PO QD for 5 days (avoid if bacteremia)  Alternative (depending on susceptibilities):  Levofloxacin 750 mg PO or IV Q24H  Moxifloxacin 400 mg PO or IV Q24H

54. November 2014www.aidsetc.org 54 Bacterial Enteric Disease: Treatment (9) Campylobacter spp. (cont.)  Bacteremia: ciprofloxacin 500-750 mg PO or 400 mg IV Q12H + aminoglycoside  Duration of therapy  Gastroenteritis: 7-10 days (5 days for azithromycin)  Bacteremia: >14 days  Recurrent bacteremic disease: 2-6 weeks

55. November 2014www.aidsetc.org 55 Bacterial Enteric Disease: Treatment (10) C difficile  Treatment as in HIV-uninfected patients

56. November 2014www.aidsetc.org 56 Bacterial Enteric Disease: Initiating ART  ART expected to decrease risk of recurrent Salmonella, Shigella, and Campylobacter infections  Follow standard guidelines  Consider patient’s ability to ingest and absorb ARV medications  Consider prompt ART initiation if Salmonella bacteremia, regardless of CD4 count (should not be delayed)

57. November 2014www.aidsetc.org 57 Bacterial Enteric Disease: Monitoring and Adverse Effects  Monitor closely for treatment response  Follow-up stool culture not required if clinical symptoms and diarrhea resolve  May be required if public health considerations and state law dictate  IRIS has not been described

58. November 2014www.aidsetc.org 58 Bacterial Enteric Disease: Treatment Failure  Consider follow-up stool culture if lack of response to appropriate antibiotic therapy  Look for other enteric pathogens including C difficile; antibiotic resistance  Consider malabsorption of antibiotics: use IV antibiotics if patient is clinically unstable

59. November 2014www.aidsetc.org 59 Bacterial Enteric Disease: Preventing Recurrence  Salmonella  Secondary prophylaxis should be considered for patients with recurrent Salmonella bacteremia; also might be considered for those with recurrent gastroenteritis (with or without bacteremia) and in those with CD4 count <200 cells/µL and severe diarrhea  This approach is not well established; weigh benefits and risks  Consider stopping secondary prophylaxis if Salmonella infection is resolved, patient is on ART with virologic suppression and CD4 count >200 cells/µL

60. November 2014www.aidsetc.org 60 Bacterial Enteric Disease: Preventing Recurrence (2)  Shigella  Chronic suppressive therapy not recommended for first- time infections  Recurrent infections: extend antibiotic treatment for up to 6 weeks  ART expected to decrease recurrence  Campylobacter  Chronic suppressive therapy not recommended for first- time infections  Recurrent infections: extend antibiotic treatment for 2-6 weeks  ART expected to decrease recurrence

61. November 2014www.aidsetc.org 61 Bacterial Enteric Disease: Considerations in Pregnancy  Diagnosis as with nonpregnant women  Management as with nonpregnant adults, except:  Expanded-spectrum cephalosporins or azithromycin should be first-line therapy for bacterial enteric infections (depending on organism and susceptibility testing)  FQs can be used if indicated by susceptibility testing or failure of first-line therapy (arthropathy in animals; no increased risk of arthropathy or birth defects in humans after in utero exposure)  Avoid TMP-SMX in 1st trimester (increased risk of birth defects)  Sulfa therapy near delivery may increase risk to newborn of hyperbilirubinemia and kernicterus

62. Bacterial Infections Bartonellosis

63. May 2013www.aidsetc.org 63 Bartonellosis: Epidemiology  Bartonella spp. cause variety of infections, including cat-scratch disease, retinitis, trench fever, relapsing bacteremia, endocarditis  In immunocompromised: also bacillary angiomatosis (BA) and peliosis hepatis  BA usually caused by B henselae or B quintana  Typically occurs late in HIV infection; median CD4 count <50 cells/µL  B henselae linked to cat scratches from cats infested with fleas, cat fleas  B quintana associated with louse infestation

64. May 2013www.aidsetc.org 64 Bartonellosis: Clinical Manifestations  In HIV-infected persons, symptoms often chronic (months-years)  May involve nearly any organ system  BA of the skin: papular red vascular lesions, subcutaneous nodules; may resemble Kaposi sarcoma or pyogenic granuloma  Osteomyelitis (lytic lesions)  Peliosis hepatica (B henselae)  Endocarditis  Systemic symptoms of fever, sweats, weight loss, fatigue, malaise

65. May 2013www.aidsetc.org 65 Bartonellosis: Clinical Manifestations (2) Credits: Left: P. Volberding, MD, UCSF Center for HIV Information Image Library Right: G. Beatty, MD; A. Lukusa, MD, HIV InSite Skin lesions of Bartonella

66. May 2013www.aidsetc.org 66 Bartonellosis: Diagnosis  Tissue biopsy: histopathologic examination  Serologic tests (available through the CDC and some state health labs)  Up to 25% of patients with advanced HIV infection and positive blood cultures for Bartonella may not develop antibodies  Antibody levels can indicate resolution and recrudescence of infection  Blood culture  PCR not widely available

67. May 2013www.aidsetc.org 67 Bartonellosis: Preventing Exposure  If CD4 count <100 cells/µL, high risk of severe disease if infected by B quintana or B henselae  Advice to patients:  B quintana  Consider risks of contact with cats  If acquiring a cat: cat should be >1 year of age, in good health, free of fleas  Avoid cats with fleas, stray cats  Avoid cat scratches  Avoid contact with flea feces  Control fleas  B henselae  Eradicate body lice, if present

68. May 2013www.aidsetc.org 68 Bartonellosis: Preventing Disease  Primary chemoprophylaxis not recommended  Macrolide or rifamycin was protective in a retrospective case-control study

69. May 2013www.aidsetc.org 69 Bartonella Infection: Treatment  No randomized controlled trials in HIV-infected patients  BA, peliosis hepatica, bacteremia, osteomyelitis  Preferred:  Doxycycline 100 mg PO or IV Q12H  Erythromycin 500 mg PO or IV Q6H  Alternative:  Azithromycin 500 mg PO QD  Clarithromycin 500 mg PO BID  Duration: at least 3 months

70. May 2013www.aidsetc.org 70 Bartonella Infection: Treatment (2)  CNS infections  Preferred: doxycycline 100 mg PO or IV Q12H +/− rifampin 300 mg PO or IV Q12H  Endocarditis (confirmed Bartonella)  Doxycycline 100 mg IV Q12H + gentamicin 1 mg/kg IV Q8H x 2 weeks, then doxycycline 100 mg IV or PO Q12H  If renal insufficiency: doxycycline 100 mg IV Q12H + rifampin 300 mg IV or PO Q12H x 2 weeks, then doxycycline 100 mg PO Q12H  Other severe infections  Doxycycline 100 mg PO or IV Q12H + rifampin 300 mg PO or IV Q12H  Erythromycin 500 mg PO or IV Q6H + rifampin 300 mg PO or IV Q12H

71. May 2013www.aidsetc.org 71 Bartonellosis: Starting ART  Bartonella CNS or ophthalmic lesions: if not on ART, probably should treat with doxycycline + a rifamycin for 2-4 weeks before initiating ART

72. May 2013www.aidsetc.org 72 Bartonellosis: Monitoring and Adverse Effects  Check Bartonella IgG titer at diagnosis and (if positive) every 6-8 weeks until 4-fold decrease  Oral doxycycline: risk of pill-associated ulcerative esophagitis  Rifamycins have significant interactions with many ARVs; some combinations must be avoided  IRIS has not been described

73. May 2013www.aidsetc.org 73 Bartonellosis: Treatment Failure  Consider alternative second-line regimens (above)  If positive or increasing Ab titer, treat until a 4-fold decrease

74. May 2013www.aidsetc.org 74 Bartonellosis: Preventing Recurrence  Secondary prophylaxis:  In case of relapse after ≥3 months of treatment, long-term suppression is recommended while CD4 count <200 cells/µL: doxycycline or macrolide  Discontinuing suppressive therapy:  After 3-4 months of therapy and CD4 count >200 cells/µL for ≥6 months; some also require a 4-fold decrease in Bartonella titers

75. May 2013www.aidsetc.org 75 Bartonellosis: Considerations in Pregnancy  No data on Bartonella infections during pregnancy in HIV-infected women; in HIV- negative women, B bacilliformis associated with increased complications and risk of death  Diagnosis as in nonpregnant women  Treatment: erythromycin recommended; avoid tetracyclines (hepatotoxicity and staining of fetal teeth)  Alternative: 3rd-generation cephalosporins (1st- and 2nd-generation cephalosporins not effective against Bartonella)

76. Bacterial Infections Syphilis

77. May 2013www.aidsetc.org 77 Syphilis: Epidemiology  Caused by Treponema pallidum  Associated with increased risk of HIV sexual acquisition and transmission  Increased incidence in men who have sex with men  HIV infection may somewhat alter diagnosis, natural history, and management of syphilis, but principles of management are the same with or without HIV infection

78. May 2013www.aidsetc.org 78 Syphilis: Clinical Manifestations  HIV may make clinical lesions more apparent and accelerate progression of syphilis  Primary syphilis  Painless nodule at site of contact, rapidly ulcerates (chancre)  In HIV-infected patients, may see multiple or atypical chancres, or no primary lesion

79. May 2013www.aidsetc.org 79 Syphilis: Clinical Manifestations (2) Chancres of primary syphilis Credit: Centers for Disease Control and Prevention

80. May 2013www.aidsetc.org 80 Syphilis: Clinical Manifestations (3)  Secondary syphilis (2-8 weeks after primary inoculation)  Protean symptoms, may involve almost any organ system and include:  Rash (macular, maculopapular, papulosquamous, or pustular); or condyloma lata  Generalized lymphadenopathy  Constitutional symptoms (fever, malaise, anorexia, arthralgias, headache)  CNS symptoms  Symptoms last days-weeks  In advanced HIV infection, may be more severe or progress more rapidly  Distinguish from primary HIV infection

81. May 2013www.aidsetc.org 81 Syphilis: Clinical Manifestations (4) Rash of secondary syphilis Credit: Centers for Disease Control and Prevention

82. May 2013www.aidsetc.org 82 Syphilis: Clinical Manifestations (5)  Latent syphilis: no overt signs/symptoms (but serologic evidence of syphilis), though relapse of manifestations of secondary syphilis may occur  Late syphilis: cardiovascular syphilis, gummatous syphilis; or slowly progressive disease in any organ system

83. May 2013www.aidsetc.org 83 Syphilis: Clinical Manifestations (6) Neurosyphilis: May occur at any stage of syphilis, with various symptoms  Cranial nerve dysfunction, stroke, meningitis, acute or chronic mental status change, loss of vibration sense, auditory or ophthalmic abnormalities, similar in HIV-uninfected patients  Concomitant uveitis and meningitis more common in HIV-positive patients

84. May 2013www.aidsetc.org 84 Syphilis: Diagnosis  Direct detection of T pallidum  Darkfield microscopy of mucocutaneous lesion, DFA- TP, biopsy with silver stain  Presumptive serologic diagnosis tests  Nontreponemal serologic tests (VDRL, RPR)  Treponemal tests (eg, FTA-ABS, TP-PA, EIAs, chemiluminescence immunoassays)

85. May 2013www.aidsetc.org 85 Syphilis: Diagnosis (2)  Testing algorithms:  Traditional: screening for nontreponemal antibodies + confirmation of reactive tests by treponemal assay  Newer: screening with treponemal test (EIA or CIA), with reflex nontreponemal test if positive  May identify previously treated syphilis infection more often than untreated infection  If positive treponemal screening test and negative reflex nontreponemal test: second treponemal test should be done (using different antigens) to confirm  I f second treponemal test is positive: assess risk factors and prior syphilis treatment  If suspected primary syphilis: treat empirically, retest with nontreponemal test in several weeks to confirm diagnosis  If no evidence of primary syphilis: treat for late-latent syphilis (unless past treatment can be confirmed)  If second treponemal test is negative: no treatment indicated

86. May 2013www.aidsetc.org 86 Syphilis: Diagnosis (3)  Early-stage disease:  Nontreponemal serologic tests (VDRL, RPR) may show atypical responses (higher, lower, or delayed) in HIV-infected patients  False-negative tests possible (as in HIV- uninfected patients); pursue other diagnostic tests if high suspicion of syphilis (eg, repeat serology, biopsy, DFA of lesion material; exclude prozone phenomenon)

87. May 2013www.aidsetc.org 87 Syphilis: Diagnosis (4)  Latent syphilis:  Serologic tests positive but no clinical manifestations  Early latent: evidence of infection <1 year  Late latent: evidence of infection >1 year or duration is not known

88. May 2013www.aidsetc.org 88 Syphilis: Diagnosis (5)  Late-stage disease:  Cardiovascular and gummatous: same as for HIV-uninfected patients

89. May 2013www.aidsetc.org 89 Syphilis: Diagnosis (6)  Neurosyphilis:  All with syphilis (regardless of stage) should be evaluated for clinical evidence of CNS or ocular involvement  CSF exam should be done for any patient with:  Neurologic, auditory, or ophthalmic symptoms or signs  Tertiary syphilis  Treatment failure (on basis of serologic tests)  CSF abnormalities (elevated protein, mononuclear pleocytosis) common in early syphilis and in HIV, without neurologic symptoms: no evidence that clinical and prognostic significance is different in HIV-infected and HIV-uninfected with early syphilis

90. May 2013www.aidsetc.org 90 Syphilis: Diagnosis (7)  Neurosyphilis:  No single test used to diagnose; instead, various combinations of reactive serologic tests, CSF cell count and protein, and reactive CSF-VDRL with or without clinical manifestations support the diagnosis

91. May 2013www.aidsetc.org 91 Syphilis: Diagnosis (8)  Neurosyphilis:  CSF examination  Mild mononuclear pleocytosis (6-200 cells/µL), normal or mildly elevated protein  CSF VDRL  Specific; not sensitive (reactive test establishes neurosyphilis; nonreactive test does not exclude it)  CSF FTA-ABS  Highly sensitive; less specific (reactive test does not establish the diagnosis; nonreactive test excludes neurosyphilis)  PCR-based methods not recommended

92. May 2013www.aidsetc.org 92 Syphilis: Diagnosis (9)  Neurosyphilis testing, considerations:  Reactive CSF VDRL plus CSF WBC ≥10 cells/µL supports diagnosis of neurosyphilis  Mild mononuclear CSF pleocytosis (6-15 cells/µL) may be associated with HIV infection itself and may complicate diagnosis of neurosyphilis; using cutoff of >20 cells/µL may improve specificity of neurosyphilis diagnosis in HIV-infected patients  Elevated CSF protein concentration should not be used as sole diagnostic criterion

93. May 2013www.aidsetc.org 93 Syphilis: Preventing Exposure  Risk screening should be routine  Client-centered risk-reduction messages; give specific actions to reduce risk of acquiring STIs and for transmitting HIV  Routine serologic testing for syphilis at least annually; Q 3-6 months if multiple partners, unprotected intercourse, injection drug or methamphetamine use, or partners with risks  Consider referral for behavioral intervention  Evaluate for other STIs

94. May 2013www.aidsetc.org 94 Syphilis: Preventing Disease  For persons exposed sexually to someone with syphilis: evaluate clinically and serologically and treat presumptively  Persons exposed within the 90 days preceding diagnosis of primary, secondary, or early-latent syphilis in a sex partner may be infected even if tests are seronegative: treat presumptively  Persons exposed >90 days before diagnosis of primary, secondary, or early-latent syphilis in a sex partner: treat presumptively if serologic test results are not available immediately and follow-up is uncertain

95. May 2013www.aidsetc.org 95 Syphilis: Treatment  Management similar to that for HIV-uninfected persons, but rates of serologic treatment failure and neurologic complications may be higher in HIV infection; closer follow-up is recommended  Penicillin is treatment of choice  Patients with penicillin allergy whose compliance or follow-up cannot be ensured: desensitize and treat with penicillin  Use alternatives to penicillin only with close clinical and serologic monitoring  Azithromycin resistance and treatment failure; especially in men who have sex with men (MSM)

96. May 2013www.aidsetc.org 96 Syphilis: Treatment (2) Early stage (primary, secondary, early-latent)  Preferred:  Benzathine penicillin G 2.4 million units IM, single dose  Alternative (for penicillin-allergic patients; monitor closely):  Doxycycline 100 mg PO BID for 14 days  Ceftriaxone 1 g IM or IV QD for 10-14 days  Azithromycin 2 g PO for 1 dose (note: reports of treatment failure and resistance; should not be used in MSM or pregnant women)

97. May 2013www.aidsetc.org 97 Syphilis: Treatment (3) Late-latent (no signs of neurosyphilis)  Preferred:  Benzathine penicillin G 2.4 million units IM weekly for 3 weeks  Alternative (for penicillin-allergic patients):  Doxycycline 100 mg PO BID for 28 days (not thoroughly evaluated in HIV-infected patients; monitor closely) Late-stage (cardiovascular or gummatous)  CSF examination; consult ID specialist  Preferred: Benzathine penicillin G 2.4 million units IM weekly for 3 weeks

98. May 2013www.aidsetc.org 98 Syphilis: Treatment (4) Neurosyphilis, otic syphilis, ocular syphilis  Preferred:  Aqueous crystalline penicillin G, 18-24 million units daily, as 3-4 million units IV Q4H or continuous infusion for 10-14 days  Consider addition of benzathine penicillin 2.4 million units IM weekly for 3 weeks after completion of IV therapy  Alternative:  Procaine penicillin G 2.4 million units IM QD + probenecid 500 mg PO QID for 10-14 days  Consider addition of benzathine penicillin 2.4 million units IM weekly for 3 weeks after completion of above  Patients with sulfa allergy should not receive probenecid, so this regimen is not recommended for them  Penicillin allergy:  Desensitization to penicillin is preferred; if not feasible, ceftriaxone 2 g IM or IV QD for 10-14 days

99. May 2013www.aidsetc.org 99 Syphilis: Starting ART  No special considerations, no evidence that ART should be delayed until after treatment for syphilis  IRIS is uncommon  Use of ART associated with:  Decreased risk of serologic failure of syphilis treatment  Lower risk of neurosyphilis  Normalization of CSF parameters after treatment

100. May 2013www.aidsetc.org 100 Syphilis: Monitoring and Adverse Events  Monitor clinical and serologic response to treatment; assure at least 4-fold decline from titer done at time of treatment:  Early stage: at 3, 6, 9, 12, 24 months  Late-latent: at 6, 12, 18, 24 months  Consider treatment failure: persistence or recurrence in clinical signs and symptoms or sustained 4-fold increase in nontreponemal test titer  Neurosyphilis: if CSF pleocytosis present initially, repeat CSF exam at 6 months; also repeat if symptoms recur or nontreponemal titer increases by 4-fold  Consider retreatment if no decrease in CSF WBC by 6 months or if WBC not normal by 2 years

101. May 2013www.aidsetc.org 101 Syphilis: Monitoring and Adverse Events (2)  After successful treatment, nontreponemal tests may remain “serofast,” ie, reactive at stable titer, usually low (≤1:8)  Sustained ≥4-fold increase in titer indicates reinfection

102. May 2013www.aidsetc.org 102 Syphilis: Monitoring and Adverse Events (3)  Jarisch-Herxheimer reaction may occur in the first 24 hours after start of syphilis treatment  Fever, headache, myalgia  Manage symptoms with antipyretics  Most frequent in those with early syphilis, high nontreponemal titers, and prior penicillin treatment

103. May 2013www.aidsetc.org 103 Syphilis: Treatment Failure Early stage  Consider CSF evaluation and retreatment if:  ≤4-fold decrease in serum nontreponemal test titer 6-12 months after therapy, or  Sustained 4-fold increase in titer after initial 4-fold reduction after treatment, or  Persistent or recurring signs or symptoms of syphilis  Reinfection is difficult to document and treatment failure is difficult to rule out  If no appropriate titer response after CSF evaluation and retreatment, management is unclear  >15% of early syphilis patients (HIV infected and uninfected) do not have 4-fold decline in titer after treatment

104. May 2013www.aidsetc.org 104 Syphilis: Treatment Failure Syphilis: Treatment Failure (2) Early stage  Retreatment: benzathine penicillin G, 2.4 million units weekly for 3 weeks (if neurosyphilis present, treat for that)

105. May 2013www.aidsetc.org 105 Syphilis: Treatment Failure (3) Late-latent stage  Repeat CSF exam and retreat if:  Clinical signs or symptoms of syphilis, or  Sustained 4-fold increase in titer after initial reduction after treatment, or  ≤4-fold decrease in serum nontreponemal test titer within 12-24 months after therapy  Treatment: benzathine penicillin G, 2.4 million units weekly for 3 weeks (if neurosyphilis present, treat for that)

106. May 2013www.aidsetc.org 106 Syphilis: Treatment Failure (4) Neurosyphilis  Consider retreatment if:  CSF WBC count has not decreased 6 months after completion of treatment, or  CSF WBC count is not normal 2 years after treatment

107. May 2013www.aidsetc.org 107 Syphilis: Preventing Recurrence  Secondary prevention and maintenance therapy not indicated

108. May 2013www.aidsetc.org 108 Syphilis: Considerations in Pregnancy  Screening:  At 1st prenatal visit in all women; in high-prevalence areas or high-risk women, repeat early in 3rd trimester and at delivery  Transmission to the fetus and adverse pregnancy outcomes highest with early-stage syphilis  Pregnancy does not alter the clinical course or diagnostic test results of syphilis in adults  Syphilis associated with increased risk of perinatal HIV transmission to infants

109. May 2013www.aidsetc.org 109 Syphilis: Considerations in Pregnancy (2)  Use penicillin, if possible, as in nonpregnant HIV-infected adults  Penicillin is effective for preventing syphilis transmission to the fetus and for treatment of fetal infection  Optimal penicillin regimen is not clear  In early syphilis, consider second injection of benzathine penicillin G 1 week after first dose  No alternatives to penicillin proven effective and safe for treatment of syphilis during pregnancy or prevention of fetal infection  Pregnant women with syphilis and history of penicillin allergy should undergo desensitization and treatment with penicillin

110. May 2013www.aidsetc.org 110 Syphilis: Considerations in Pregnancy (3)  Jarisch-Herxheimer reaction in 2nd half of pregnancy may precipitate preterm labor or fetal distress  In 2nd half of pregnancy, sonographic evaluation for fetal or placental syphilis  Consult with OB specialists  After treatment, repeat serologic titers in 3rd trimester and at delivery  Insufficient data on serologic responses after therapy  Treatment likely inadequate if delivery ≤30 days of treatment, if woman has sign of infection at delivery, or if maternal titer is 4-fold higher than pretreatment titer

111. May 2013www.aidsetc.org 111 Websites to Access the Guidelines  http://www.aidsetc.org  http://aidsinfo.nih.gov

112. May 2013www.aidsetc.org 112  This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in June 2013  See the AETC NRC website for the most current version of this presentation: http://www.aidsetc.org About This Slide Set