Cephalosporin-Resistant Gonorrhea Response Plan for Texas

Goal

To minimize the impact of cephalosporin-resistant gonorrhea (Ceph-R NG) on the prevention and control of gonorrhea (GC) and its sequelae at the community level in Texas.

Assumptions

• Gonorrhea resistance to cephalosporins is inevitable.
• Resistance to cephalosporins in Texas will probably show up first in one of the communities where gonorrhea is commonly diagnosed. However, there is a possibility that resistance will show up in a smaller community.
• The CDC will probably tell us to start using a new treatment regimen before we see resistance in Texas.

Objectives

1. Surveillance systems will detect suspected or probable Ceph-R NG infections.

See Appendix A for surveillance responsibilities.

1. Heighten surveillance (in addition to GISP - Goncoccal Isolate Surveillance Project) in clinics where GC is commonly diagnosed.
2. Add a field in STD-MIS for Antibiotic Susceptibility Testing (AST).
3. Monitor antimicrobial susceptibility of isolates.
4. Monitor and investigate patients with multiple reports of GC infection within the preceding 30 to 60 days to determine treatment failure.

Challenges to Surveillance

1. Surveillance systems are not sensitive or timely enough to detect emergence of Ceph-R NG
2. Inadequate level of resources and surveillance personnel

Activities

1. Train surveillance staff on urgency of heightened surveillance, what AST is and why it is needed, how to enter data, etc.
2. Monitor patients with multiple reports of GC infection within the preceding 30 to 60 days to determine treatment failure vs. re-infection
3. Report suspected treatment failures to the local health authority in the regional or local health department immediately

2. Clinicians will have access to a laboratory that performs AST.

See Appendix E for responsibilities of state and local health departments.

1. Determine which public health labs in Texas have culture capability
2. Determine which private labs in Texas have AST capability
3. Provide access to appropriate clinical and laboratory supplies

Laboratory Challenges

1. Lack of appropriate testing supplies in clinicians’ offices and lab equipment, supplies, and storage in public health labs
2. Private labs are the only labs able to perform susceptibility testing
3. Few options for culture transport that preserve GC viability
4. Understaffed/underfunded public health labs
5. Resistance criteria are unclear

Activities

1. Survey public health labs to determine culture capacity
2. Survey private labs to determine AST capability
3. Inform laboratorians of the importance of prompt reporting of isolates that meet the criteria for suspect or probable Ceph-R NG
4. Encourage providers to determine procedures for ordering and performing AST with a private lab before they need to order the test

3. Clinicians will recognize Ceph-R NG and will take appropriate public health action in cases of suspected or probable cases.

See Appendix B.

Clinician Challenges

1. Clinicians may be unaware of risk factors for GC, case definitions for Ceph R NG, partner services, public health follow up, etc.
2. Communication barriers between the clinician and the patient may lead to sub-optimal sexual histories
3. Clinicians may not be aware of the correct treatment
4. Clinicians may treat patients based on symptoms without culturing or testing the patient
5. Most clinicians do not have appropriate supplies in their office for collecting cultures
6. Clinicians may not know when and where to report STDs

Activities

Publish “Dear Colleague” letter from the DSHS Infectious Disease Medical Officer outlining actions clinicians should implement in their practices to enhance the early detection of Ceph-R NG:

1. Maintain vigilance
2. Take a thorough sexual history
3. Obtain specimens from all exposure sites for culture and AST from patients with suspected treatment failure
4. Promptly report cases that meet the criteria for suspected or probable Ceph-R NG to the state or local health department (See Appendix D to find the Local Reporting Authority by region and county).

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APPENDIX A
Surveillance Responsibilities

1. Heighten surveillance (in addition to GISP) in the communities where GC is commonly diagnosed.
2. Monitor and investigate patients with multiple reports of GC infection within the preceding 30 to 60 days to determine whether infection is a treatment failure (or duplicative report or re-infection).
3. Report suspected or probable Ceph-R NG to the local health authority in the regional or local health department immediately.
4. The local reporting authority will report suspected or probable Ceph-R NG to DSHS STD Surveillance.
5. STD Program Managers should routinely review local GC AST results from the local public health labs and commercial labs that are performing AST.

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APPENDIX B
Clinician Responsibilities

Detecting Possible Cephalosporin Treatment Failure

Clinicians should maintain a high index of suspicion when treating gonorrhea infections. Cephalosporin treatment failure is the persistence of N. gonorrhoeae infection despite appropriate cephalosporin treatment and could indicate infection with Ceph-R NG. See clinical case definitions below. Patients diagnosed with gonorrhea should be educated about Ceph-R NG and instructed to return to care if symptoms do not resolve within 3–5 days. Routinely recommend test of cure if the patient is a man who has sex with men (MSM). Patients also should be informed of the need for their partners to be treated and advised to avoid sex for one week following treatment.

Treatment failure due to Ceph-R NG infection should be considered in:

1. Patients whose symptoms do not resolve within 3-5 days after appropriate treatment and who report no sexual contact during the post-treatment follow-up period
2. Patients with a positive test of cure (positive culture =72 hours or positive nucleic acid amplification test [NAAT] =7 days after appropriate treatment) when no sexual contact is reported during the post-treatment follow-up period
3. Patients with a positive N. gonorrhoeae culture within 30–60 days (but more than 72 hours) after treatment for gonorrhea who are found to have elevated cephalosporin MICs on AST, regardless of whether sexual contact is reported during the post-treatment follow up period.

Obtaining specimens for culture and AST

1. Clinicians should obtain culture specimens from all anatomic exposure sites (urethral, cervical, pharyngeal, and/or rectal) for AST from patients with possible treatment failure.
2. Clinicians should consider obtaining culture specimens from patients who have been diagnosed with another N. gonorrhoeae infection in the past 30–60 days, even when re-infection cannot be excluded.
3. Clinicians should be prepared for the possibility of a treatment failure if they serve populations at increased risk for gonorrhea (i.e., sexually active patients with one or more of the following risk factors: age under 25 years, MSM, history of previous gonorrhea infection or other sexually transmitted infection, new or multiple sex partners, inconsistent condom use, sex work, or drug use).
4. STD clinics and other clinicians should work with the closest private lab that does AST in order to obtain the appropriate specimen collection supplies and to develop a procedure for transporting specimens. Lab Corp and Quest are two private labs that perform AST.

Lab locations can be found on their websites - labcorp.com and questdiagnostics.com. Clinicians that do not have nearby private lab services should contact their local or regional health department for assistance.

Management of Suspected or Probable Ceftriaxone Treatment Failures

1. Clinicians should consult with a local infectious disease (ID) expert, the Denver STD Prevention Training Center, the state Infectious Disease physician, their local health department or regional health department regarding re-treatment and partner management. See Appendix D for a directory of experts.
2. Based on anatomic exposure history, obtain specimens for culture from pharyngeal, rectal, and/or genital sites for AST. Clinicians should notify the laboratory that the specimen was obtained from a patient with possible cephalosporin treatment failure. Clinicians should specify which antibiotic was used for initial treatment.
3. Ensure eradication of infection with a test of cure after re-treatment, preferably with culture (=72 hours after re-treatment), or 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 for active infection and to allow for AST.
4. Test the patient's sex partners from the two months preceding the patient’s initial gonorrhea diagnosis date (preferably with culture from all exposed sites) and empirically treat these partners with the same antimicrobial regimen with which the index patient was re-treated and which most likely will cure him/her (based on consultation with a local infectious disease expert, state or local health department, and CDC)
5. Promptly notify the regional or local health department within 24 hours of identification. The regional or local health departments will inform DSHS STD Surveillance.

Management of Suspected or Probable Cefixime Treatment Failure

1. Based on anatomic exposure history, obtain specimens for culture from pharyngeal, rectal, and genital sites for AST. Clinicians should notify the laboratory that the specimen was obtained from a patient with possible cephalosporin treatment failure.
2. Re-treat with 250 mg of ceftriaxone as a single intramuscular dose and azithromycin 1 gram, orally as a dual therapy
3. Ensure eradication of infection with a test of cure after re-treatment, preferably with culture (=72 hours after re-treatment), or if culture is not available, with NAAT (=7 days after re-treatment).
4. If the test of cure NAAT is positive, a specimen for culture should be obtained to both ensure that the NAAT result is reliable for active infection and to allow for AST.
5. Test the patient’s sex partners from the two months preceding the patient’s initial gonorrhea diagnosis date (preferably with culture from all exposed sites) and empirically treat these partners with ceftriaxone 250 mg intramuscularly and azithromycin 1 gram orally as dual therapy.
6. Promptly notify the state or local health departments within 24 hours of identification.
7. If the patient was treated with cefixime (i.e., via patient-delivered partner therapy), treat with 250mg ceftriaxone and 1gm of azithromycin. Have patient return for test of cure. If treatment failure is suspected or probable, then collect a specimen for AST.

Reporting

1. Cases that meet the criteria for suspect or probable Ceph-R NG infection should be reported to the regional or local health departments listed in Appendix D.
2. Clinicians should also contact the regional health department or their respective local health department listed in Appendix D if they require assistance obtaining access to culture and AST.
3. Clinicians desiring an infectious disease consult may contact any of the resources listed in Appendix D.

Clinical Case Definitions

Definitions

Suspected Case

The patient experienced possible cephalosporin treatment failure (symptomatic or asymptomatic) with the following specific components:

Patient had laboratory-confirmed N. gonorrhoeae infection, and

• Patient 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 a positive NAAT =7 days after treatment), and
• Patient did not engage in sexual activity after treatment

OR

AST of pre-treatment or post-treatment isolate of N. gonorrhoeae demonstrates:

• Cefixime MIC =0.25µg/ml, or
• Ceftrizxone MIC =0.125µg/ml

Probable Case

The patient experienced possible cephalosporin treatment failure (symptomatic or asymptomatic) with the following specific components:

• Patient had laboratory-confirmed N. gonorrhoeae infection, and
• Patient 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), and
• Patient did not engage in sexual activity after treatment

AND

AST of pre-treatment or post-treatment isolate of N. gonorrhoeae demonstrates:

• Cefixime MIC =0.25 µg/ml, or
• Ceftriaxone MIC =0.125 µg/ml

OR

Elevated Laboratory Criteria

AST of pre-treatment or post-treatment isolate of N gonorrhoeae demonstrates:

• Cefixime MIC =0.5 µg/ml, or
• Ceftriaxone MIC =0.25µg/ml

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APPENDIX C
Laboratorian Responsibilities

1. Laboratorians who identify a N. gonorrhoeae isolate with AST results that are consistent with suspect or probable Ceph-R NG (see page 8) should promptly notify (within 24 hours) the ordering clinician as well as the surveillance authority for their jurisdiction.
2. Results from isolates associated with possible clinical treatment failures should also be promptly reported to the Local Reporting Authority.
3. Culture specimens obtained from all patients with possible treatment failure or suspect or probable Ceph-R NG infection should be sent to CDC for AST by agar dilution and stored at the local laboratory and/or CDC in case further testing is needed. Instructions for shipping isolates to CDC can be found on the CDC website. N. gonorrhoeae is classified as Category B (UN 3373).

Defining laboratory criteria for Ceph-R NG infection is challenging. The Clinical and Laboratory Standards Institute (CLSI) has not defined minimum inhibitory concentration (MIC) breakpoints for resistance. Furthermore, since cephalosporin treatment failures have not been reported yet in the United States, there is no clear understanding of the relationship between MIC breakpoints and likelihood of treatment failure. The MIC breakpoints for cefixime used in the case definitions below differ from the breakpoints for ceftriaxone because cefixime MICs are generally one-dilution higher than ceftriaxone MICs.

The laboratory criteria in this document refer to cephalosporin MICs obtained by the agar dilution method. CDC is currently in the process of evaluating antimicrobial susceptibility results obtained by the E-test and disk diffusion methods and is working to establish E-test and disk diffusion breakpoints that are equivalent to the agar dilution breakpoints listed below. Until these data are available, facilities using the E-test method should use the MIC breakpoints listed below (the same breakpoints that are used for agar dilution). Facilities using the disk diffusion method should use the standards published by the CLSI.

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APPENDIX D
Resource Directory

Infectious Disease Consults
Denver Prevention Training Center
Teri Anderson
303-602-3602
John Fitch
303-602-3616

Nurse Consultant
HIV/STD Section
Texas Department of State Health Services

Reporting Authority by Region and County

Private Labs That Perform AST

• Lab Corp
• Quest Diagnostics

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APPENDIX E
Regional and Local Health Department's Responsibilities

The Department of State Health Services (DSHS) and Local Health Departments should scale up general GC prevention and control including early diagnosis, timely and effective treatment, and partner services activities in order to reduce the overall disease burden.

Roles and responsibilities include:

1. Monitoring and investigating patients with multiple reports of GC infections documented within the preceding 30 or 60 days to determine whether they are suspected or probable treatment failures.
2. Obtaining a test of cure from suspected or probable treatment failures or making sure they return to their provider for one.
3. Ensuring partners of suspected or probable treatment failures are tested using culture and AST.
4. Facilitating provider access to the nearest private lab to obtain the appropriate specimen collection supplies and to develop a procedure for transporting specimens.
5. Ensuring partners are adequately treated.
6. Reporting cases of suspected or probable Ceph-R NG to DSHS STD Surveillance.
7. Assisting in the establishment of regional networks and referral systems to identify where patients can go for testing.
8. Working with clinicians and professional organizations to scale up screening and ensure proper diagnosis and treatment by providing educational materials and information about evidence-based interventions (i.e., patient-delivered and field-delivered partner therapy).
9. Training their own surveillance personnel about quickly taking action on AST reports that show resistance.

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