Practical Therapeutics Drugs 14: 57-67 (1977) © ADIS Press 1977
Effective Treatment of Gonorrhoea B .I. Eisenstein Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
Summary
Effective therapy of gonorrhoea has changed drastically over the years, reflecting the progressive acquisition of relative antibiotic resistance by the causative organism. Although in the US, the 1974 USPHS recommendations are the best guidelinesfor management at present, recent epidemiological trends may obviate some of these provisions. The most important of these trends is the emergence of R -factor carrying strains capable ofproducing penicillinase, thereby making these strains absolutely resistant to clinically achievable levels of penicillin. This review analyses this problem in the context of reasonable therapeutic goals and also discusses optimum management of patients with such complications as pharyngeal infection, pelvic inflammatory disease and disseminated gonococcal infection.
At present gonorrhoea, in its multiple clinical syndromes, is the most common communicable illness in the world (Clark, 1973). The causative organism, Neisseria gonorrhoeae, is widespread in the community and can be recovered from about 3 % of sexually active asymptomatic females in the US (Holmes, 1977). Although the majority of infections are trivial, the potential for pelvic inflammatory disease, sterility, bacteraemia and destructive arthritis makes the use of optimal effective treatment mandatory in every patient diagnosed with the disease. This review will be concerned with the subject of therapy in the adult and the impact of the new penicillinase-producing strains. For excellent discussions of the clinical syndromes, diagnosis, epidemiology, prophylaxis and paediatric approach, the reader is referred to articles appearing elsewhere (Barrett-Connor, 1975; Holmes, 1974; Litt et aI., 1974; Rein, 1975; Willcox, 1972).
1. Evolution of Gonorrhoea Therapy 1.1 Treatment Failure Related to Progressive Drug Resistance The therapy of gonorrhoea has evolved greatly over the past 30 years, primarily due to the progressive acquisition of relative antibiotic resistance in the gonococcus (table I). Although other reasons for lack of response to therapy have been cited (Sparling, I 972), antibiotic resistance has been the major cause of treatment failure. Before antibiotics came into regular clinical use, the gonococcus was uniformly sensitive to penicillin, tetracycline and streptomycin (Reyn, 1958). Sulpha drugs, which resulted in cure rates of over 90 % when they were fIrst introduced, lost their usefulness after World War II (Farrar, 1972).
58
Effective Treatment of Gonorrhoea
Table I. Changing penicillin sensitivity of gonococci in the United States (after Sparling. 1972; Jaffe et al.. 1976a; and Reynolds et al.. 1976)'
achieve 90 to 95 % cure rates (Cornelius et aI., 1971; Olsen and Lomholt, 1969). 1.2 Treatment Results with Present Regimens
Percentage with MIC (units/mil Year
0.5
1950-55 1965 1968-69 1972 1975
99 58 35 19 37
37 51 54 49
0 5 14 27 14
Some numbers are approximations based on conversion of pg/ml to units/ml
Whereas 99 % of strains from the year 1955 had minimal inhibitory concentrations (MICS) to penicillin of less than 0.1 units per ml, only 35% were as sensitive by 1969 (Martin et aI., 1970; Sparling, 1972). Recent trends have been towards a levelling out of resistance (Jaffe et aI., I 976a) or even a change to slightly greater sensitivity (Eisenstein et aI., I 977a; Reynolds et aI., 1976). The correlation between low level or relative penicillin resistance and increased failure rates using previously adequate antibiotic regimens has been clearly shown in many studies. At a time when penicillin MICs were all below 0.1 units per ml, a single injection of 150,000 units penicillin G was curative (Sparling, 1972). As antibiotic resistance increased, those patients harbouring the most resistant gonococci had the highest treatment failure rates (Curtis and Wilkinson, 1958; Jaffe et aI., 1976a; Leigh et aI., 1969). Curtis and Wilkinson (J 958) showed that 300,000 units of penicillin G 1M would cure only 50 % of patients harbouring gonococci with MICs of 0.25 units/ml and none with MICs of 0.5 units/ml. Several recent studies (Holmes et aI., 1973; Johnson et aI., 1970) showed that doses of penicillin which were effective only several years ago resulted in high failure rates. Thus the renal tubular secretion blocking agent, probenecid, had to be added to the already high-dose penicillin or ampicillin regimens to
Using the most recent CDC treatment recommendation of 4.8 million units of aqueous procaine penicillin G (APPG) plus I g of probenecid for both men and women (Center for Disease Control, 1974), Jaffe et al. (J 976a) found treatment failure rates of 13 % in patients infected with strains having MICs :> l].lg/ml (about 1.7 units/mI), and 6% with strains having MICs of 0.5].lg/ ml (table 11). Similar correlations between antibiotic resistance and treatment failure prompted Krook and Juhlin (I965) to recommend a dose of penicillin that would result in blood antibiotic levels at least five times that of the MIC of the organism being treated. Parallel treatment correlations with penicillin resistance have been found with tetracycline (Judson and Rothenberg, 1976) and ampicillin (Jaffe et aI., I 976a). Whereas Kousa et al. (J 974) found that spectinomycin failures increased with penicillin resistance, Jaffe et al. (J 976a) did not. The treatment results with these other antibiotics are not unexpected since Maness and Sparling (1973) have shown that low level resistance to penicillin correlates with similar levels of resistance to tetracycline, whereas spectinomycin resistance of clinical importance is an Table II. Treatment failure rates after 4.8 million units aqueous procaine penicillin G (APPG) plus 19 probenecid as II function of penicillin sensitivity (after Jaffe et al.. 1976a)
MIC (pg/mll
Percentage of isolates
Failure rates (%)
Effective Treatment of Gonorrhoea B .I. Eisenstein Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
Summary
Effective therapy of gonorrhoea has changed drastically over the years, reflecting the progressive acquisition of relative antibiotic resistance by the causative organism. Although in the US, the 1974 USPHS recommendations are the best guidelinesfor management at present, recent epidemiological trends may obviate some of these provisions. The most important of these trends is the emergence of R -factor carrying strains capable ofproducing penicillinase, thereby making these strains absolutely resistant to clinically achievable levels of penicillin. This review analyses this problem in the context of reasonable therapeutic goals and also discusses optimum management of patients with such complications as pharyngeal infection, pelvic inflammatory disease and disseminated gonococcal infection.
At present gonorrhoea, in its multiple clinical syndromes, is the most common communicable illness in the world (Clark, 1973). The causative organism, Neisseria gonorrhoeae, is widespread in the community and can be recovered from about 3 % of sexually active asymptomatic females in the US (Holmes, 1977). Although the majority of infections are trivial, the potential for pelvic inflammatory disease, sterility, bacteraemia and destructive arthritis makes the use of optimal effective treatment mandatory in every patient diagnosed with the disease. This review will be concerned with the subject of therapy in the adult and the impact of the new penicillinase-producing strains. For excellent discussions of the clinical syndromes, diagnosis, epidemiology, prophylaxis and paediatric approach, the reader is referred to articles appearing elsewhere (Barrett-Connor, 1975; Holmes, 1974; Litt et aI., 1974; Rein, 1975; Willcox, 1972).
1. Evolution of Gonorrhoea Therapy 1.1 Treatment Failure Related to Progressive Drug Resistance The therapy of gonorrhoea has evolved greatly over the past 30 years, primarily due to the progressive acquisition of relative antibiotic resistance in the gonococcus (table I). Although other reasons for lack of response to therapy have been cited (Sparling, I 972), antibiotic resistance has been the major cause of treatment failure. Before antibiotics came into regular clinical use, the gonococcus was uniformly sensitive to penicillin, tetracycline and streptomycin (Reyn, 1958). Sulpha drugs, which resulted in cure rates of over 90 % when they were fIrst introduced, lost their usefulness after World War II (Farrar, 1972).
58
Effective Treatment of Gonorrhoea
Table I. Changing penicillin sensitivity of gonococci in the United States (after Sparling. 1972; Jaffe et al.. 1976a; and Reynolds et al.. 1976)'
achieve 90 to 95 % cure rates (Cornelius et aI., 1971; Olsen and Lomholt, 1969). 1.2 Treatment Results with Present Regimens
Percentage with MIC (units/mil Year
0.5
1950-55 1965 1968-69 1972 1975
99 58 35 19 37
37 51 54 49
0 5 14 27 14
Some numbers are approximations based on conversion of pg/ml to units/ml
Whereas 99 % of strains from the year 1955 had minimal inhibitory concentrations (MICS) to penicillin of less than 0.1 units per ml, only 35% were as sensitive by 1969 (Martin et aI., 1970; Sparling, 1972). Recent trends have been towards a levelling out of resistance (Jaffe et aI., I 976a) or even a change to slightly greater sensitivity (Eisenstein et aI., I 977a; Reynolds et aI., 1976). The correlation between low level or relative penicillin resistance and increased failure rates using previously adequate antibiotic regimens has been clearly shown in many studies. At a time when penicillin MICs were all below 0.1 units per ml, a single injection of 150,000 units penicillin G was curative (Sparling, 1972). As antibiotic resistance increased, those patients harbouring the most resistant gonococci had the highest treatment failure rates (Curtis and Wilkinson, 1958; Jaffe et aI., 1976a; Leigh et aI., 1969). Curtis and Wilkinson (J 958) showed that 300,000 units of penicillin G 1M would cure only 50 % of patients harbouring gonococci with MICs of 0.25 units/ml and none with MICs of 0.5 units/ml. Several recent studies (Holmes et aI., 1973; Johnson et aI., 1970) showed that doses of penicillin which were effective only several years ago resulted in high failure rates. Thus the renal tubular secretion blocking agent, probenecid, had to be added to the already high-dose penicillin or ampicillin regimens to
Using the most recent CDC treatment recommendation of 4.8 million units of aqueous procaine penicillin G (APPG) plus I g of probenecid for both men and women (Center for Disease Control, 1974), Jaffe et al. (J 976a) found treatment failure rates of 13 % in patients infected with strains having MICs :> l].lg/ml (about 1.7 units/mI), and 6% with strains having MICs of 0.5].lg/ ml (table 11). Similar correlations between antibiotic resistance and treatment failure prompted Krook and Juhlin (I965) to recommend a dose of penicillin that would result in blood antibiotic levels at least five times that of the MIC of the organism being treated. Parallel treatment correlations with penicillin resistance have been found with tetracycline (Judson and Rothenberg, 1976) and ampicillin (Jaffe et aI., I 976a). Whereas Kousa et al. (J 974) found that spectinomycin failures increased with penicillin resistance, Jaffe et al. (J 976a) did not. The treatment results with these other antibiotics are not unexpected since Maness and Sparling (1973) have shown that low level resistance to penicillin correlates with similar levels of resistance to tetracycline, whereas spectinomycin resistance of clinical importance is an Table II. Treatment failure rates after 4.8 million units aqueous procaine penicillin G (APPG) plus 19 probenecid as II function of penicillin sensitivity (after Jaffe et al.. 1976a)
MIC (pg/mll
Percentage of isolates
Failure rates (%)
