ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1991, p. 1228-1229 0066-4804/91/061228-02$02.00/0 Copyright X) 1991, American Society for Microbiology
Vol. 35, No. 6
Cocaine Hydrochloride and Benzoylecgonine Have No In Vitro Inhibitory Effect against Neisseria gonorrhoeae JONATHAN M. ZENILMAN,12* CINDY A. REICHART,1 THERESA M. NEUMANN,1 AND EDWARD W. HOOK III12 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,1 and Preventive Medicine and Epidemiology, Baltimore City Health Department, Baltimore, Maryland 212022 Received 14 November 1990/Accepted 28 March 1991
We evaluated 72 clinical Neisseria gonorrhoeae isolates for in vitro susceptibility to cocaine hydrochloride and its metabolite benzoylecgonine and to penicillin, tetracycline, erythromycin, ceftriaxone, and ofloxacin. Although there was a wide range of susceptibilities to the antimicrobial agents, cocaine and its major metabolite, benzoylecgonine, had no demonstrable antigonococcal activity. Cocaine use is frequently associated with outbreaks of sexually transmitted disease. We hypothesized that the dramatically decreasing incidence of gonorrhea over the past 15 years may be in part due to pharmacological effects of cocaine. However, since cocaine and its metabolite have no in vitro antigonococcal activity, this hypothesis is unlikely.
In the past decade, cocaine abuse has become epidemic in the United States, possibly as a consequence of the availability of inexpensive cocaine formulations (such as "crack"). Self-reported cocaine use has been associated with a variety of public health problems. Recent studies in New York found toxicological evidence of recent cocaine use in 18% of persons who died in motor vehicle accidents (10) and in 76% of males arrested for criminal offenses (3). In addition, cocaine use has been associated with risk of human immunodeficiency virus infection in intravenous drug abusers (1) and with the increased frequency of self-reported sexually transmitted diseases (STDs) (6). Among men attending the Baltimore City Health Department STD clinics for evaluation of new problems, 8% have evidence of recent cocaine use by urine assay (unpublished data). Recently, changes in the epidemiology of syphilis and gonorrhea have also been attributed in part to cocaine use. Between 1985 and 1988, the incidence of primary and secondary syphilis increased 66%, reaching the highest level in 40 years (4). Although there are probably many reasons for these increases, behaviors associated with cocaine use, especially use of crack cocaine, such as "sex for drugs," have been implicated as important risk factors for syphilis acquisition in adults in Connecticut and Philadelphia (1) and among the mothers of babies with congenital syphilis in New York City (2). While the incidence of reported gonococcal infections has decreased over the past 10 years, gonorrhea (4) and particularly outbreaks of antibiotic-resistant gonorrhea have also been increasingly associated with cocaine use. Nonetheless, considering the explosive increase in the incidence of syphilis, the declining number of patients with gonorrhea has not been fully explained. The decreased incidence of gonorrhea appears to be real, as it cannot be explained by changes in reporting procedures. Although behaviors leading to increases in occurrence of one STD might be expected to lead to increased risk of another STD, host susceptibility might also be altered by the presence of drugs such as cocaine. For example, lidocaine and other local alkaloid anesthetics have been demonstrated to have in vitro bactericidal effects *
Corresponding author.
against both gram-positive and gram-negative organisms (9, 15). Thus, we hypothesized that cocaine hydrochloride or its metabolite(s) might have an inhibitory effect on Neisseria gonorrhoeae at concentrations in serum commonly attained by frequent users. Since cocaine use is highly prevalent in the population at risk for STDs, this would potentially help explain the observed decreases in gonorrhea incidence. We evaluated 72 gonococcal isolates for in vitro susceptibility to cocaine hydrochloride, benzoylecgonine (the major metabolite of cocaine found in plasma and urine [7]), penicillin, tetracycline, erythromycin, ofloxacin, ceftriaxone, and spectinomycin. All isolates were tested by using the agar dilution method and twofold dilutions of antibiotics, cocaine HCI, and benzoylecgonine (8) with GC-II Agar Base supplemented with IsoVitaleX (Becton-Dickinson, Cockeysville, Md.). Cocaine hydrochloride and benzoylecgonine were evaluated over a dilution range of 0.001 to 4.0 ,ug/ml (10 times the peak concentration observed in human plasma). In humans, peak concentrations of cocaine in plasma vary with the route of administration. Smoking 100 mg of cocaine paste results in peak concentrations in plasma of 0.478 ,ug/ml in less than 5 min (12); when administered intranasally, the same dose yielded a peak concentration of 0.161 ,ug/ml in 45 to 90 min (14). Levels of cocaine metabolites in plasma or urine have not been well characterized. The organisms for this study were selected from isolates which were systematically collected as part of a national gonococcal isolate surveillance program program (13) and from studies conducted in the Baltimore STD clinics. Twelve isolates had plasmnid-mediated antibiotic resistance (2 were penicillinase-producing N. gonorrhoeae isolates, 9 isolates had plasmid-mediated tetracycline resistance, and 1 was a penicillinase-producing tetracycline-resistant isolate), and nine of the other isolates had MICs of penicillin of >1.0 jig/ml (clinically significant chromosomally mediated penicillin resistance). Although a wide range of susceptibility to antibiotics was demonstrated in these organisms (Table 1), neither cocaine hydrochloride nor benzoylecgonine had any demonstrable antigonococcal activity. The stability of cocaine and its metabolites in agar medium has not been determined. However, the melting points of cocaine (195°C) and benzoylecgo1228
NOTES
VOL. 35, 1991 TABLE 1. Susceptibility characteristics of 73 N. gonorrhoeae isolatesa Antibiotic
Penicillin Tetracycline Erythromycin Ceftriaxone Ofloxacin Cocaine HCl Benzoylecgonine
Range 0.015-32.0 0.060-32.0 0.015-2.0 0.001-0.03 0.004-0.03 >4.0 >4.0
MIC (,ug/ml)b 5/ Geometric 5W mean
0.24 0.79 0.30 0.005 0.009 >4.0 >4.0
0.25 1.00 0.25 0.008 0.008 >4.0 >4.0
4. 90% 0
1.00 16.00 1.00 0.001 0.015 >4.0 >4.0
a Isolates tested include 2 penicillinase-producing N. gonorrhoeae isolates, 1 penicillinase-producing tetracycline-resistant isolate, and 9 tetracyclineresistant isolates. b 50% and 90%, MICs for 50 and 90% of the isolates tested, respectively.
nine (86 to 92°C) (11) are substantially higher than the 50°C used in our agar preparation procedure. The possibility that there is a pharmacological basis for the association of cocaine use with the decrease in incidence of gonorrhea is unlikely. Whether the decreased incidence of gonococcal infections is due to changes in sexual behavior among populations at risk needs to be further evaluated. This project was supported in part by the Gonococcal Isolate Surveillance Project, Division of Sexually Transmitted Diseases, Centers for Disease Control. REFERENCES 1. Centers for Disease Control. 1988. Relationship of syphilis to drug use and prostitution-Connecticut and Philadelphia, Pennsylvania. Morbid. Mortal. Weekly Rep. 37:755-758, 764. 2. Centers for Disease Control. 1989. Congenital syphilis-New York City, 1986-1988. Morbid. Mortal. Weekly Rep. 38:825829. 3. Centers for Disease Control. 1989. Urine testing for drug use
5. 6.
7.
8.
9.
10. 11. 12. 13.
14. 15.
1229
among male arrestees-United States, 1989. Morbid. Mortal. Weekly Rep. 38:780-783. Centers for Disease Control. 1990. Progress toward achieving the 1990 objectives for the nation for sexually transmitted diseases. Morbid. Mortal. Weekly Rep. 39:53-57. Chaisson, R. E., P. Bacchetti, D. Osmond, B. Brodie, M. A. Sande, and A. R. Moss. 1989. Cocaine use and HIV infection in intravenous drug users in San Francisco. JAMA 261:561-566. Fullilove, R. E., M. T. Fullilove, B. P. Bowser, and S. A. Gross. 1990. Risk of sexually transmitted disease among black adolescent crack users in Oakland and San Francisco, California. JAMA 263:851-855. Jatlow, P. I. 1987. Drug of abuse profile: cocaine. Clin. Chem. 33(Suppl. 11B):66B-71B. Jones, R. N., T. L. Gavan, C. Thornsberry, P. C. Fuchs, E. H. Gerlach, J. S. Knapp, P. Murray, and J. A. Washington II. 1989. Standardization of disk diffusion and agar dilution susceptibility tests for Neisseria gonorrhoeae: interpretive criteria and quality control guidelines for ceftriaxone, penicillin, spectinomycin, and tetracycline. J. Clin. Microbiol. 27:2758-2766. Kleinfeld, J., and P. P. Ellis. 1967. Inhibition of microorganisms by topical anesthetics. Appi. Microbiol. 15:1296-1298. Marzuk, P. M., K. Tardiff, A. C. Leon, M. Stajic, E. B. Morgan, and J. Mann. 1990. Prevalence of recent cocaine use among motor vehicle fatalities in New York City. JAMA 263:250-256. Merck & Company. 1983. Merck Index, 10th ed. Merck & Company, Rahway, N.J. Paly, D., P. Jatlow, C. Van Dyke, F. R. Jeri, and R. Byck. 1982. Plasma cocaine concentrations during cocaine paste smoking. Life Sci. 30:731-738. Schwarcz, S. K., J. M. Zenilman, D. Schnell, J. S. Knapp, E. W. Hook III, S. E. Thompson III, F. N. Judson, K. K. Holmes, and the Gonococcal Isolate Surveillance Project. 1990. National surveillance of antimicrobial resistance in Neisseria gonorrhoeae. JAMA 264:1413-1417. Van Dyke, C., P. G. Barash, P. Jatlow, and R. Byck. 1976. Cocaine: plasma concentrations after intranasal application in man. Science 191:859-861. Wimberley, N., S. Willey, N. Sullivan, and J. G. Bartlett. 1979. Antibacterial properties of lidocaine. Chest 76:37-40.
Vol. 35, No. 6
Cocaine Hydrochloride and Benzoylecgonine Have No In Vitro Inhibitory Effect against Neisseria gonorrhoeae JONATHAN M. ZENILMAN,12* CINDY A. REICHART,1 THERESA M. NEUMANN,1 AND EDWARD W. HOOK III12 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,1 and Preventive Medicine and Epidemiology, Baltimore City Health Department, Baltimore, Maryland 212022 Received 14 November 1990/Accepted 28 March 1991
We evaluated 72 clinical Neisseria gonorrhoeae isolates for in vitro susceptibility to cocaine hydrochloride and its metabolite benzoylecgonine and to penicillin, tetracycline, erythromycin, ceftriaxone, and ofloxacin. Although there was a wide range of susceptibilities to the antimicrobial agents, cocaine and its major metabolite, benzoylecgonine, had no demonstrable antigonococcal activity. Cocaine use is frequently associated with outbreaks of sexually transmitted disease. We hypothesized that the dramatically decreasing incidence of gonorrhea over the past 15 years may be in part due to pharmacological effects of cocaine. However, since cocaine and its metabolite have no in vitro antigonococcal activity, this hypothesis is unlikely.
In the past decade, cocaine abuse has become epidemic in the United States, possibly as a consequence of the availability of inexpensive cocaine formulations (such as "crack"). Self-reported cocaine use has been associated with a variety of public health problems. Recent studies in New York found toxicological evidence of recent cocaine use in 18% of persons who died in motor vehicle accidents (10) and in 76% of males arrested for criminal offenses (3). In addition, cocaine use has been associated with risk of human immunodeficiency virus infection in intravenous drug abusers (1) and with the increased frequency of self-reported sexually transmitted diseases (STDs) (6). Among men attending the Baltimore City Health Department STD clinics for evaluation of new problems, 8% have evidence of recent cocaine use by urine assay (unpublished data). Recently, changes in the epidemiology of syphilis and gonorrhea have also been attributed in part to cocaine use. Between 1985 and 1988, the incidence of primary and secondary syphilis increased 66%, reaching the highest level in 40 years (4). Although there are probably many reasons for these increases, behaviors associated with cocaine use, especially use of crack cocaine, such as "sex for drugs," have been implicated as important risk factors for syphilis acquisition in adults in Connecticut and Philadelphia (1) and among the mothers of babies with congenital syphilis in New York City (2). While the incidence of reported gonococcal infections has decreased over the past 10 years, gonorrhea (4) and particularly outbreaks of antibiotic-resistant gonorrhea have also been increasingly associated with cocaine use. Nonetheless, considering the explosive increase in the incidence of syphilis, the declining number of patients with gonorrhea has not been fully explained. The decreased incidence of gonorrhea appears to be real, as it cannot be explained by changes in reporting procedures. Although behaviors leading to increases in occurrence of one STD might be expected to lead to increased risk of another STD, host susceptibility might also be altered by the presence of drugs such as cocaine. For example, lidocaine and other local alkaloid anesthetics have been demonstrated to have in vitro bactericidal effects *
Corresponding author.
against both gram-positive and gram-negative organisms (9, 15). Thus, we hypothesized that cocaine hydrochloride or its metabolite(s) might have an inhibitory effect on Neisseria gonorrhoeae at concentrations in serum commonly attained by frequent users. Since cocaine use is highly prevalent in the population at risk for STDs, this would potentially help explain the observed decreases in gonorrhea incidence. We evaluated 72 gonococcal isolates for in vitro susceptibility to cocaine hydrochloride, benzoylecgonine (the major metabolite of cocaine found in plasma and urine [7]), penicillin, tetracycline, erythromycin, ofloxacin, ceftriaxone, and spectinomycin. All isolates were tested by using the agar dilution method and twofold dilutions of antibiotics, cocaine HCI, and benzoylecgonine (8) with GC-II Agar Base supplemented with IsoVitaleX (Becton-Dickinson, Cockeysville, Md.). Cocaine hydrochloride and benzoylecgonine were evaluated over a dilution range of 0.001 to 4.0 ,ug/ml (10 times the peak concentration observed in human plasma). In humans, peak concentrations of cocaine in plasma vary with the route of administration. Smoking 100 mg of cocaine paste results in peak concentrations in plasma of 0.478 ,ug/ml in less than 5 min (12); when administered intranasally, the same dose yielded a peak concentration of 0.161 ,ug/ml in 45 to 90 min (14). Levels of cocaine metabolites in plasma or urine have not been well characterized. The organisms for this study were selected from isolates which were systematically collected as part of a national gonococcal isolate surveillance program program (13) and from studies conducted in the Baltimore STD clinics. Twelve isolates had plasmnid-mediated antibiotic resistance (2 were penicillinase-producing N. gonorrhoeae isolates, 9 isolates had plasmid-mediated tetracycline resistance, and 1 was a penicillinase-producing tetracycline-resistant isolate), and nine of the other isolates had MICs of penicillin of >1.0 jig/ml (clinically significant chromosomally mediated penicillin resistance). Although a wide range of susceptibility to antibiotics was demonstrated in these organisms (Table 1), neither cocaine hydrochloride nor benzoylecgonine had any demonstrable antigonococcal activity. The stability of cocaine and its metabolites in agar medium has not been determined. However, the melting points of cocaine (195°C) and benzoylecgo1228
NOTES
VOL. 35, 1991 TABLE 1. Susceptibility characteristics of 73 N. gonorrhoeae isolatesa Antibiotic
Penicillin Tetracycline Erythromycin Ceftriaxone Ofloxacin Cocaine HCl Benzoylecgonine
Range 0.015-32.0 0.060-32.0 0.015-2.0 0.001-0.03 0.004-0.03 >4.0 >4.0
MIC (,ug/ml)b 5/ Geometric 5W mean
0.24 0.79 0.30 0.005 0.009 >4.0 >4.0
0.25 1.00 0.25 0.008 0.008 >4.0 >4.0
4. 90% 0
1.00 16.00 1.00 0.001 0.015 >4.0 >4.0
a Isolates tested include 2 penicillinase-producing N. gonorrhoeae isolates, 1 penicillinase-producing tetracycline-resistant isolate, and 9 tetracyclineresistant isolates. b 50% and 90%, MICs for 50 and 90% of the isolates tested, respectively.
nine (86 to 92°C) (11) are substantially higher than the 50°C used in our agar preparation procedure. The possibility that there is a pharmacological basis for the association of cocaine use with the decrease in incidence of gonorrhea is unlikely. Whether the decreased incidence of gonococcal infections is due to changes in sexual behavior among populations at risk needs to be further evaluated. This project was supported in part by the Gonococcal Isolate Surveillance Project, Division of Sexually Transmitted Diseases, Centers for Disease Control. REFERENCES 1. Centers for Disease Control. 1988. Relationship of syphilis to drug use and prostitution-Connecticut and Philadelphia, Pennsylvania. Morbid. Mortal. Weekly Rep. 37:755-758, 764. 2. Centers for Disease Control. 1989. Congenital syphilis-New York City, 1986-1988. Morbid. Mortal. Weekly Rep. 38:825829. 3. Centers for Disease Control. 1989. Urine testing for drug use
5. 6.
7.
8.
9.
10. 11. 12. 13.
14. 15.
1229
among male arrestees-United States, 1989. Morbid. Mortal. Weekly Rep. 38:780-783. Centers for Disease Control. 1990. Progress toward achieving the 1990 objectives for the nation for sexually transmitted diseases. Morbid. Mortal. Weekly Rep. 39:53-57. Chaisson, R. E., P. Bacchetti, D. Osmond, B. Brodie, M. A. Sande, and A. R. Moss. 1989. Cocaine use and HIV infection in intravenous drug users in San Francisco. JAMA 261:561-566. Fullilove, R. E., M. T. Fullilove, B. P. Bowser, and S. A. Gross. 1990. Risk of sexually transmitted disease among black adolescent crack users in Oakland and San Francisco, California. JAMA 263:851-855. Jatlow, P. I. 1987. Drug of abuse profile: cocaine. Clin. Chem. 33(Suppl. 11B):66B-71B. Jones, R. N., T. L. Gavan, C. Thornsberry, P. C. Fuchs, E. H. Gerlach, J. S. Knapp, P. Murray, and J. A. Washington II. 1989. Standardization of disk diffusion and agar dilution susceptibility tests for Neisseria gonorrhoeae: interpretive criteria and quality control guidelines for ceftriaxone, penicillin, spectinomycin, and tetracycline. J. Clin. Microbiol. 27:2758-2766. Kleinfeld, J., and P. P. Ellis. 1967. Inhibition of microorganisms by topical anesthetics. Appi. Microbiol. 15:1296-1298. Marzuk, P. M., K. Tardiff, A. C. Leon, M. Stajic, E. B. Morgan, and J. Mann. 1990. Prevalence of recent cocaine use among motor vehicle fatalities in New York City. JAMA 263:250-256. Merck & Company. 1983. Merck Index, 10th ed. Merck & Company, Rahway, N.J. Paly, D., P. Jatlow, C. Van Dyke, F. R. Jeri, and R. Byck. 1982. Plasma cocaine concentrations during cocaine paste smoking. Life Sci. 30:731-738. Schwarcz, S. K., J. M. Zenilman, D. Schnell, J. S. Knapp, E. W. Hook III, S. E. Thompson III, F. N. Judson, K. K. Holmes, and the Gonococcal Isolate Surveillance Project. 1990. National surveillance of antimicrobial resistance in Neisseria gonorrhoeae. JAMA 264:1413-1417. Van Dyke, C., P. G. Barash, P. Jatlow, and R. Byck. 1976. Cocaine: plasma concentrations after intranasal application in man. Science 191:859-861. Wimberley, N., S. Willey, N. Sullivan, and J. G. Bartlett. 1979. Antibacterial properties of lidocaine. Chest 76:37-40.
