Sex and the Superbug: - PowerPoint Presentation

Slide1

Sex and the Superbug:Next Steps in Dealing with Multi-drug Resistant Gonorrhea in Maryland

Khalil Ghanem, MD, PhD

Associate Professor of Medicine

Johns Hopkins University School of MedicineDirector, STD/HIV/TB Clinical ServicesBaltimore City Health Department

October 4, 2012

Jafar H. Razeq, PhD, HCLD(ABB)Chief, Public Health MicrobiologyLaboratories AdministrationMaryland Department of Health and Mental HygieneSlide2

E-mail your questions for the presenters to:maphtc@jhsph.eduSlide3

Khalil Ghanem

, MD, PhD

Part 1Slide4

DisclosuresNo relevant financial disclosuresSlide5

Gonorrhea Rates, United States

1941-2007

5Slide6

Gonorrhea Prevalence by Geographic Region6Slide7

Gonorrhea Prevalence by Race/Ethnicity7Slide8

Gonorrhea Prevalence by Age8Slide9

Source: Center for STI Prevention, Maryland Department of Health and Mental Hygiene

Gonorrhea Incidence Rates

in Maryland, 2007-2011Slide10

Source: Center for STI Prevention, Maryland Department of Health and Mental Hygiene

Gonorrhea Incidence Rates by Gender

Maryland, 2007-2011Slide11

Source: Center for STI Prevention, Maryland Department of Health and Mental Hygiene

Gonorrhea by Age (10–25)

Maryland, 2010-2011Slide12

The Percent of Asymptomatic STDs Slide13

Screening for Gonorrhea in Women Targeted screening is recommended for high-risk women (e.g. previous gonorrhea infection, other STIs, new or multiple sex partners, and inconsistent condom use;

CSW and drug use; area of high prevalence)Screening is recommended at the first prenatal visit for pregnant women who are in a

high-risk group for gonorrhea infection. Those who are at continued risk, and for those who acquire a new risk factor, a second screening should be conducted during the third trimester

Repeat testing (i.e. retesting or rescreening) of GC+ patients recommended 3 months after treatment Slide14

Screening for Gonorrhea in Men The USPSTF found insufficient evidence to recommend for or against routine screening for gonorrhea infection in men at increased risk for infection, but CDC recommends annual gonorrhea screening for all sexually active MSM by testing for urethral infection in men who have had insertive intercourse in past year, rectal infection in men who have had receptive anal intercourse in past year, and pharyngeal infection in men who have had receptive oral intercourse in past

yearRepeat testing (i.e. retesting or rescreening) of GC+ patients recommended 3 months after treatment Slide15

Prevalence of Extragenital Sexual BehaviorsORAL SEXANAL SEX

Oral Sex

Males

Females

Active Oral

Passive OralActive OralPassive OralLifetime77%79%68%73%Last sex

27%

28%

19%

28%

Young MSM: 50%

Young heterosexual men and women: 14-49%

Ekstrand M, et al. AIDS 1999; 13 (12): 1525-33

Halperin D, et al. AIDS Patient Care STDs 1999; 13(12); 717-30

Michael RT,

et al.

Sex in America: A Definitive Survey.

Little

, Brown and Co. UK.

1994Slide16

Extragenital Gonorrhea and Chlamydia InfectionsStudies suggest that up to 65% of cases of gonorrhea and 50% of cases of chlamydia among MSM may be missed if genital-only testing were performed Sex Transm Dis. 2008;35(10):845

Clin Infect Dis. 2005;41(1):67

In women, 10% of CT and 31% of GC infections would have been missed if extragenital testing were not done Sex Transm Dis. 2011;38(9):783

The majority of rectal and pharyngeal GC & CT infections are ASYMPTOMATICRectal and pharyngeal infections are of public health significance Clin Infect Dis. 2009;49(12):1793Slide17

Extragenital STI DiagnosticsAll persons should be tested for rectal and pharyngeal gonorrhea if they report pharyngeal or rectal exposuresSensitivity of culture <50% to detect rectal and pharyngeal GC vs. >90% sensitivity for Nucleic Acid Amplification Tests (NAATs) Sex Transm Infect. 2009 Jun;85(3):182-

6The CDC recommends that NAATs be used to detect these extragenital infections

MMWR Recomm Rep. 2011 ;60(1):18

If NAATs for extragenital testing of GC are not feasible in your setting, use culture to detect these infections. It is an acceptable alternativeSlide18

Extragenital NAATsAlthough none of the NAATs are FDA cleared to use with extragenital specimens, most large laboratories have conducted in-house validation assays and they are able to provide this serviceCheck with your local laboratory to see if they can provide extragenital NAATs testingSee slide on ‘CPT Codes and Laboratory Test Codes’ at the end of my presentation for additional detailsSlide19

Efficacy of Antibiotics for GCCephalosporinsMacrolides

Ceftriaxone 250mg IM X 1>98% anogenital>98% pharyngealCefixime 400mg PO X 1>97% anogenital

90% pharyngeal

Azithromycin 1g PO X 197% anogenital? PharyngealAzithromycin 2g PO X 1*99% anogenital99% pharyngeal * 20% vomiting within 1hSlide20

Unemo M, Shafer WM. Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. Ann N Y Acad Sci. 2011;1230:E19-28

History of Antibiotic ResistanceSlide21

GC Macrolide Resistance U.S.126 GISP isolates with reduced susceptibility to azithromycin (at MIC ≥2 μg per milliliter) have been reported in the United States since 2005, including 27(0.5% of GISP isolates) in

2010The first strain with high-level resistance to

azithromycin(MIC ≥512 μg per milliliter) identified in the United States was detected in Hawaii in

2011 and several strains have now been detected in Hawaii and CaliforniaClin Infect Dis 2012; 54:841MMWR;60(18):579-81Slide22

Reduced Susceptibility to Cephalosporins WorldwideSlide23

Cephalosporin MICs in the US:2000-2011MMWR 2011 Jul 8;60(26):873-7

Although the MIC breakpoints

for resistance to cephalosporin

have not been defined, theCLSI defines susceptibility tocefixime and ceftriaxone as MICs of 0.25 μg per milliliter or below, and 0.125 μg per milliliter or below, respectivelyN Engl J Med. 2012;366(6):485-7Slide24

GC Cephalosporin Resistance in BaltimoreIn November 2011, the Baltimore GISP Program identified the first cephalosporin resistant strain.

The Baltimore strain was resistant to cefixime and cefpodoxime (MIC of 0.5), sensitive to ceftriaxone (MIC of 0.06) and sensitive to ciprofloxacinSlide25

Mechanisms of Resistance to CephalosporinsCombined effects of several chromosomal mutations:PenA (PBP2)PenB (PorB1b)MtrR (MTRCDE- encoded pump repressor)Mosaic PenANovel mutation resulting in cefixime resistance

Acquired via horizontal transfer from oral commensal bacteria

N Engl J Med

. 2012;366(6):485-7Slide26

Importance of Maintaining GC Culture Capacity26

Culture is currently the only reliable method for determining antibiotic susceptibility

Maryland is one of the few states that has maintained culture capacity

GISP analyses are based on (a) demographic and clinical data from the first 25-30 male patients attending the sentinel clinics each month who have been identified to have a positive urethral culture for N. gonorrhoeae, and (b) antimicrobial susceptibility data from these urethral isolates.Slide27

Updated CDC Treatment Recommendations for GonorrheaFirst-Line (preferred)Ceftriaxone 250 mg IM X1 + Azithromycin

1g PO X 1 or Doxycycline 100mg PO BID X 7 daysAzithromycin is preferred over doxycycline but both are acceptable

Use dual therapy even if C. trachomatis is ruled out

!Alternate Cefixime 400mg PO X1 + Azithromycin 1g PO X1 or Doxycycline 100mg PO BID X 7 days

Azithromycin 2g PO X 1 (single therapy single dose) Azithromycin 2g PO X1 is the only regimen currently available to treat a patient who has an allergy to cephalosporins

MMWR 2012 ;61(31):590-4Slide28

Test of CureIf an alternate regimen is used to treat GC, patient should return 1 week after treatment

for a TEST OF CURE (culture is preferred but NAAT is also acceptable)

If a NAAT is performed as the test of cure and the follow-up NAAT result is positive, a specimen for culture should be obtained so that susceptibility testing can be performedSlide29

Treatment Failure with Cefixime-Based Regimen or Single-Dose Azithromycin RegimenCulture relevant clinical sites

and perform antimicrobial susceptibility testing

using disk diffusion, Etest, or agar dilution

Treat with Ceftriaxone 250 mg IM X 1 PLUS azithromycin 2g orally as a single doseTEST OF CURE:

culture (≥72 hours after re-treatment), if culture is not available, with NAAT (≥7 days after re-treatment). If the test of cure NAAT is positive, a specimen for culture should be obtained to both ensure that the NAAT result is reliable and

to allow for antimicrobial susceptibility testingEvaluate sex partners from the preceding 60 days with culture from all exposed sites and treat with ceftriaxone 250 mg IM X 1 PLUS azithromycin 2g orally as a single dose The laboratory should retain the isolate for possible further testing

MMWR

2012

;

61(31):590-4Slide30

Treatment Failure with Ceftriaxone-Based RegimenCulture relevant clinical specimens and perform antimicrobial susceptibility testing using disk diffusion, Etest, or agar

dilutionConsult an ID specialist, an STD/HIV Prevention Training Center (

http://www.nnptc.org), or CDC (404-639-8659 )for treatment advice, and report the case to CDC through the local or state health department within 24 h of diagnosis

A test-of-cure should be conducted 1 week after re-treatmentEvaluate sex partners from the preceding 60 days and treat with the same antimicrobial regimen with which the index patient was re-treated

MMWR 2012 ;61(31):590-4Slide31

Suspected Treatment Failure: Evaluating and Treating Sex Partners

If you suspect treatment failure, assure treatment for both patient and sex partner(s)

In Maryland, local health departments can help assure that sex partners of patients with suspected treatment failure get treatedSlide32

Case Reporting: It’s the Law! All Maryland providers are obligated by law to report all gonococcal infections and treatment information to local or State health officials http://baltimorehealth.org/std.html

http://

ideha.dhmh.maryland.gov/SitePages/reportable-diseases.aspxSlide33

Cephalosporin-Resistant Case ClassificationClinical CriteriaLaboratory CriteriaPatient

had laboratory-confirmed N. gonorrhoeae infection, andPatient received CDC-recommended cephalosporin-based antimicrobial regimen as treatment, and

Patient subsequently had a positive N. gonorrhoeae test result (positive culture ≥72 hours after treatment or positive NAAT ≥7 days after treatment), andPatient did not engage in sexual activity after treatment

Antimicrobial susceptibility testing of pre-treatment or post-treatment isolate of N. gonorrhoeae demonstrates:Cefixime MIC ≥0.25 μg/ml, orCeftriaxone MIC ≥0.125 μg/ml33

www.cdc.gov/std/treatment/Ceph-R-ResponsePlanJuly30-2012.pdfSlide34

Test-of-Cure vs. Re-screening Test of Cure (TOC)Rescreening

All persons who are treated with an alternate regimen for GC, or who have laboratory-evidence of cephalosporin resistance, or who are suspected of GC treatment failure should undergo a

TOC If culture is used for TOC, it can be done ≥72h after initial therapy

If NAATs are used for TOC, they can be performed ≥7d after initial therapy. The possibility of false-positivity with NAAT as early as 7 days after treatment is a concern, but is likely to be low*The goal of TOC is to rule out TREATMENT FAILUREAll persons who are treated for gonorrhea, chlamydia, or trichomoniasis should be rescreened 3 months after treatment For GC, rescreening can be done with either culture or NAATs (NAATs are more sensitive)The goal of rescreening is to rule out REINFECTION

*J Clin

Microbiol 2002;40(10):3596-601Slide35

Expedited Partner Therapy (EPT)At this time, Baltimore City Health Department (BCHD) is providing EPT services for gonorrhea and chlamydiaEPT may be expanded beyond BCHD in the not too distant futureIf a heterosexual partner of a patient cannot be linked to evaluation and treatment in a timely fashion, then expedited partner therapy should be considered, using oral combination antimicrobial therapy for gonorrhea (cefixime 400 mg and azithromycin 1 g) delivered to the partner by the patient, a disease investigation specialist, or through a collaborating

pharmacy

Emergence of resistance is threatening the viability of EPT for gonorrhea

MMWR 2012 ;61(31):590-4Slide36

Future Antimicrobial OptionsGentamicin Has been used as first-line treatment in Malawi during the past 15 years without any observed emergence of resistance ? Efficacy in pharynx

Carbapenems Depends on the ceftriaxone resistance mechanisms and the

penA alterations, of which most of them substantially also affect the carbapenem MICsSlide37

CPT Codes and Laboratory Test Codes

CPT Code

LabCorp Test Code

Quest Test CodeGC Culture (urethral, cervical, rectal, pharyngeal)87081* 008128480XGenital: 6916RAnal: 141275REye: 86421AGC NAA Genital

87591183194** (several)11362X* (several)

GC NAA Rectal8759118873016504XGC NAA Pharyngeal8759118874870049XGC + CT Rectal NAA87491 & 87591

188672

16506X

GC+CT Pharyngeal NAA

87491 & 87591

188698

70051X

*If

culture is positive, identification will be performed

using separate CPT

code(s): 87077 or 87140 or 87143 or 87147 or

87149. Antibiotic

susceptibilities are only performed when appropriate (CPT code(s): 87181 or 87184 or 87185 or 87186

)

** Several Lab Test Codes exist depending on the specimen source (urethral, urine, cervical)

NAA=nucleic acid amplification test; GC= gonorrhea; CT= chlamydiaSlide38

Injectable Ceftriaxone250mg, 500mg, 1g, and 2g vialsStored at 20°C to 25°C (68°F to 77°F) unopened

Once powder is diluted (usually with 1% lidocaine), may be stored in refrigerator and used within 72 hours of reconstitutionCost: $5-$12 for each 250mg doseSlide39

Jafar H.

Razeq

,

PhD

Part 2Slide40

DisclosuresNo relevant financial disclosuresSlide41

The “Superbug”David B.

FankhauserUniversity of Cincinnati Claremont CollegeSlide42

Neisseria gonorrhoeae (NG) is not considered part of human normal flora and the isolation of this organism is considered to be always significant.NG is an exclusive human pathogen.The organism is fastidious and environmentally sensitive pathogen;

The ideal and best way to recover the organism is to use Dacron or Rayon swabs to collect patient specimens. Inoculate immediately onto selective (unexpired) media, incubate at 35-37°C, under 5% CO

2, or transport the inoculated plate in a CO2-

generating system at room temperature. JCM 1988, 26:54-56 Cotton swabs can be toxic to NG. Manual of Clinical Microbiology, ASM, 10th ed.Slide43

“Z” Pattern Primary Inoculation Cross-Streaked

Proper Inoculation and StreakingSlide44

Proper Inoculation MethodStep 1

Slide45

Actual PlateSlide46

Proper Inoculation and Streaking Step 2 Slide47

Ideal PlateSlide48

Antimicrobial Susceptibility Testing(AST)

AST is offered at some Private Laboratories Our

Maryland State Public Health Laboratory is among the few state laboratories in the U.S. that offers AST for NGSlide49

For disc diffusion: discs containing known amounts of antimicrobial agents are placed on the surface of an agar plate that has been inoculated with NG isolated.Susceptible isolates usually show inhibition of growth around the disc.Slide50

The E-test is a strip containing a known gradient of an antimicrobial and calibrated to give results as MIC of that antibiotic.The strip is placed on the surface of an agar plate that has been inoculated with NG.Slide51

Global PictureFrom 2000 to 2009, more than 11,400 isolates from countries in Latin America were tested and found:Ciprofloxacin resistance increased from 2% to 31%Azithromycin resistance increased from 6% to 23%

Sex Transm

Dis. 2012 Oct,39(19):813-821Results from 17 EU Member

States in 2009 showed that 5% of isolates had decreased susceptibility to cefixime, an upward trend in the minimum inhibitory concentrations of ceftriaxone and a high prevalence of resistance to ciprofloxacin (63%) and azithromycin (13%).The European gonococcal antimicrobial survelliance programme, 2009.Slide52

Global Picture (continued)Emergence of high-level azithromycin resistance in N. gonorrhoeae in England and Wales

.The 2009 study showed a major shift in six isolates recovered from patients attending STI clinics with azithromycin MICs of > 256 mg/L.

J. Antimicrob Chemother 2009; 64, 353-358

The proportion of N. gonorrhoeae isolates with decreased susceptibility and resistance to cefixime and ceftriaxone have increased over the years in Sweden.All available Swedish isolates (331) from 1998-2009 were tested and results showed that 9.1% of the isolates displayed resistance to cefixime, and 0.3% resistance to ceftriaxone.Sex Transm Infect 2010; 86:454-460Slide53

National Picture

USA % Resistant

2009

2010

Penicillin

3.8

3.5

Tetracycline

7.9

9.4

Ciprofloxacin

2.1

2.9

For

Cefixime and Ceftriaxone

:

An average of 5,865 isolates tested annually

during 2000-2010

The percentage of isolates with an MIC of

>

0.25 µg/ml

for

cefixime

increased from 0.2% in 2000 to 1.4% in 2010

The percentage of isolates with an MIC of

>

0.125 µg/ml for ceftriaxone increased from 0.1% in 2000 to

0.3

% in 2010Slide54

Maryland State Picture

MD % Resistant

2009

2010

Penicillin

3

6

Tetracycline

20

27

Ciprofloxacin

5.4

4

Azithromycin

:

5 isolates have been detected with an MIC of

>

1.0 µg/mlSlide55

CDC recommends that State and local health departments should promote maintenance of laboratory capacity to culture NG to allow antimicrobial susceptibility testing

of isolates for cephalosporin resistance

` CDC/MMWR July 8, 2011/(60), 26:873-877

Alarming elevated MICs to CephalosporinsSlide56

Laboratories - Maintain Culture Capacity

The capacity of laboratories in the United States to isolate

NG

by culture is declining rapidly because of the widespread use of NAATs for gonorrhea diagnosis.It is essential that culture capacity for NG be maintained to monitor antimicrobial resistance trends and determine susceptibility to guide treatment following treatment failure. Laboratories must maintain culture capacity or develop partnerships with laboratories that can perform culture.

Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections. MMWR August 10, 2012 / 61(31);590-594. Slide57

Providers - Maintain Ability to Culture

To help control gonorrhea in the United States, health-care providers must maintain the ability to collect specimens for culture and be knowledgeable of laboratories to which they can send specimens for culture.

Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections. MMWR August 10, 2012 / 61(31);590-594. Slide58

Health Systems & Health Departments – Support Access to Culture

Health-care systems and health departments must support access to culture.

Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections. MMWR August 10, 2012 / 61(31);590-594. Slide59

IF NOT, then we will go from Resistant NG

and Multi-Drug Resistant NG

TO

Extensively-Drug-resistant NGPan/Totally Drug-Resistant NGUntreatable NG!Slide60

“It is probably only a matter of time before extensively drug-resistant N. gonorrhoeae strains become widespread and treatment failures, particularly for pharyngeal gonorrhoea, become commonplace.”

“Action is therefore urgently needed at local and international levels to combat the problem. We advise that government agencies take this threat seriously and provide urgently needed funds for increased research, surveillance activities and vaccine development.”

Whiley

DM,

Goire N, Lahra MM, et al. The ticking time bomb: escalating antibiotic resistance in

Neisseria gonorrhoeae is a public health disaster in waiting. J Antimicrob Chemother 2012; 67: 2059-2061. Slide61

Resources in Maryland

Maryland Department of Health and Mental Hygiene

Prevention and Health Promotion Administration

Center for Sexually Transmitted Infection Prevention410-767-6690http://ideha.maryland.gov/OIDPCS/CSTIP/SitePages/cstip-for-healthcare-providers.aspx

Division of Infectious Disease Surveillance Center for Surveillance, Infection Prevention and Outbreak Response 410-767-6700 http://ideha.maryland.gov/SitePages/reportable-diseases.aspx

Laboratories Administration

Division of Public Health Microbiology

http://dhmh.maryland.gov/laboratories/SitePages/micro.aspxSlide62

Questions/DiscussionE-mail questions for

the presenters to:

maphtc@jhsph.edu