1. “High Percentages of Resistance to Tetracycline and Penicillin and Reduced Susceptibility to Azithromycin Characterize the Majority of Strain Types of Neisseria gonorrhoeae Isolates in Cuba, 1995-1998” Sosa J, Ramirez-Arcos S, Ruben M, Li H, Llanes R, Llop A, Dillon JA (Sexually Transmitted Diseases 2003 May; 30(5):443-8.) Presentation: Jim Starman, MS-II Faculty Advisor: David Paterson, MD

2. Background Gonococcal disease is a significant problem within Latin American countries such as Cuba. Between 1960 and 1994, cases of gonorrhea reported in Cuba increased from 130 in 1960 to 34,224 in 1994 and 33,948 in 1997. 1 During the last two decades, significant resistance has developed within N. gonorrhoeae strains worldwide to antibiotics such as azithromycin, penicillin, and tetracycline. The resistance profile of the gonococcal strains in a particular region should be considered when choosing a treatment in order to avoid using ineffective antibiotics.

3. GASP The Gonococcal Antimicrobial Surveillance Program (GASP) is an international initiative developed to characterize current patterns of resistance and to monitor developing new resistances of gonococcal strains in the Americas and Caribbean. GASP is based on the model of other microbial surveillance programs already in place as a result of the efforts of the Pan American Health Organization.

4. GASP The program’s goal is to provide accurate recommendations to physicians about the most effective choices of antibiotics for treatment of gonococcal infection in their region, based on the latest resistance patterns detected. Although Cuba has been a member since 1999, prior to this article, no study has fully characterized the patterns and types of antibiotic resistance within N. gonorrhoeae in the country.

5. Healthcare and Health Surveillance in Cuba: An Overview 11,273,000 total inhabitants (2002) The health system is structured in three levels that correspond to the political and administrative subdivisions of the country: national, provincial, and municipal.

6. Healthcare and Health Surveillance in Cuba: An Overview The national level is governed by the ministry of public health (MINSAP). MINSAP plays a steering role and carries out methodological, regulatory, coordination, and control functions. The municipal level consists of departments of public health that “are subject to the authority of municipal people's councils, polyclinics, and health areas.” 2 There are 145 local/municipal healthcare units, and 14 regional units across the country. These may be utilized as information gathering points for the GASP surveillance program. (11 of the 14 regional units served as sources for this study)

7. Map of Cuba

8. Health Surveillance in Cuba: The Problem Cuba’s attempts to monitor resistance patterns in strains of N. gonorrhoeae have been sporadic and limited due to economic constraints, resulting in a lack of up to date or even basic information about the distribution of resistant strains within the country. Without surveillance, Cuban healthcare workers lack the information to make intelligent decisions about which antibiotics to use when treating gonococcal infection. This leads to ineffective treatment, poor use of limited medical resources, and promotion of additional resistance development.

9. Study Objectives To collect and analyze strains of Neisseria gonorrhoeae from provincial healthcare centers across Cuba collected between 1995 and 1998, in order to assess the existing types and levels of resistance. To evaluate current treatment recommendations in each regional center and suggest changes where needed. To highlight the need for up to date surveillance of antibiotic resistance in N. gonorrhoeae and other microbes in Cuba and elsewhere.

10. Study Design 91 isolates were gathered from 11 of the 14 provincial health centers across Cuba between 1995 and 1998, and were sent to the Center for the Gonococcal Antimicrobial Surveillance Program in the Americas and the Caribbean, in Ottawa, for evaluation of resistance patterns.

11. Study Design Isolates were tested to find the minimum inhibitory concentrations (MIC) of the following antibiotics: Penicillin Tetracycline Spectinomycin Ceftriaxone Azithromycin Ciprofloxacin

12. Study Design MIC’s above a specific level for each antibiotic constitute “resistance” of a strain to that antibiotic. MIC’s above the normal MIC level but below the critical level for the definition of resistance constitute strains with decreased susceptibility to a given antibiotic.

13. Study Design All isolates were also analyzed for their auxotype, serotype, and pulse field gel electrophoresis characteristics. This was intended to identify the total number of distinct strains in the study, the individual resistance patterns of each strain, and finally, their distribution and prevalence in the country.

14. Results 68.1% of all isolates (62/91) were resistant to penicillin, of which most (52) were penicillinase producing N. gonorrhoeae. 83.5% of all isolates (76/91) were resistant to tetracycline. There were 45 isolates which had resistance to both penicillin and tetracycline (49.4%).

15. Results 9.9% (9/91) of isolates were resistant to azithromycin. In addition, 47.3% (43/91) of isolates showed decreased susceptibility (an elevated MIC). All isolates were susceptible to spectinomycin, ceftriaxone, and ciprofloxacin.

16. Results: A/S and PFGE Auxotype/Serotype Class Total Number of Isolates Number of Sub- Classes Major Antibiotic resistance types NR/IA-6358 Plasmids conferring penicillin and tetracycline resistance: (32/35) P/IA-6113 Chromosome-mediated penicillin and tetracycline resistance: (5/11) Plasmids conferring resistance to tetracycline: (8/11) NR/IB-1156 Reduced azithromycin susceptibility: (15/15)

17. Discussion Almost all isolates had resistance or decreased susceptibility to Penicillin, reflecting the previously reported resistances in other Latin American countries. In addition, all isolates had at least reduced levels of susceptibility to tetracycline. Most of the developed resistance patterns are plasmid mediated.

18. Discussion Resistance is more common today than in the late 1980s and early 1990s, and new forms continue to emerge. Cuba has already developed strains that are resistant to the two cheapest antibiotics, Penicillin and Tetracycline, and is likely to face resistance to more expensive drugs as well in the near future.

19. Discussion There were 4 recent cases from one Cuban town in which reduced susceptibility to ciprofloxacin was reported, and in other parts of the world such as the Asian-Pacific region, ciprofloxacin resistance has been reported in as many as 30% of isolates. Therefore, although no ciprofloxacin resistance was detected in the current Cuban study, it is likely to increase in the near future.

20. Discussion It is crucial to continue to develop and maintain adequate surveillance networks through the GASP program in order to maintain effective treatment strategies. Antibiotic recommendations for current use should more closely reflect the data collected by the present study of resistance patterns. (This is an important point, since it is likely that the updated information is not currently distributed in an effective manner to those who may utilize it)

21. Discussion Information about the geographic distribution of resistant strains may be useful for a public health strategy aimed at disease prevention. Some other important related issues to consider: 1)Compliance to prescribed therapies. 2)Quality of medications/ adequate supply.

22. References 1)Minesterio de salud Publica de Cuba. Programma national de control de las ITS in Cuba. Minesteria de salud Publica, Cuidad de la Habana. 2001. 2) Pan American Health Organization (http://www.paho.org)http://www.paho.org 3) World Health Organization (http://www.who.org)http://www.who.org

23. Thank You!