Penicillin-Resistant Gonorrhea in the

Transcription

1 Penicillin-Resistant Gonorrhea in the Luis Mayo LaO, M.D., D.T.M. & H.,* Ma. Luisa Montes LaO, M.D.,** Ascencio Bautista, M.D.,*** Melquiades Francisco M.D.**** and Glicerio Mijares M.D.***** Reprinted from the Journal of the Manila Medical Society Vol XVI No. 1, Jan.-March, l978; *Associate Professor and Head, Infectious Disease Board, Hospital Ng Maynila, Manila, Philippines; **Medical Specialist, Out Patient Department, Hospital Ng Maynila, Manila, Philippines; ***Medical Officer, Out Patient Department, Hospital Ng Maynila, Manila, Philippines; ****Head, Department of Pathology, Hospital Ng Maynila, Manila, Philippines; *****Head Out Patient Department, Hospital Ng Maynila, Manila, Philippines) SUMMARY Including the present series there are 362 reported cases of penicillin-resistant cases of gonorrhea in the Philippines. Initial reports of isolated cases came from Southeast Asia. In the present study, isolates are from hospitality girls who came from Olongapo City and Angeles City to take advantage of the International Monetary Fund Meeting and the opening of the big hotels in Manila last October These girls have had contact with American servicemen at the US bases and do not respond to currently recommended dosage of penicillin. At the same time, we made studies on the efficacy and tolerance of two alternative antibiotic regimens namely: cotrimoxazole quicksolv forte double strength and tetracycline. This study showed that cotrimoxazole quicksolv forte given at 2 day treatment schedule is more satisfactory than the l-day schedule and much better than the single dose regimen of tetracycline (2.5 gm). [Phil J Microbiol Infect Dis 1978; 7(1):31-38] Key Words: N. gonorrhea, penicillin, penicillin-resistant gonorrhea, STD INTRODUCTION Until the end of 1956, gonorrhea has responded well to small doses of penicillin, but after that, an increasing number of failures in treatment were noted. Many of them were found to be associated with the presence of strains with a diminished sensit ivity to penicillin, usually of 0.06 to 1.0 unit per ml for inhibition in vitro. The problem is thought to be particularly acute in the Far East when in 1975, strains of gonococci that produce a beta-lactamase or penicillinase began to appear. Soon enough cases of penicillin-resistant gonorrhea were reported in Great Britain. Lately, the National Center for Disease Control in Atlanta, Georgia reported that it has already been found in 26 states and in other countries like Australia, Belgium, Canada, Denmark, Ghana, Japan, the Netherlands, New Zealand, Norway, South Korea, South Africa, Sweden and Switzerland. The lay papers have described these penicillin-resistant cases as Super Gonorrhea against which penicillin has no effect. As early as 1971, we reported a group of 40 cases done at the UST Out Patient Department, while Punzalan et al from the UP Institute of Public Health reported 22 additional cases during the SEAMEO TROP MED Seminar held in Kuala Lumpur last August Because of the fact that these cases would not respond to the currently recommended regimen of 4,800,000 units of penicillin with probenecid plus the CDC report that gonococci isolated during 1972 to 1974 were no more resistant than those isolated during , has led to a reexamination of methods of treatment and a search for alternatives to penicillin. MATERIALS AND METHODS The present study was made at the Hospital Ng Maynila Out Patient Department VD Clinic from the period July-December During that period a total of 1,409 cases of females with vaginal discharges were referred to the Clinic for the study. Our criteria for admission into the study include the following:

2 1. Has received the standard one-shot treatment of 4.8 mega units of procaine penicillin with 1 gm probenecid with no effect. 2. A repeat treatment with the same regimen with no effect. 3. The organism on culture proved to be N. gonorrhea with disc diffusion sensitivity showing complete resistance. On consultation, patients were subjected to complete and thorough history and physical examinations. Specimens were obtained from the cervix and urethra. Cotton ball on ring forceps were used to remove mucus from the cervical area before getting the specimen from the endocervical canal. Gram's stain was done on one smear. The specimen swab was rolled in the culture plate and incubated under CO 2 jar at 37 C for 24 hours. Sensitivity testing was done on DST Oxoid Agar. The Thayer-Martin culture media was the one used for culturing the organisms. For confirmatory tests, oxidase test and sugar fermentation tests were done. So that typical colonies of oxidase positive; gram-negative diplococci on T-M culture media were sufficient criteria for identification of N. gonorrhea. Sensitivity testing for the following were done: cotrimoxazole, penicillin, tetracycline, erythromycin, and kanamycin. The smear and culture were done before the start of treatment and one and two weeks after the end of therapy. Out of the 1,409 cases with vaginal discharges, 409 turned out positive to N. gonorrhea and 300 of them were resistant to penicillin. All of these are hospitality girls who came from Olongapo City and Angeles City seeking new employment in the rows of nightclubs and entertainment houses along Roxas Boulevard. They came to Hospital Ng Maynila for clearance before employment in the nearby hospitality rows. The age ranged from 16 to 24 years old. The patients were divided into 3: groups: Group 1 patients received cotrimoxazole quicksolv double strength tablet (800 mg SMZ mg TMP) at the dose of 3 tablets in the morning and 2 tablets in the afternoon as single day treatment; Group II patients were given the same tablet but at a dose of 2 tablets in the morning and 2 in the afternoon for two days; and the Group III patients received tetracycline hydrochloride at a dose of 2.5 gms per orem as single dose. The new preparation of cotrimoxazole used in this study is a quicksolv double strength tablet consisting of 800 mg sulphamethoxazole mg trimethoprim. The tablet is dissolved in any liquid and taken per orem. The preparation is sometimes called "the gono cocktail" as it could be mixed with water or liquid. RESULTS Table 1 shows the age and number incidence of the series in this group who completed the study. It will be noted that most of the cases occurred in the age groups. Table 1. Age and Number Incidence Age (years) Number

3 Table 2 shows the reported incidence of penicillin-resistant gonorrhea in the Philippines. Punzalan et al from the UP Institute of Public Health reported 22 cases while Lao et al from UST and Hospital Ng Maynila had 40 cases in their series of Table 2. Incidence of Penicillin Resistant Gonorrhea in the Philippines Author Number Year Punzalan et al Lao et al Lao et al Table 3 revealed that out of the 1,409 cases of adult females with vaginal discharges referred in the study, 409 cases turned out positive to N. gonorrhea, of which 300 were penicillinresistant. These are the cases who have used the recommended aqueous procaine penicillin G 4,800,000 units with one gram probenecid oral with no effect. Sensitivity studies revealed they are both sensitive to cotrimoxazole and tetracycline. Table 3. Bacteriologic Studies Cases Smear (+) Culture (+) Penicillin-Resistant 1, From these cases, we run a comparative study between cotrimoxazole quicksolv forte and tetracycline as alternative regimens to penicillin. As Table 4 shows, we compared the one-day and two-day treatment of cotrimoxazole quicksolv forte to the single dose treatment of tetracycline. Results revealed that both the one-day and two-day treatment schedule of cotrimoxazole gave only 4 failures each out of the 100 cases in each group, while tetracycline gave 8 failures out of 100 cases. Table 4. Results of Treatment Treatment Patient Treated Cured Failure Cotrimoxazole 1-Day Treatment (96%) 4 (4%) 2-Day Treatment (96%) 4 (4%) Tetracycline Single dose (2.5 gm) (92%) 8 (8%) We studied also the adverse reactions to the medications as Table 5 shows. With the oneday treatment of cotrimoxazole quicksolv forte, there were more nausea and vomiting reported compared to the two other regimens. There were more rashes and pruritus that developed with the one-day treatment schedule of cotrimoxazole quicksolv forte regimen. From this study, the more satisfactory treatment schedule would be the 2-day schedule of cotrimoxazole as there were few adverse reactions encountered. DISCUSSION The patients in the present series are all hospitality girls who came from Olongapo City and Angeles City to ply their trade in Manila at the time of the International Monetary Fund Meeting. This is also the time when the big hotels in the City are scheduled to open in time for the international meeting. The girls come to our VD Clinic for diagnosis and treatment. The Hospital Ng Maynila is located right in the center of the big hotels along Roxas Boulevard and is very convenient for the girls to go to for consultation.

4 For the period July-December 1977 (7 months), there were about 1,409 cases with vaginal discharges referred to the clinic. Only 409 turned out positive to N. gonorrhea and from this, 300 are penicillin-resistant cases. Table 5. Adverse Reactions Side Effects 1-Day Treatment 2-Day Treatment Tetracycline 1. Rash Pruritus Nausea, Vomiting F. R. Curtis, A.H. Wilkinson, and J. E. Gradock-Waton; R. A. Shooter and C. S. Nicol of Great Britain reported in 1958 on strains of gonococci relatively insensitive to penicillin. It is a common finding that infections with strains needing more than 0.1 microgram per ml. of penicillin for inhibition in vitro often fail to respond clinically. In Greenland, Olsen and Lemholt actually observed a decrease in resistance to penicillin with the use of 5,000,000 units of crystalline penicillin G. combined with probenecid. In 1971 we reported a series of 40 cases of penicillin-resistant cases of gonorrhea isolated at the UST Out-Patient Department, which was reported in the SEAMEO-TROPMED seminar held in Bangkok last The resistance to penicillin that strains of N. gonorrhea have developed over the past 20 years has led to the increase in the dosage of penicillin. Today, the recommended dosage of penicillin is 4,800,000 units plus one gram of probenecid. This is about 30 times the dosage used by Mahoney et al in 1943 when the needed dosage is only 160,000 units. This schedule has been shown to be highly effective in the treatment of uncomplicated gonococcal infections. The Center for Disease Control in Atlanta, Georgia in a large collaborative study found out that the relative resistance to penicillin of isolated N. gonorrhea had apparently reached a plateau; that is gonococci isolated during 1972 to 1974 were no more resistant than those isolated during This is apparently due to the fact that the highly effective treatment schedule - 4,800,000 units of penicillin G plus 1.0 g. of probenecid has retarded the selection of resistant mutants. This complacency was short-lived because about the end of 1975, strains of gonococci that produce the enzyme beta-lactamase or penicillinase were reported in the Far East and later in the United States and Great Britain. With this report patients would not respond anymore to the currently recommended regimen consisting of 4,800,000 units of aqueous procaine penicillin G plus 1.0 g. of probenecid. So that alternative antibiotics must be employed. In the Philippines Punzalan et al at the Kuala Lumpur meeting last August, 1977 reported on 22 cases of penicillinase-secreting N. gonorrhea. This study was made at the Manila VD Control Center at Quiricada Street. Our present study would add up to the series that has been reported elsewhere and proved that we have these penicillin-resistant strains in our country. Our cases come mostly from Olongapo City and Angeles City nightclubs who have come to take advantage of the big international meeting that was held at the Philippine International Convention Center. The girls come to our VD Clinic at the Out-Patient Department of the Hospital Ng Maynila for treatment before they can get employment at the rows of nightclubs along Roxas Boulevard, which are very near our hospital. The 300 cases of penicillin-resistant cases that we gathered since the opening of our VD Clinic a year ago have used the recommended 4,800,000 units of penicillin G plus one gram probenecid without any effect. These are the cases in which we use the alternative antibiotics, namely: cotrimoxazole quicksolv forte and tetracycline. In the space of 7 months, we have accumulated this number of cases. That just goes to say that we have in our country truly the penicillin-resistant gonorrhea as reported in the papers. There are two ways by which microorganisms may become resistant to antibiotics, namely: chromosomal mutation and the other is by the formation of a segment of

5 extrachromosomal DNA called a plasmid or R factor. Sparling et al have proven that the resistance to penicillin that developed during the past 20 years is due to mutants and not to the production of an enzyme that destroys penicillin. From this study, we have found out that the new preparation of cotrimoxazole quicksolv forte is more effective than tetracycline in the treatment of penicillin-resistant gonorrhea. The 2- day schedule for cotrimoxazole that is two tabs b.i.d, for two days is more effective and has less adverse reactions than the one day treatment. The tablet that was used is the new presentation called quicksolv forte double strength so that a tablet o this corresponds to 2 tabs of the original. This is quite convenient for the patients or they can crush the tablet: and mix with water or any liquid just like a cocktail. Tetracycline on the other hated is less effective and may lead to relatively resistant gonococci. Many of the patients complain of nausea and vomiting, dizziness and weakness. So that we recommend that this antibiotic be reserved for patients with penicillin allergy. The one day treatment with cotrimoxazole quicksolv forte would be more convenient only that more adverse reactions occurred like nausea and vomiting and rashes. We therefore recommend the 2- day treatment schedule of cotrimoxazole forte in the treatment of penicillin-resistant gonorrhea. Failures in this series were mostly due to undetected complications, which developed during therapy. REFERENCES 1. McCormack WM. Treatment of gonorrhea - is penicillin passé? Editorial. N Engl J Med 1977; 16: Karney WW, et al. Spectinomycin versus Tetracycline for the treatment of gonorrhea. N Engl J Med 1977; 16:296, Klein,EJ, et al. Anorectal gonococcal infection. Ann Intern Med 1977; 88: LaO LM, et al. SMZ:TM in the treatment of acute penicillin-resistant cases of gonorrhea in women. Asian J of Med 1971; Mahoney JF, Ferguson C, Buchholtz M, et al. The use of penicillin sodium in the treatment of sulfonamide resistant gonorrhea in men: a preliminary report. Am J Syphil Gonorr Vener Dis 1943; 27: Martin JE Jr, Lester A. Price EV, et al. Comparative study of gonococcal susceptibility to penicilliln in the United States, J Infect Dis 1970; 22: Sparling PF, Sarubbi FA Jr., Blackman E. Inheritance of low-level resistance to penicillin, tetracycline, and chloramphenicol in Neisseria gonorrhea. J Bacteriol 1975; 124: Center for Disease Control. Gonorrhea. CDC recommended treatment schedules, MMWR 1974; 23(40): Kaufman RE, Johnson RB, Jaffe HW, et al. National gonorrhea therapy monitoring study: Treatment re sults. N Engl J Med1976; 294: Jaffe HW, Biddle JW, Thornsberry G, et al. National goonorrhea therapy monitoring study: In vitro antibiotic susceptibility and its correlation with treatment results. N Engl J Med 1976; 294: Center for Disease Control. Penicillinase-producing Neisseria gonorrhea. MMWR 1976; 25(33): Ashford WA, Golash RO, Hemming VG. Penicillinase-producing Neisseria gonorrhoea, Lancet 1976; 2: Phillips T. B-lactamase-producing penicillin-resistant gonococcus. Lancet 1976; 2: Sparling PF, Holmes KK, Weisner PJ, et al. Conference on the problem of penicillin-resistant gonococci. J Infect Dis (in press). 15. McCormack WM, Finland M. Spectinomycin. Ann Intern Med 1976; 84: Lawrence A. Phillips I, Nico1 C. Various regimens of trimethroprim -sulfamethozaxole used in the treatment of gonorrhea. J Infect Dis 1975; 128 (suppl): S673-S Svindland HB. Treatment of gonorrhea with sulfamethozaxole-trimethoprim. Br J Vener Dis 1973; 49:50-53.