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Update on Gonococcal Resistance in the United States Susan A. Wang, MD, MPH Division of STD Prevention National Center for HIV, STD, and TB Prevention swang3@cdc.gov March 2004. The continuing saga: history of antimicrobial resistance in Neisseria gonorrhoeae in the United States.

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The continuing saga: history of antimicrobial resistance in Neisseria gonorrhoeae in the United States

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Update on Gonococcal Resistance in the United States Susan A. Wang, MD, MPHDivision of STD PreventionNational Center for HIV, STD, and TB Preventionswang3@cdc.govMarch 2004


The continuing saga: history of antimicrobial resistance in Neisseria gonorrhoeaein the United States

  • 1936: sulfanilamide introduced

  • 1945: 1/3 of gonorrhea sulfanilamide-resistant; 50,000 units of penicillin becomes therapy of choice

  • 1972: therapeutic penicillin dose reaches 4.8 million units

  • 1976: PPNG first identified in U.S. patient with recent travel to Southeast Asia


History - Part II

  • early 1980s: PPNG strains spread in the U.S.; beta-lactamase testing commonplace

  • 1985: widespread tetracycline-resistance among gonococci; CDC recommends that tetracycline not be used for gonorrhea therapy

  • 1987: penicillin abandoned; ceftriaxone becomes primary treatment

  • 1989: ciprofloxacin (FQ) recommended by CDC

  • 1991: QRNG identified in Hawaii


History - Part III

  • 1998: marked QRNG increase in Hawaii

  • 2000: CDC recommends that FQs no longer be used to treat gonorrhea acquired in Hawaii, Pacific Islands, or Asia; need travel hx for all GC pts

  • 2002: CDC recommends that use of FQs in California and in other areas with increased QRNG may be inadvisable

  • 2002-2004: local QRNG alerts and treatment recommendation changes


Quinolone Resistance Among Gonococci Elsewhere in the World

Australia – 8.1%England & Wales – 9.8%

China – 92.5% (GRASP, 2002)

Japan – 73.4% Norway - 15%

Korea – 63.3% (Aavitsland, et al 2002)

Phillippines – 57.5%Canada – 2.1%

Singapore – 46.5% (Sarwal, et al, 2001)

Vietnam – 46.0%Israel – 61% (WHO WPR GASP, 2002) (Dan, et al, 2000)


Surveillance for gonococcal resistance in the United States

  • National sentinel surveillance

  • Local susceptibility surveillance


The Gonococcal Isolate Surveillance Project (GISP)

  • National sentinel surveillance established in 1986 by CDC to monitor trends in antimicrobial susceptibilities of N. gonorrhoeae

  • Consists of public STD clinicsin26-30 cities and 5 Regional Laboratories

  • Every month each clinic submits first 25 male urethral gonococcal isolates to a Regional Laboratory

  • Each Regional Lab performs antimicrobial susceptibility testing by agar dilution

  • Each clinic also submits patient demographic and clinical data for all submitted isolates  allows us to monitor characteristics of patients with gonorrhea


Gonococcal Isolate Surveillance Project (GISP)

Locations of clinics and regional laboratories:

United States, 2003

Seattle

Portland

Minneapolis

Detroit

Philadelphia

Chicago

Cleveland

San Francisco

Salt Lake

City

Baltimore

Cincinnati

Las

Vegas

Denver

Regional Labs

St. Louis

Birmingham

Los Angeles

Atlanta

Oklahoma

City

Greensboro

Long Beach

Denver

Orange Co.

Seattle

Albuquerque

San Diego

Phoenix

Cleveland

Atlanta

Dallas

Birmingham

New

Orleans

Anchorage

Tripler AMC

Honolulu

Miami


100

other

spectinomycin

tetracyclines

ofloxacin

penicillins

80

ciprofloxacin

60

Percent of GISP patients

cefixime

ceftriaxone

40

250 mg

20

ceftriaxone

125 mg

other cephalosporins

0

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003*

Gonorrhea treatment for GISP participants,

1988-2003*

*2003 data are preliminary.


5.5

5

4.5

4

3.5

3

Percent of isolates

2.5

2

1.5

1

0.5

0

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003*

Resistance

Intermediate resistance

Percentage of GISP isolates with intermediate resistance or resistance to ciprofloxacin, 1990-2003*

*2003 data are preliminary.


Ciprofloxacin-resistant GISP isolates in the U.S.

Year Sentinel Sites Isolates

1991 Honolulu 1

1993 Honolulu 1

1994 Honolulu, San Francisco 2

1995 Honolulu, San Francisco, Seattle, Denver 8

1996 Seattle 2

1997 Honolulu, San Diego, Portland, Atlanta 5

1998 Honolulu, San Francisco, Cincinnati 4

1999 Honolulu, San Francisco, San Diego, Orange Co,

Seattle, Anchorage, Denver, Cincinnati,

New Orleans, Fort Bragg 19

2000 Honolulu, San Francisco, San Diego, Orange Co,

Seattle, Anchorage 19

2001 Honolulu, San Francisco, San Diego, Orange Co,

Long Beach, Denver 38

2002 Honolulu, San Francisco, San Diego, Orange Co,

Long Beach, Anchorage, Portland, Seattle, Phoenix,

Minneapolis, Cincinnati, Philadelphia, Miami 116

2003* Honolulu, Tripler, San Francisco, Los Angeles, San Diego,

prelim Orange Co, Long Beach, Portland, Seattle, Las Vegas,

Phoenix, Denver, Minneapolis, Chicago, Cincinnati, Cleveland,

Philadelphia, Baltimore, Dallas, New Orleans, Miami 259*


% of isolates with ciprofloxacin resistance

22

100

% of isolates with ciprofloxacin intermediate

20

resistance

gonorrhea rate per 100,000 population

18

75

16

14

12

gonorrhea rate per 100,000 population

Percent of isolates

50

10

8

6

25

4

2

0

0

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003**

Prevalence of ciprofloxacin-resistant Neisseria gonorrhoeae among tested gonococcal isolates,* and gonorrhea rate, Hawaii, 1993-2003**

*Includes GISP and non-GISP isolates for every year except 2003.

**2003 data are preliminary and only GISP data.


% of isolates with ciprofloxacin resistance

22

100

% of isolates with ciprofloxacin intermediate

20

resistance

18

gonorrhea rate per 100,000 population

75

16

14

12

gonorrhea rate per 100,000 population

Percent of isolates

50

10

8

6

25

4

2

0

0

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003*

Prevalence of ciprofloxacin-resistant GISP isolates and gonorrhea rate, California, 1993-2003*

*2003 data are preliminary


1.3

1.2

1.1

1.0

0.9

0.8

0.7

Percent of isolates

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003*

Percent ciprofloxacin-resistant isolates in GISP, excluding Hawaii and California, 1990-2003*

*2003 data are preliminary.


Preliminary 2003 GISP Data – QRNG (incomplete)

QRNG (all sites)4.1% (243/5936)

Orange Co32.5% (49/151)

Long Beach21.5% (17/79)

San Francisco19.0% (51/268)

Los Angeles13.3% (22/165)

Honolulu13.3% (16/120)

San Diego 12.1% (26/215)

Seattle 7.0% (18/258)

Tripler 4.2% (1/24)

Portland 3.0% (4/132)

Las Vegas 2.4% (7/287)


Preliminary 2003 GISP Data - QRNG

Minneapolis2.3% (5/215)

Phoenix 2.2% (4/183)

Chicago2.1% (6/285)

Dallas2.1% (6/288)

Philadelphia1.3% (4/316)

Miami1.2% (2/164)

New Orleans 0.7% (1/152)

Cincinnati 0.4% (1/276)

Denver0.4% (1/250)

Baltimore0.4% (1/289)

Cleveland0.3% (1/292)


14

12

10

MSW

8

Percent of isolates

MSM

6

all

4

2

0

2002

2003*

2002

2003*

GISP QRNG by Sexual Orientation, 2002 and 2003*

*2003

data are

preliminary

Excluding Hawaii and California

All sites


Preliminary Non-GISP QRNG in 2003incomplete

  • New Hampshire – 28.6% (6/21)

  • Massachusetts – 13.9% (56/402)

  • Michigan – 2.9% (17/582)

  • New York City – 2.9% (30/1026)

  • Indianapolis – 0.4 (2/491)

  • Other places where QRNG have been identified: Kansas (1), Maine (1), New Jersey (2), New York (1), Ohio (1), Utah (1)

  • In 2002, no health dept susceptibility testing data for 72% of STD programs and limited susceptibility data available for the other 28%


QRNG clusters in 2003

  • New York City(Reddy, P013): ~8% GC cases tested; 13% QRNG among MSM, 2% among MSW and among women

  • Massachusetts(Ratelle, P014): ~12% GC cases tested; 11% QRNG among MSM and 2% among MSW

  • Michigan(Macomber, LB10): ~4% GC cases tested; 12% QRNG among MSM, 9% among MSW, 2% among women

  • Seattle(Whittington, Tues LB): 22% QRNG among MSM and 3% among MSW and women

  • Cost-effectiveness model to identify threshold for changing treatment (Roy, P068)


Factors Associated with Acquisition of QRNG(in areas where QRNG is not endemic)

  • Residence in or history of recent travel to Asia or the Pacific Islands, Hawaii, California, or other areas with increased QRNG prevalence or sex partner with such history

  • Asian and White races

  • Heterosexual transmission (England, Norway, Australia, U.S.)

  • In 2002-2003, MSM transmission in the U.S.


GISP Trends for Other Antimicrobials

  • In 2002, prevalence of resistance for penicillin was 8.2% and for tetracycline was 14.7%

  • No isolates resistant to spectinomycin since 1994

  • Proportion of isolates with azithromycin Minimum Inhibitory Concentrations (MICs)  1.0 mg/L increased from 0 in 1992 to 0.6% in 2002

  • No isolates with decreased susceptibility to ceftriaxone since 1997 (but trend toward higher MICs).


GISP Trends for Other Antimicrobials,

  • Multi-drug resistant isolates identified in 2001 in Hawaii and again in 2003 in Los Angeles: resistant to penicillin, tetracycline, ciprofloxacin; decreased susceptible to cefixime and azithromycin

    • these types of isolates identified since 1999 in Japan where cefixime treatment failures have also been reported


The Challenges of Monitoring Gonococcal Resistance

  • Few laboratories performing susceptibility testing

    • primarily public health laboratories, yet >60% of GC reported from private sector

  • Absence of culture testing so no organism to susceptibility test

    • non-culture tests (NAATs) rapidly replacing culture; some health depts no longer have GC culture capacity at all


The Challenges of Monitoring Gonococcal Resistance

  • Bias toward over representation of data from rectal and pharyngeal isolates since only culture has FDA indication for those anatomic sites

    • fewer data from urethral and endocervical isolates

  • Extremely limited sampling or no sampling of certain populations

    • e.g., military, women, private patients


Summary

  • Antimicrobial resistance remains a key consideration in the treatment and control of gonorrhea

  • Preliminary 2003 data show QRNG remained endemic in Hawaii and California. Significant QRNG increases were noted in Seattle, New Hampshire, Massachusetts, New York City, and Michigan, and were identified with increasing frequency elsewhere in the U.S.

  • QRNG increases among MSM are a concern

  • Significant challenges exist in 2004 for monitoring resistance


Acknowledgements

  • The many GISP collaborators:

    • GISP Regional Laboratories (Atlanta, Birmingham, Cleveland, Denver, Seattle): Laura Doyle, Josephine Ehret, Connie Lenderman, James Thomas, Wil Whittington, Karen Winterscheid, Carlos del Rio, King Holmes, Ned Hook, Frank Judson, Gary Procop

    • the 30 GISP Sentinel Sites: lab, clinic, program staff

    • Alesia Harvey, Susan Conner

  • Health departments performing local susceptibility testing: Massachusetts, Michigan, New York City, New Hampshire, Hawaii, Indianapolis, Wisconsin, and more…


http://www.cdc.gov/std/gisp/

Resource website for information on antimicrobial resistant Neisseria gonorrhoeae.

Please report GC treatment failures or identification of resistant GC to CDC (via program consultant or 404 639-8373 or swang3@cdc.gov).


Gonorrhea Treatment(from CDC STD Treatment Guidelines, May 10, 2002 MMWR)

Cefixime 400 mg

or

Ceftriaxone 125 mg IM

or

Ciprofloxacin 500 mg or

Ofloxacin 400 mg or Levofloxacin 250 mg

[plus, treatment for Chlamydia trachomatis infection]

* Need to obtain travel history from patients suspected to have gonorrhea. A patient who may have acquired gonorrhea in Asia or Hawaii or the Pacific Islands or whose sex partner(s) may have acquired gonorrhea in those places should NOT be treated with quinolones! Use of quinolones is probably inadvisable for infections acquired in California and in other areas with increased prevalence of quinolone resistance.


100%

none or other

80%

doxycycline or

60%

tetracycline

Percent of GISP patients

40%

azithromcyin

20%

or

erythromycin

0%

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003*

Treatment of Chlamydia trachomatisinfection in GISP participants, 1992-2003*

For each year, “other” accounted for < 1% and erythromycin accounted for no more than 1% of treatment. *2003 data are preliminary.


Observations on QRNG surveillance

  • Most QRNG patients have NOT been identified as a result of recognition of treatment failures but through susceptibility testing

  • Where QRNG surveillance is taking place, susceptibility data generally represent <15% of GC cases


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