MULTIDRUG-RESISTANT GONORRHEA Accessible version: - PowerPoint PPT Presentation

THE GROWING THREAT OF MULTIDRUG-RESISTANT GONORRHEA Accessible version: https://youtu.be/rE2th3A0Oxs  Edward W. Hook, III, MD University of Alabama, Birmingham Neisseria gonorrhoeae Infections and the Emergence of Antimicrobial Resistance  William Shafer, PhD Emory University Molecular Basis of N. gonorrhoeae Resistance to Antimicrobials  Carolyn Deal, PhD National Institute for Allergy and Infectious Disease, National Institutes of Health New Tools to Combat Multidrug Resistance  Robert D. Kirkcaldy, MD, MPH National Center for HIV, Viral Hepatitis, STD, and TB Prevention, CDC What Public Health Can Do Now and in the Future 1

Neisseria gonorrhoeae Infections and the Emergence of Antimicrobial Resistance Edward W. Hook, III, MD Professor of Medicine University of Alabama at Birmingham Jefferson County Department of Health Birmingham, Alabama 2

Disclosure  Receive grant support for clinical trials from Cepheid, Becton Dickinson, Roche Molecular GenProbe, and Cempra Pharmaceuticals  Receive fees from MedHelp.org for serving as a content expert 3

Outline  N. gonorrhoeae (gonococcus) infections  Evolution of antimicrobial treatment  Surveillance for antimicrobial resistance  Current treatment recommendations  The emerging threat of cephalosporin-resistant N. gonorrhoeae 4

Burden of Gonococcal Disease in the United States  >300,000 cases reported in 2010  Approximately 50% underestimation  The spectrum of gonococcal infections  Uncomplicated local disease (urethrititis/cervicitis)  Complications disproportionately impact women 5

Complications of Untreated Gonorrhea  Pelvic inflammatory disease (PID) leads to scarring and  Infertility  Ectopic pregnancy  Chronic abdominal pain  Disseminated gonococcal infection  Childhood blindness (neonatal infection)  Increased risk for HIV transmission and acquisition 6

Gonorrhea Case Report Rates United States, 1941 – 2010 500 Rate (per 100,000 population) 400 300 200 100 0 1941 1946 1951 1956 1961 1966 1971 1976 1981 1986 1991 1996 2001 2006 Year CDC. Sexually Transmitted Disease Surveillance 2010. Atlanta: U.S. Department of Health and Human Services; 2011 7

Gonorrhea Case Report Rates by County, 2010 Rate per 100,000 population <19.0 (n = 1,408) 19.1 – 100.0 (n = 1,107) >100.0 (n = 627) CDC. Sexually Transmitted Disease Surveillance 2010. Atlanta: U.S. Department of Health and Human Services;2011 8

Gonorrhea Case Report Rates by Race/Ethnicity, 2001 – 2010 600 Rate (per 100,000 population) 500 400 American Indians/Alaska Natives 300 Asians/Pacific Islanders Blacks Hispanics 200 Whites 100 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Year CDC. Sexually Transmitted Disease Surveillance 2010. Atlanta: U.S. Department of Health and Human Services; 2011 9

Treatments for Gonorrhea Before 1937 Were Ineffective and/or Toxic 10

Sulfonamides and Penicillin for Treatment of Gonorrhea  Sulfonamide therapy introduced 1937  Penicillin proved effective 1940s  Sulfonamide resistance in 34% of patients  Penicillin dosage increased; probenicid added 1972  Penicillin no longer drug of choice 1989 11

Antimicrobials Previously Recommended for Treatment of Gonorrhea  Sulfonamides  Penicillin  Macrolides  Tetracyclines  Aminoglycosides  Spectinomycin  Fluoroquinolones 12

The Gonococcal Isolate Surveillance Project (GISP)  CDC-supported U.S. sentinel surveillance since 1987  Monitors trends in N. gonorrhoeae susceptibility to antimicrobials  30 STD clinic sites  Methods  Urethral N. gonorrhoeae isolates obtained from the first 25 men per site each month  Susceptibility testing conducted by 5 regional laboratories  Minimum inhibitory concentrations (MICs) by agar dilution  Confirmatory testing by CDC NG , Neisseria gonorrhoeae STD, Sexually transmitted diseases 13

GISP Sites and Regional Laboratories 2012 S e a t t l e P o r t l a n d M i n n e a p o l i s P o n t i a c N e w Y o r k C i t y P h i l a d e l p h i a C l e v e l a n d C h i c a g o D e n v e r S a n F r a n c i s c o B a l t i m o r e K a n s a s C i t y R i c h m o n d L a s V e g a s L o s A n g e l e s G r e e n s b o r o O k l a h o m a C i t y O r a n g e C o . A l b u q u e r q u e B i r m i n g h a m S a n D i e g o P h o e n i x A t l a n t a D a l l a s A u s t i n N e w O r l e a n s T r i p l e r A M C S e n t i n e l S i t e s H o n o l u l u S i t e s a n d M i a m i R e g i o n a l L a b s GISP, Gonococcal Isolate Surveillance Project 14

Antimicrobial Options for Treatment of Gonorrhea in 2006 ONE OF THE FOLLOWING Ceftriaxone 125 mg IM Cefixime 400 mg PO Ciprofloxacin 500 mg PO* Ofloxacin 400 mg PO* Levofloxacin 250 mg PO* AND Azithromycin 1 g single dose or doxycycline 100 mg twice a day for 7 days if chlamydial infection is not ruled out * Not for MSM or travelers CDC. Sexually Transmitted Disease Treatment Guidelines, 2006. MMWR 2006; Volume 55 (RR-11) IM, intramuscularly PO, by mouth MSM, men who have sex with men 15

Ciprofloxacin Resistance and Intermediate Resistance in N. gonorrhoeae, United States, 1990 – 2008 20 Intermediate Resistance Prevalence, % 16 Resistance 12 8 4 0 1990 1993 1996 1999 2002 2005 2008 16 Year GISP, Gonococcal Isolate Surveillance Project, 1990 – 2008 Resistant isolates have ciprofloxacin MICs ≥1 µg/ml. Isolates with intermediate resistance have ciprofloxacin MICs of 0.125 - 0.5 µg/ml Susceptibility to ciprofloxacin was first measured in GISP in 1990 16

Ciprofloxacin Resistance in N. gonorrhoeae, United States, 1990 – 2007 40 35 Prevalence , % 30 California Hawaii 25 20 15 Rest of 10 the US 5 0 1990 1995 2000 2005 Year GISP, Gonococcal Isolate Surveillance Project, 1990 – 2007 Resistant isolates have ciprofloxacin MICs ≥1 µg/ml 17

Ciprofloxacin Resistance in N. gonorrhoeae, by Sex of Sex Partner, United States, 1999-2007 45 40 Prevalence, % 35 MSM 30 25 20 15 10 MSW 5 0 1999 2001 2003 2005 2007 Year GISP, Gonococcal Isolate Surveillance Project, 1990 – 2007 Resistant isolates have ciprofloxacin MICs ≥1 µg/ml MSM, men who have sex with men MSW, men who have sex exclusively with women 18

Changes in Gonorrhea Treatment, 2007 ONE OF THE FOLLOWING Ceftriaxone 125 mg IM Cefixime 400 mg PO Ciprofloxacin 500 mg PO* Ofloxacin 400 mg PO* Levofloxacin 250 mg PO* AND Azithromycin 1 g single dose or doxycycline 100 mg twice a day for 7 days if chlamydial infection is not ruled out * Not for MSM or travelers CDC. Sexually Transmitted Disease Treatment Guidelines, 2006. MMWR 2006; Volume 55 (RR-11) IM, intramuscularly PO, by mouth MSM, men who have sex with men 19

Antimicrobial Options for Treatment of Gonorrhea, 2010 Ceftriaxone 250 mg IM OR Cefixime 400 mg PO AND Azithromycin 1 g single dose OR Doxycycline 100 mg twice daily for 7 days CDC. Sexually Transmitted Disease Treatment Guidelines, 2010. MMWR 2010; Volume 59 (RR-12) IM, intramuscularly PO, by mouth 20

Elevated Cefixime and Ceftriaxone MICs in N. gonorrhoeae 3 Cefixime 2.5 Prevalence, % 2 Ceftriaxone 1.5 1 0.5 0 2006 2007 2008 2009 2010 2011* Year GISP, Gonococcal Isolate Surveillance Project * Cefiixime susceptibility not tested in 2007 and 2008 Elevated cefixime MICs ≥ 0.25 μg/ml; elevated ceftriaxone MICs ≥ 0.125 g/ml MIC, minimum inhibitory concentration 21

Percentage of Gonococcal Isolates with Elevated Cefixime MICs (≥0.25 µg/ml), 2005– 2011* 5 4 MSM Isolates, % West 3 2 1 Midwest MSW Northeast/South 0 2005 2006 2009 2010 2011* Year Gonococcal Isolate Surveillance Project, January-August, 2011 Susceptibility to cefixime not tested during 2007 – 2008 MSM, men who have sex with men; MSW = men who have sex exclusively with women MIC, minimum inhibitory concentration 22

Possible Changes in Treatment Recommendations  Recommended  Ceftriaxone 250 mg PLUS  Azithromycin 1 g single dose or doxycycline 100 mg twice a day for 7 days  Oral therapy as alternative (“second - line”) 23

Molecular Basis of N. gonorrhoeae Resistance to Antimicrobials William Shafer, PhD Professor of Microbiology and Immunology Emory University Atlanta, Georgia 24

Outline  Resistance mechanisms expressed by the gonococcus  Culture-based antimicrobial susceptibility testing  Detection of antimicrobial resistance markers using molecular assays 25

Genetic Basis of Antimicrobial Resistance of the Gonococcus  The gonococcus mutates rapidly  Resistance results from mutations and acquisition of new genes  Resistance is promoted by selection pressure  Antimicrobials kill susceptible strains, but allow resistant strains to survive  Resistance genes then spread to other strains of the gonococcus 26

Resistance of Gonococci to Penicillin and Ciprofloxacin  Importance of mechanisms by which the gonococcus developed resistance to penicillin and ciprofloxacin  Persistence of resistance genes  Some of the same systems are making the gonococcus less susceptible to ceftriaxone and cefixime, which are the main antimicrobials used to cure gonorrhea today 27