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Some Aspects of Rational Trachoma Therapy
SOME ASPECTS O F RATIONAL TRACHOMA T H E R A P Y M.D. Moscow, USS.R.
Y. F. MAIC HUK,
In the last few years, considerable prog ress has been made in the control of tra choma as a result of the implementation of various national programs and of measures carried out under the auspices of the World Health Organization.1"9 Trachoma has been eradicated as an important public health problem in the U.S.S.R. where it was once a prevalent disease. According to Dr. A. G. Safonov's report,10 the prevalence of active trachoma (Stages I, II, I I I ) in the U.S.S.R. decreased 407.5 times during the period 196068. In recent years, the typical clinical course of trachoma has also changed, probably as a result of general improvement in public health facilities, higher sanitary and eco nomic levels, more and better health educa tion, and active treatment of infectious eye disease. The tendency has been toward a milder trachoma, even in areas where the disease used to be a major cause of blind ness. Although most cases of trachoma are cured in the course of mass treatment cam paigns, there are always a certain number that remain active, most of them in patients with a persistent form of the disease. These cases are often characterized by periods of improvement, when the disease appears to be healed, followed by relapses. There has been a gradual reduction in the number of re lapses, however. Mass treatment with chloramphenicol ( Synthomycin) some years ago was followed by relapses in from 6 to 25% of cases,11 whereas the relapse rate in recent campaigns has ranged from 0.34 to 1.5%. In 1968, for example, a survey of a rural popu lation sample of 1509 patients with a past
history of active trachoma, or with signs of healed trachoma, showed relapses occurring in only 0.7%. Relapses in trachoma are attributable to one or more of the following factors : associ ated systemic disease ; diminished host resis tance; allergic (including autoallergic) reac tions; secondary disease of the eyelid, con junctiva, or both; and inadequate or irra tional chemotherapy. Especially important are (1) lesions of the lacrimal apparatus, and (2) concurrent bacterial, particularly staphylococcal, infection of the conjunctiva that is resistant to the administered drugs. 13,1* Apart from all of these factors, specific drug resistance of particular strains of tra choma agent also merits attention.
At this stage of our efforts to eradicate trachoma, the subclinical form of the disease is epidemiologically important. Unless such subclinical cases are diagnosed and cured at an early stage, they become a major source of fresh infections. The different clinical forms of trachoma call for different methods of treatment. Studies in recent years have demonstrated convincingly that there is no single method to be preferred for all cases under all condi tions. On the contrary, it is from the wide variety of therapeutic agents available and the variety of ways of applying them that the most rational treatment for each type of case should be chosen. The present paper summarizes the results of our studies of trachoma therapy. Our spe cial concerns were ( 1 ) the sensitivity of tra choma agent to the various drugs under con sideration, and (2) the concentration of the drug in the conjunctiva. When considered in accordance with these variables, rational che From the Virus Clinical Department, Moscow motherapy—that is, the method that best Helmholtz Research Institute of Eye Diseases, takes into account the clinical course of the Moscow. Reprint requests to Y. F. Maichuk, M.D., Moscow disease and the available medical facilities— Helmholtz Research Institute of Eye Diseases, calls for the following decisions : ( 1 ) choice Moscow, U.S.S.R.
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TABLE 1 EFFECT OF TETRACYCLINE (T), DITETRACYCLINE (D), AND OLETETRINE (O)* ON THE GROWTH OF TRACHOMA AGENT IN EMBRYONATED EGGS Titer of Trachoma Agent InoculumL Antibiotic Dose (fg/egg) 10.0
5.0 2.5 1.0
Controls
10-
1
10-»
10-»
T
D
0
T
D
O
T
D
O
0/6t
0/6 1/6 3/5 5/6 6/6
0/6 2/6 5/5 6/6 6/6
0/5 1/6 4/6 5/5 5/5
0/6 0/6 3/6 4/6 6/6
0/6 0/6 4/6 6/6 6/6
0/6 0/6 4/6 5/5 6/6
0/6 0/6 0/6 1/6 6/6
0/6 0/6 2/6 2/5 6/6
2/6 5/6 6/6 5/5
* Combined oleandomycin and tetracycline in ratio of 1:2. t Embryo deaths/embryos inoculated.
of the drug, (2) choice of the form of the drug and the route of administration, (3) choice of the frequency of drug application, and (4) choice of the treatment schedule. CHOICE OF DRUG
The antibiotic or sulfonamide should be chosen on the basis of its specificity for chlamydial agents. When sensitivity tests have been run on chick embryo cultures of chlamydias, the antibiotics and sulfonamides to which the agents have been found to be most sensitive are the following: tetracycline, di tetracycline, erythromycin, oleandomycin, oletetrine, chloramphenicol, sulfapyridazine, sulfadimethoxydiazine, and sulfalene. In ex periments on emtryonated eggs infected with trachoma agent, it was found that when most of these antibiotics were administered in low doses (1 μg/ embryonated egg), they exhib ited some inhibitory effect, and that when 10 !*g/egg were introduced, they inhibited the agent completely (Table 1). The antichlamydial effect of the long-acting antibiotics, di tetracycline and oletetrine (an antibiotic combination), was more pronounced than that of tetracycline. Our own studies have shown that among the sulfonamides, sodium sulfapyridazine and sulfadimethoxydiazine (Madribon) are the most effective against trachoma,15 and that next in order are sulfadimethoxydiazine,
norsulfazol, sodium sulfazil (Albucid), and ethazole. We have also studied the inhibitory concentration of some of these drugs at the sites of reproduction of the trachoma agent— that is, in the contents and envelope of the yolk sac and in the allantoic fluid (Table 2 ) . The inhibitory concentration at these sites was found not to exceed 0.91 μg/ml for tetra cycline HC1, 0.59 {ig/ml for ditetracycline, and 0.34 [ig/ml for oletetrine. In choosing an antibiotic or sulfonamide on the basis of its specific activity against trachoma agent, the therapist should bear in mind that not all strains are equally sensi tive, and that the sensitivity of any one strain is probably not invariable. Various strains isolated from active trachoma have been found to be resistant to tetracycline, erythromycin, penicillin, and the sulfon amides, respectively; and in the cases from which these resistant strains have been iso lated, the drug in question has frequently been found to be less than usually effective therapeutically. Attempts to account for persistence of the disease on the basis of the development of drug resistance (analogous to the drug re sistance that develops in staphylococci) have been only partly successful, however ; under experimental conditions such development of resistance has occurred in connection with sulfonamides15 but not in connection with antibiotics.16·17
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TABLE 2 CONCENTRATION OF ANTIBIOTICS IN TISSUES AND FLUIDS OF TRACHOMA-INFECTED EMBRYONATED EGGS AFTER INOCULATION WITH 1 0 I»G OF ANTIBIOTIC
No. Hours after Injection
Allantoic Fluid G*g/ml)
Yolk Sac (cg/ml)
Amniotic Fluid G*g/ml)
Yolk Sac Membrane (Mg/ml)
Embryo G*g/g)
Allantoic Membrane (Mg/g)
Tetracycline 1 24 48 96
0.81±0.04 0.89±0.02 0.91 ±0.20 0.57±0.16
0.77±0.03 0.54±0.01 0.87+0.20 0.40±0.01
0 0 0 0
0.53±0.02 0.48±0.02 0.62±0.07 0.44±0.05
0 0 0 Trace
0 0-trace 0-trace 0
Ditetracycline 1 24 96
0.46±0.03 0.47±0.02 0.53±0.04
0.36±0.04 0.46±0.02 0.49±0.05
0 0 0
0.44±0.01 0.45±0.02 0.47±0.04
0 0 0
0 0 0
Olete trine 1 24 96
0.34±0.02 0.11±0.02 0.08 + 0.02
0.16±0.02 0.28±0.02 0.11±0.01
0 0 0
O.lOiO.01 0.12+0.08 0.09±0.02
0 0 0
0 0 0
So far as clinical observations are con cerned, it has been demonstrated convinc ingly that there is a progressive loss of drug efficacy in the course of mass treatment cam paigns. Strains resistant to tetracycline,18 for example, are more likely to survive during mass campaigns of treatment with tetracy cline, and these strains are likely thereafter to be more widespread in the area concerned than less resistant strains. From this point of view, alternating-inter mittent treatment seems to be advanced. This is treatment with two antibiotics, each inter mittently (first one and then the other). The antibiotics should be taken from different groups active against trachoma agents. One
'.9 auapontion
2.9 ointaent
3,g aqueous Bolution
U. PVAaolution
Fig. 1 (Maichuk). Antibiotic concentrations (μβ/ ml) in conjunctival sac six hours after single ap plication of tetracycline prepared in various vehicles.
of them may be replaced by a long-acting sulfonamide for topical application. CHOICE OF DRUG FORM AND ROUTE OF ADMINISTRATION
In handling this question, particular im portance has been attached to the concentra tion of the drug in the tissues and media of the eye, and to comparing it with the concen tration required to inhibit trachoma agent at its site of reproduction. After administering a single dose of tetra cycline, erythromycin, oletetrine, oleandomycin, or other antibiotic, each of which was prepared as a 1% aqueous solution, a sus pension, or an ointment in a lanolin-petrola tum base, we found the antibiotic regularly in the conjunctival sac for six hours. The concentration level varied, however, not only from drug to drug but even from compound to compound of the same antibiotic—an ob servation that may be of practical impor tance. The hydrochloride of tetracycline, for example, contributes more than other com pounds to a high concentration of the drug in the conjunctival sac, to good penetration of the ocular tissues and media, and to a highly therapeutic effect.
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il 3 Fig. 2 (Maichuk). Antibiotic phannacodynamics in conjunctival sac after single instillation of erythromycin prepared in aqueous or PVA solutions. U0ÜK3
Still more important is the nature of the vehicle in which the antibiotic is prepared (Fig. 1). Experimental and clinical investi gations have shown that when the polymeric base, polyvinyl alcohol ( P V A ) , is used as the vehicle, a preparation that is more effec tive than an aqueous solution results. Its ad vantages are (1) that the antibiotic has a longer acting effect and remains at a higher level of concentration (Fig. 2) ; (2) that the antibiotic penetrates the ocular tissues and media better (Fig. 3) ; (3) that the activity of an unstable antibiotic persists longer 19 ; (4) that drug toxicity is reduced; (5) that tissue irritation is obviated and corneal epithelialization enhanced ; (6) that drug al lergies are much less likely to occur; and (7) that good therapeutic results are achieved with longer intervals between drug applica tions than are otherwise possible. The influ ence of PVA in lengthening the drug effect was also evident when it was used as a ve hicle for ethazole and sodium sulfapyridazine.
Aqueous PVA solution solution Fig. 3 (Maichuk). Antibiotic concentration in rabbits aqueous humor three hours after instillation of erythromycin in aqueous and PVA solutions.
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TABLE 3 CONCENTRATION OF DRUG (mg%) AFTER SINGLE CONJUNCTIVAL INSTILLATION OF 1 0 % SULFAPYRIDAZINE IN AQUEOUS OR P V A SOLUTIONS
Ocular Tissue of Fluid
2 Hours
1 Hour PVA
Aqueous
Conjunctiva
3.07± 0.36
1.66± 0.23
Cornea
2.11 + 0.4
0.17± 0.1
Aqueous humor
Trace
—
PVA
12 Hours
24 Hours
Aqueous
PVA
Aqueous
PVA
Aqueous
3.5± 0.37
1.3 + 0.3
1.5± 0.15
Trace
0.58± 0.15
—
2.17 + 0.43
0.5± 0.08
0.5 + 0.06
—
0.36± 0.06±
—
0.10
Trace
Trace
—
—
—
When we first tried PVA as a vehicle for antibiotics and sulfonamides, we used a 5 or 10% solution, but at present 2.5% is the concentration of choice. The potency of a 10% sodium sulfapyridazine solution in 2.5% PVA was not reduced during a ninemonth period when the drug was stored at room temperature. After a single instillation, the drug attained a concentration at six hours of 3.5 mg% in the conjunctiva and 2.7 mg% in the cornea ; at 12 hours the concen tration was 1.5 mg% in the conjunctiva and 0.5 mg% in the cornea. When an aqueous solution was used instead, the respective con centrations at six hours were 1.5 mg% and 0.5 mg%, and at 12 hours no sulfonamide could be detected in the ocular tissues (Table 3). It was found that the polymeric vehicle such as polyacrilamide (PAA) provided even more advantages for antibiotics and sulfonamides. Following a single instillation of 10% sulfapyridazine solution in 1% PAA, the drug was detected in the conjunctiva in a concentration of 1.66 mg% after 24 hours and 0.58 mg% after 48 hours. Of practical interest are long-acting anti biotics and sulfonamides topically applied. After a single application of 1% ditetracycline ointment (Table 4 ) , the antibiotic was detected in patients at 24 hours (2.5 μg/ml) and at 48 hours (1.8 μg/ml) in concentra tions that exceeded the concentration re
quired for an antiviral effect at the site of reproduction of trachoma agent. CHOICE OF THE FREQUENCY OF APPLICATION
The frequency with which the drug is ap plied predetermines to a large extent the concentration of the drug that is achieved and maintained in the conjunctiva. Our prin ciple is that rational chemotherapy calls for different levels of antiviral medication in the conjunctival sac (hence the use of a variety of drug forms and of applying them with different frequencies), the choice to be made in accordance with the specific pattern of the course of the disease. In connection with erythromycin, for ex ample, hospitalized patients require five ap plications of 1% ointment daily (Fig. 4 ) . This schedule achieves a high concentration of the drug, its lowest level being 58.6 ± 3.3 μg/ml in the daytime and 6.5 ± 0.7 μg/nll in the morning. When the ointment is applied only twice daily (Fig. 5), its concentration is lower (the lowest level ranging from 3.8 ± 0.3 to 4.8 ± 0.4 μg/ml) but still sufficient to produce the desired therapeutic effect. Ginical observations on 535 trachoma pa tients have shown that varying the proce dures for applying erythromycin in accor dance with the clinical picture of the disease has been very effective. The administration of 1% tetracycline ointment, or of an antibi otic combination (oletetrine), four to five
times daily in severe cases and two to three times daily in mild cases, has also yielded good results. The use of soluble antibiotics (tetracycline HC1, erythromycin ascorbinate, oletetrine) and sulfonamides (ethazole, sodium sulfapyridazine) in PVA permits a reduction in the required number of instillations. As a rule the long-acting 1% ditetracycline oint ment is effective when applied once daily or every other day. In one trial of our series, three applications of ditetracycline ointment weekly during seven weeks cured trachoma in 81.3% of subjects.20 In cases of severe and persistent trachoma, however, the local application of antibiotics or sulfonamides should be combined with the systemic admin istration of either ethazole or sulfapyridazine. It should be emphasized that long-acting sulfonamides should be used systemically only in emergencies and under hospital con ditions favorable for the control of the side effects that may occur.21"24 We have not our selves accumulated any evidence that the sys temic administration of such long-acting sul fonamides, when used alone for the treat ment of trachoma, is highly efficacious. A se ries of 53 children, aged five to seven years, and suffering from severe, florid trachoma,
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TABLE 4 ANTIBIOTIC CONCENTRATION AFTER SINGLE CONJUNCTIVAL APPLICATION OF 1 % DITETRACYCLINE OINTMENT IN RABBITS AND TRACHOMA PATIENTS
Time after Application (No. Hours)
Antibiotic Concentration G*g/ml) Rabbits 25.6 + 3.1 5.8 + 0.9 3.0 + 0.38 2.4±0.31 1.9±0.02 1.6±0.1 1.1±0.14
1 3 6 9 12 24 48
Trachoma Patients
—
26.2±1.4 5.5±0.2
—
4.6±0.2 2.5±0.1 1.8+0.1
were treated with a long-acting sulfonamide, phanazil, once weekly for eight weeks. The initial daily dosage was 30 to 40 mg/kg, and the subsequent dosage 25 mg/kg. Of one group of 22 children who were given sys temic treatment only, 13 were cured, five were improved, and in four the condition re mained unchanged. The lack of an immedi ate effect was apparent in the very slight im provement that took place in the allied con junctivitis. In a second group of 31 children, the sys temic treatment was supplemented by topical applications of 1% ditetracycline ointment twice weekly; 25 were cured and five im proved. The more pronounced therapeutic
l\
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V \
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13
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X
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Fig. 4 (Maichuk). Antibiotic concentration in conjunctival sac of trachoma patients after application of 1% erythromycin ointment five times daily.
AMERICAN JOURNAL OF OPHTHALMOLOGY
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Fig. 5 (Maichuk). Antibiotic concentration in conjunctival sac of trachoma patients after application of 1% erythromycin ointment twice daily. effect of the combined treatment may be at tributed to the fact that systemic antichlamydial therapy with sulfonamides was supple mented by topical action on both the tra choma agent and the associated pathogenic microflora. For example, of 30 subjects with associated bacterial conjunctivitis who were treated in this way, 26 were cured. The pathogenic conjunctival flora disappeared in all cases after the first week of treatment. CHOICE OF TREATMENT SCHEDULE
The treatment schedule is of great impor tance in rational chemotherapy, since its aim is to achieve the continuous maintenance of a definite concentration of the drug in the con junctiva. When persistent, relapsing, and subclinical forms of the disease are encoun tered, it is of course the aim of all treatment methods to ensure the cure of each patient. This can best be achieved by applying drugs to which resistance has not yet developed, and above all by following treatment sched ules that will induce a high and stable con centration of the drug sufficient to act even on partially sensitive strains of the agent. On the basis of studies of the pharmacodynamics of antibiotics, the following regi men is recommended : four to six times daily applications of the drug at regular intervals (every three or every five hours) from 7 to 8
A.M. to 10 or 11 P.M., the last application to be made before the patient falls asleep. In this way a uniform concentration can be maintained in the conjunctival sac during the daytime, and retention of the drug through out the night is favored. For example, tetra cycline introduced according to this proce dure remains at or above 20 μg/ml (Fig. 6 ) , which is significantly higher than the concen tration that assures an antichlamydial effect at the site of reproduction of the trachoma agent. As stated above, the use of PVA as the vehicle in the preparation of the antibiotics prolongs their action. This permits their ap plication at longer intervals (three to four applications daily), and reduces the risk of allergic reactions. Our clinical observations of more than 2000 trachoma patients treated with various antibiotics have demonstrated the advantages of using PVA as the vehicle and of applying the drugs at regular inter vals. For the mass treatment of trachoma and associated bacterial conjunctivitis, a program calling for the intermittent treatment of the entire population, family by family, has in our experience proven to be the most practi cal and economical method. We noted with considerable regularity that if tetracycline was administered shortly before the patient
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retired for the night, it tended to be retained throughout the night. This prompted us to suggest the following schedule for mass treatment campaigns in the Sudan: (1) tetracycline (in suspension or in a polymeric solution) to be administered once daily in the evening25 on six consecutive days, this to constitute one cycle of treatment; and (2) one cycle to be carried out once each month for six months, this to constitute one course of treatment. A total of 10,074 inhabitants were treated in this way, family by family. The preva lence of active trachoma dropped from 39.9 to 8.9% after the first course of treatment, then to 5.6% by the end of the first year of observation. When a second course was given to recalcitrant cases, the 5.6% preva lence was reduced twofold. The incidence of fresh infections declined from 8.9% (during the first six months) to 0.7% (during the first year), and the incidence of relapses dropped from 5.0 to 0.5%. To step up the concentration of the drug in the ocular tissues in the morning so as to
701
make it comparable to the evening levels, two or three instillations can be made at short in tervals early in the day. It has been sug gested that three instillations of 10 %sulfapyridazine solution in PVA be made during one hour in the morning and one instillation in the evening.26 An analysis of the pharmacodynamics of the drugs in the ocular tissues makes it pos sible to interpret results obtained in clinical trials of various treatment procedures. For example, a study in Sudan of two methods of intermittent treatment in primary schools (2032 school children), in which one daily instillation for 36 days (Group 1) was com pared with two daily instillations for 36 days (Group 2)—that is, 36 or 72 instillations— showed the two regimens to be equally effica cious. Six months after completion of the treatment course, the percentage of cured subjects was 82.6% in Group 1 and 84.1% in Group 2. The efficacy of the two regimens was also identical in two other respects : they were equally effective for the treatment of conjunctivitis patients (the cure rate was
TiuSATHIOT
·«-
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MO
TDtE
Fig. 6 (Maichuk). Pharmacodynamics of tetracycline in conjunctival sac of trachoma patients treated six times daily at regular intervals. Antibiotic levels (μξ/αύ) shown at left.
702
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER, 1972
■cuwauan A».
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A
X •a 4 B
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88.8% in Group 1 and 86.5% in Group 2) ; and the same length of time was required for the elimination of pathogenic flora from the conjunctival sac. In studying the levels of drug concentra tion, we found that the application of a tetra cycline suspension twice daily with a threehour interval between instillations resulted in a short-term enhancement of the antibiotic activity, which was not the case when one daily instillation was made (Fig. 7). By virtue of the prolongation of the anti biotic effect brought about by the use of a polymeric vehicle, the concentration of the antibiotic in the conjunctival sac 24 hours after the instillation of 1% tetracycline HC1 in PVA was still 1.25 ± 0.2 pg/ml. The drug was introduced once daily, and prefer ence was given to the family method which facilitated treatment in the evening. The to tal treatment course included 36 instillations. Among 155 trachoma patients, cure was achieved in 82.7% and alleviation of clinical symptoms in another 8.3%. Of 311 subjects with bacterial conjunctivitis, 82.4% were
cured after six days of treatment. KochWeeks bacillus was eliminated in all cases and Morax-Axenfeld diplobacillus in most cases. SUMMARY
On the basis of an analysis of the pharma codynamics of a drug in the ocular tissues, and a correlation of the results with the sen sitivity of trachoma agent to the drug in question, a variety of treatment regimens for trachoma can be developed from which the regimen best suited to the clinical course of the case to be treated can be selected. Impor tant factors in such rational chemotherapy of trachoma are the choice of the drug, the form in which it is prepared, its route of ad ministration, the frequency of its applica tion, and the treatment schedule to be followed. REFERENCES
1. WHO : Expert Committee on Trachoma, Third Report. Geneva, WHO Technical Report, 1962. 2. WHO: Fourth WHO Scientific Group on
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Trachoma Research. Geneva, WHO Technical Re port, 1966. 3. Dudina, Z. T. : Organized control of trachoma. In Textbook of Eye Diseases, vol. 2. Moscow, Medgiz, 1960, p. 115. 4. Daghfus, T. : Organization of the fight against trachoma and purulent ophthalmia in Tunisia. New Delhi, Int. Cong. Ophth., 1962. 5. Erwinn, S. : A statement on trachoma in In donesia. WHO Inter-regional Conf. on Trachoma, 1962. 6. Kamel, S.: Trachoma and acute ophthalmias in Egypt. Arch. Ophth. 69:117, 1963. 7. Litricin, O. : Trachom u Jugoslavia. Narodno Zdrav. 8:223, 1963. 8. Rostkowcki, L. : Trente ans de la lutte métho dique contre le trachome en Pologne. Rev. Int. Trach. 40:270, 1968. 9. Gupta, U. C. : Trachoma in India. Rev. Int. Trach. 42:102,1965. 10. Safonov, A. G. : Ways and means for consol idating the results of trachoma control in the USSR. Vesta. Oftal. 1:3, 1969. 11. Chumakov, M. P. : Synthomycin therapy of trachoma. In Antibiotic Therapy of Trachoma. Moscow, Medgiz, 1955, p. 4. 12. Vassilieva, A. D., and Shoulpenkova, A. Z. : Trachoma Relapses. Some of the Problems of In fectious Eye Diseases. Moscow, Chuvashizdat, 1968, pp. 28, 36. 13. Maichuk, Y. F . : Clinical picture of lacrimal pathology in trachoma patients. Proc. XXI Conf. Moscow Helmholtz Inst. Eye Dis. Moscow, Chu vashizdat, 1961, p. 120. 14. : Significance of secondary bacterial infection in the persistent forms of trachoma. Some
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of the problems of infectious eye diseases, 1968, p. 131. 15. Lenkevich, M. M., and Kournosova, L. M. : Pharmacological analysis of inhibitions of metabo lism in trachoma agents. Pharm. Toxicol. 27:584, 1964. 16. Tarizzo, M. L., and Nabli, B. : The effect of antibiotics on the growth of TRIC agents in embryonated eggs. Am. J. Ophth. 63:1585, 1967. 17. Tarizzo, M. L. : Discussion in trachoma and allied diseases. Am. J. Ophth. 63:1585, 1967. 18. Shiao, L. C , Wang, S. P., and Grayston, J. T.: Sensitivity and resistance of TRIC agents to peni cillin, tetracycline, and sulfa drugs. Am. J. Ophth. 63:1558,1967. 19. Maichuk, Y. F. : Polyvinyl alcohol as medici nal basis for antibiotics in practice of ophthalmol ogy. Oftal. Zn. 5:350, 1964. 20. : Ditetracycline—a long-acting antibi otic for the treatment of trachoma and conjunctivi tis. Progress in Antimicrobial and Anticancer Che motherapy, 1970, p. 953. 21. Grayston, J. T.: Discussion. Am. J. Ophth. 63:1583,1967. 22. Thygeson, P. : Discussion. Am. J. Ophth. 63 : 1585, 1967. 23. Dawson, C. R. : Discussion. Am. J. Ophth. 63:1585,1967. 24. Tarizzo, M. L., and Nataf, R. : The treatment of trachoma. Rev. Int. Trach. 47:72, 1970. 25. Maichuk, Y. F . : Treatment of patients suf fering from trachoma and conjunctivitis in Sudan. Vesta. Oftal. 79:31, 1966. 26. Posdniyakov, V. I. : Polymeric basis for pro longation of sulfapyridazine. Moscow, Proc. Conf. of MONIKI, 1967, p. 712.
O P H T H A L M I C MINIATURE
T h e r e h e was, in a town all noisy with letters and words, in a carriage full of men reading the news of the world in their newspapers, in a Lon don full of printed stuff, of boards and placards each giving its tidings. Yet he was travelling like a blind man, asking his way, asking help as he went. Another must expound to him the meaning of the plates with the word Monument painted on them. T h e n he would get out of the train and look cunningly to see by which of the staircases men were mounting to the street, for the words W a y O u t tell him naught. I n the course of the day he must have asked many questions and told many men that he could not read. Macdonald Critchley Developmental Dyslexia W m . Heinemann, 1968
Y. F. MAIC HUK,
In the last few years, considerable prog ress has been made in the control of tra choma as a result of the implementation of various national programs and of measures carried out under the auspices of the World Health Organization.1"9 Trachoma has been eradicated as an important public health problem in the U.S.S.R. where it was once a prevalent disease. According to Dr. A. G. Safonov's report,10 the prevalence of active trachoma (Stages I, II, I I I ) in the U.S.S.R. decreased 407.5 times during the period 196068. In recent years, the typical clinical course of trachoma has also changed, probably as a result of general improvement in public health facilities, higher sanitary and eco nomic levels, more and better health educa tion, and active treatment of infectious eye disease. The tendency has been toward a milder trachoma, even in areas where the disease used to be a major cause of blind ness. Although most cases of trachoma are cured in the course of mass treatment cam paigns, there are always a certain number that remain active, most of them in patients with a persistent form of the disease. These cases are often characterized by periods of improvement, when the disease appears to be healed, followed by relapses. There has been a gradual reduction in the number of re lapses, however. Mass treatment with chloramphenicol ( Synthomycin) some years ago was followed by relapses in from 6 to 25% of cases,11 whereas the relapse rate in recent campaigns has ranged from 0.34 to 1.5%. In 1968, for example, a survey of a rural popu lation sample of 1509 patients with a past
history of active trachoma, or with signs of healed trachoma, showed relapses occurring in only 0.7%. Relapses in trachoma are attributable to one or more of the following factors : associ ated systemic disease ; diminished host resis tance; allergic (including autoallergic) reac tions; secondary disease of the eyelid, con junctiva, or both; and inadequate or irra tional chemotherapy. Especially important are (1) lesions of the lacrimal apparatus, and (2) concurrent bacterial, particularly staphylococcal, infection of the conjunctiva that is resistant to the administered drugs. 13,1* Apart from all of these factors, specific drug resistance of particular strains of tra choma agent also merits attention.
At this stage of our efforts to eradicate trachoma, the subclinical form of the disease is epidemiologically important. Unless such subclinical cases are diagnosed and cured at an early stage, they become a major source of fresh infections. The different clinical forms of trachoma call for different methods of treatment. Studies in recent years have demonstrated convincingly that there is no single method to be preferred for all cases under all condi tions. On the contrary, it is from the wide variety of therapeutic agents available and the variety of ways of applying them that the most rational treatment for each type of case should be chosen. The present paper summarizes the results of our studies of trachoma therapy. Our spe cial concerns were ( 1 ) the sensitivity of tra choma agent to the various drugs under con sideration, and (2) the concentration of the drug in the conjunctiva. When considered in accordance with these variables, rational che From the Virus Clinical Department, Moscow motherapy—that is, the method that best Helmholtz Research Institute of Eye Diseases, takes into account the clinical course of the Moscow. Reprint requests to Y. F. Maichuk, M.D., Moscow disease and the available medical facilities— Helmholtz Research Institute of Eye Diseases, calls for the following decisions : ( 1 ) choice Moscow, U.S.S.R.
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TABLE 1 EFFECT OF TETRACYCLINE (T), DITETRACYCLINE (D), AND OLETETRINE (O)* ON THE GROWTH OF TRACHOMA AGENT IN EMBRYONATED EGGS Titer of Trachoma Agent InoculumL Antibiotic Dose (fg/egg) 10.0
5.0 2.5 1.0
Controls
10-
1
10-»
10-»
T
D
0
T
D
O
T
D
O
0/6t
0/6 1/6 3/5 5/6 6/6
0/6 2/6 5/5 6/6 6/6
0/5 1/6 4/6 5/5 5/5
0/6 0/6 3/6 4/6 6/6
0/6 0/6 4/6 6/6 6/6
0/6 0/6 4/6 5/5 6/6
0/6 0/6 0/6 1/6 6/6
0/6 0/6 2/6 2/5 6/6
2/6 5/6 6/6 5/5
* Combined oleandomycin and tetracycline in ratio of 1:2. t Embryo deaths/embryos inoculated.
of the drug, (2) choice of the form of the drug and the route of administration, (3) choice of the frequency of drug application, and (4) choice of the treatment schedule. CHOICE OF DRUG
The antibiotic or sulfonamide should be chosen on the basis of its specificity for chlamydial agents. When sensitivity tests have been run on chick embryo cultures of chlamydias, the antibiotics and sulfonamides to which the agents have been found to be most sensitive are the following: tetracycline, di tetracycline, erythromycin, oleandomycin, oletetrine, chloramphenicol, sulfapyridazine, sulfadimethoxydiazine, and sulfalene. In ex periments on emtryonated eggs infected with trachoma agent, it was found that when most of these antibiotics were administered in low doses (1 μg/ embryonated egg), they exhib ited some inhibitory effect, and that when 10 !*g/egg were introduced, they inhibited the agent completely (Table 1). The antichlamydial effect of the long-acting antibiotics, di tetracycline and oletetrine (an antibiotic combination), was more pronounced than that of tetracycline. Our own studies have shown that among the sulfonamides, sodium sulfapyridazine and sulfadimethoxydiazine (Madribon) are the most effective against trachoma,15 and that next in order are sulfadimethoxydiazine,
norsulfazol, sodium sulfazil (Albucid), and ethazole. We have also studied the inhibitory concentration of some of these drugs at the sites of reproduction of the trachoma agent— that is, in the contents and envelope of the yolk sac and in the allantoic fluid (Table 2 ) . The inhibitory concentration at these sites was found not to exceed 0.91 μg/ml for tetra cycline HC1, 0.59 {ig/ml for ditetracycline, and 0.34 [ig/ml for oletetrine. In choosing an antibiotic or sulfonamide on the basis of its specific activity against trachoma agent, the therapist should bear in mind that not all strains are equally sensi tive, and that the sensitivity of any one strain is probably not invariable. Various strains isolated from active trachoma have been found to be resistant to tetracycline, erythromycin, penicillin, and the sulfon amides, respectively; and in the cases from which these resistant strains have been iso lated, the drug in question has frequently been found to be less than usually effective therapeutically. Attempts to account for persistence of the disease on the basis of the development of drug resistance (analogous to the drug re sistance that develops in staphylococci) have been only partly successful, however ; under experimental conditions such development of resistance has occurred in connection with sulfonamides15 but not in connection with antibiotics.16·17
696
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TABLE 2 CONCENTRATION OF ANTIBIOTICS IN TISSUES AND FLUIDS OF TRACHOMA-INFECTED EMBRYONATED EGGS AFTER INOCULATION WITH 1 0 I»G OF ANTIBIOTIC
No. Hours after Injection
Allantoic Fluid G*g/ml)
Yolk Sac (cg/ml)
Amniotic Fluid G*g/ml)
Yolk Sac Membrane (Mg/ml)
Embryo G*g/g)
Allantoic Membrane (Mg/g)
Tetracycline 1 24 48 96
0.81±0.04 0.89±0.02 0.91 ±0.20 0.57±0.16
0.77±0.03 0.54±0.01 0.87+0.20 0.40±0.01
0 0 0 0
0.53±0.02 0.48±0.02 0.62±0.07 0.44±0.05
0 0 0 Trace
0 0-trace 0-trace 0
Ditetracycline 1 24 96
0.46±0.03 0.47±0.02 0.53±0.04
0.36±0.04 0.46±0.02 0.49±0.05
0 0 0
0.44±0.01 0.45±0.02 0.47±0.04
0 0 0
0 0 0
Olete trine 1 24 96
0.34±0.02 0.11±0.02 0.08 + 0.02
0.16±0.02 0.28±0.02 0.11±0.01
0 0 0
O.lOiO.01 0.12+0.08 0.09±0.02
0 0 0
0 0 0
So far as clinical observations are con cerned, it has been demonstrated convinc ingly that there is a progressive loss of drug efficacy in the course of mass treatment cam paigns. Strains resistant to tetracycline,18 for example, are more likely to survive during mass campaigns of treatment with tetracy cline, and these strains are likely thereafter to be more widespread in the area concerned than less resistant strains. From this point of view, alternating-inter mittent treatment seems to be advanced. This is treatment with two antibiotics, each inter mittently (first one and then the other). The antibiotics should be taken from different groups active against trachoma agents. One
'.9 auapontion
2.9 ointaent
3,g aqueous Bolution
U. PVAaolution
Fig. 1 (Maichuk). Antibiotic concentrations (μβ/ ml) in conjunctival sac six hours after single ap plication of tetracycline prepared in various vehicles.
of them may be replaced by a long-acting sulfonamide for topical application. CHOICE OF DRUG FORM AND ROUTE OF ADMINISTRATION
In handling this question, particular im portance has been attached to the concentra tion of the drug in the tissues and media of the eye, and to comparing it with the concen tration required to inhibit trachoma agent at its site of reproduction. After administering a single dose of tetra cycline, erythromycin, oletetrine, oleandomycin, or other antibiotic, each of which was prepared as a 1% aqueous solution, a sus pension, or an ointment in a lanolin-petrola tum base, we found the antibiotic regularly in the conjunctival sac for six hours. The concentration level varied, however, not only from drug to drug but even from compound to compound of the same antibiotic—an ob servation that may be of practical impor tance. The hydrochloride of tetracycline, for example, contributes more than other com pounds to a high concentration of the drug in the conjunctival sac, to good penetration of the ocular tissues and media, and to a highly therapeutic effect.
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TRACHOMA THERAPY
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.
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il 3 Fig. 2 (Maichuk). Antibiotic phannacodynamics in conjunctival sac after single instillation of erythromycin prepared in aqueous or PVA solutions. U0ÜK3
Still more important is the nature of the vehicle in which the antibiotic is prepared (Fig. 1). Experimental and clinical investi gations have shown that when the polymeric base, polyvinyl alcohol ( P V A ) , is used as the vehicle, a preparation that is more effec tive than an aqueous solution results. Its ad vantages are (1) that the antibiotic has a longer acting effect and remains at a higher level of concentration (Fig. 2) ; (2) that the antibiotic penetrates the ocular tissues and media better (Fig. 3) ; (3) that the activity of an unstable antibiotic persists longer 19 ; (4) that drug toxicity is reduced; (5) that tissue irritation is obviated and corneal epithelialization enhanced ; (6) that drug al lergies are much less likely to occur; and (7) that good therapeutic results are achieved with longer intervals between drug applica tions than are otherwise possible. The influ ence of PVA in lengthening the drug effect was also evident when it was used as a ve hicle for ethazole and sodium sulfapyridazine.
Aqueous PVA solution solution Fig. 3 (Maichuk). Antibiotic concentration in rabbits aqueous humor three hours after instillation of erythromycin in aqueous and PVA solutions.
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TABLE 3 CONCENTRATION OF DRUG (mg%) AFTER SINGLE CONJUNCTIVAL INSTILLATION OF 1 0 % SULFAPYRIDAZINE IN AQUEOUS OR P V A SOLUTIONS
Ocular Tissue of Fluid
2 Hours
1 Hour PVA
Aqueous
Conjunctiva
3.07± 0.36
1.66± 0.23
Cornea
2.11 + 0.4
0.17± 0.1
Aqueous humor
Trace
—
PVA
12 Hours
24 Hours
Aqueous
PVA
Aqueous
PVA
Aqueous
3.5± 0.37
1.3 + 0.3
1.5± 0.15
Trace
0.58± 0.15
—
2.17 + 0.43
0.5± 0.08
0.5 + 0.06
—
0.36± 0.06±
—
0.10
Trace
Trace
—
—
—
When we first tried PVA as a vehicle for antibiotics and sulfonamides, we used a 5 or 10% solution, but at present 2.5% is the concentration of choice. The potency of a 10% sodium sulfapyridazine solution in 2.5% PVA was not reduced during a ninemonth period when the drug was stored at room temperature. After a single instillation, the drug attained a concentration at six hours of 3.5 mg% in the conjunctiva and 2.7 mg% in the cornea ; at 12 hours the concen tration was 1.5 mg% in the conjunctiva and 0.5 mg% in the cornea. When an aqueous solution was used instead, the respective con centrations at six hours were 1.5 mg% and 0.5 mg%, and at 12 hours no sulfonamide could be detected in the ocular tissues (Table 3). It was found that the polymeric vehicle such as polyacrilamide (PAA) provided even more advantages for antibiotics and sulfonamides. Following a single instillation of 10% sulfapyridazine solution in 1% PAA, the drug was detected in the conjunctiva in a concentration of 1.66 mg% after 24 hours and 0.58 mg% after 48 hours. Of practical interest are long-acting anti biotics and sulfonamides topically applied. After a single application of 1% ditetracycline ointment (Table 4 ) , the antibiotic was detected in patients at 24 hours (2.5 μg/ml) and at 48 hours (1.8 μg/ml) in concentra tions that exceeded the concentration re
quired for an antiviral effect at the site of reproduction of trachoma agent. CHOICE OF THE FREQUENCY OF APPLICATION
The frequency with which the drug is ap plied predetermines to a large extent the concentration of the drug that is achieved and maintained in the conjunctiva. Our prin ciple is that rational chemotherapy calls for different levels of antiviral medication in the conjunctival sac (hence the use of a variety of drug forms and of applying them with different frequencies), the choice to be made in accordance with the specific pattern of the course of the disease. In connection with erythromycin, for ex ample, hospitalized patients require five ap plications of 1% ointment daily (Fig. 4 ) . This schedule achieves a high concentration of the drug, its lowest level being 58.6 ± 3.3 μg/ml in the daytime and 6.5 ± 0.7 μg/nll in the morning. When the ointment is applied only twice daily (Fig. 5), its concentration is lower (the lowest level ranging from 3.8 ± 0.3 to 4.8 ± 0.4 μg/ml) but still sufficient to produce the desired therapeutic effect. Ginical observations on 535 trachoma pa tients have shown that varying the proce dures for applying erythromycin in accor dance with the clinical picture of the disease has been very effective. The administration of 1% tetracycline ointment, or of an antibi otic combination (oletetrine), four to five
times daily in severe cases and two to three times daily in mild cases, has also yielded good results. The use of soluble antibiotics (tetracycline HC1, erythromycin ascorbinate, oletetrine) and sulfonamides (ethazole, sodium sulfapyridazine) in PVA permits a reduction in the required number of instillations. As a rule the long-acting 1% ditetracycline oint ment is effective when applied once daily or every other day. In one trial of our series, three applications of ditetracycline ointment weekly during seven weeks cured trachoma in 81.3% of subjects.20 In cases of severe and persistent trachoma, however, the local application of antibiotics or sulfonamides should be combined with the systemic admin istration of either ethazole or sulfapyridazine. It should be emphasized that long-acting sulfonamides should be used systemically only in emergencies and under hospital con ditions favorable for the control of the side effects that may occur.21"24 We have not our selves accumulated any evidence that the sys temic administration of such long-acting sul fonamides, when used alone for the treat ment of trachoma, is highly efficacious. A se ries of 53 children, aged five to seven years, and suffering from severe, florid trachoma,
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699
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TABLE 4 ANTIBIOTIC CONCENTRATION AFTER SINGLE CONJUNCTIVAL APPLICATION OF 1 % DITETRACYCLINE OINTMENT IN RABBITS AND TRACHOMA PATIENTS
Time after Application (No. Hours)
Antibiotic Concentration G*g/ml) Rabbits 25.6 + 3.1 5.8 + 0.9 3.0 + 0.38 2.4±0.31 1.9±0.02 1.6±0.1 1.1±0.14
1 3 6 9 12 24 48
Trachoma Patients
—
26.2±1.4 5.5±0.2
—
4.6±0.2 2.5±0.1 1.8+0.1
were treated with a long-acting sulfonamide, phanazil, once weekly for eight weeks. The initial daily dosage was 30 to 40 mg/kg, and the subsequent dosage 25 mg/kg. Of one group of 22 children who were given sys temic treatment only, 13 were cured, five were improved, and in four the condition re mained unchanged. The lack of an immedi ate effect was apparent in the very slight im provement that took place in the allied con junctivitis. In a second group of 31 children, the sys temic treatment was supplemented by topical applications of 1% ditetracycline ointment twice weekly; 25 were cured and five im proved. The more pronounced therapeutic
l\
|Vj 1—^v;
V \
^
_
13
Γ
»
X
/
Fig. 4 (Maichuk). Antibiotic concentration in conjunctival sac of trachoma patients after application of 1% erythromycin ointment five times daily.
AMERICAN JOURNAL OF OPHTHALMOLOGY
700
OCTOBER, 1972
too Mi» $00
\
100
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Fig. 5 (Maichuk). Antibiotic concentration in conjunctival sac of trachoma patients after application of 1% erythromycin ointment twice daily. effect of the combined treatment may be at tributed to the fact that systemic antichlamydial therapy with sulfonamides was supple mented by topical action on both the tra choma agent and the associated pathogenic microflora. For example, of 30 subjects with associated bacterial conjunctivitis who were treated in this way, 26 were cured. The pathogenic conjunctival flora disappeared in all cases after the first week of treatment. CHOICE OF TREATMENT SCHEDULE
The treatment schedule is of great impor tance in rational chemotherapy, since its aim is to achieve the continuous maintenance of a definite concentration of the drug in the con junctiva. When persistent, relapsing, and subclinical forms of the disease are encoun tered, it is of course the aim of all treatment methods to ensure the cure of each patient. This can best be achieved by applying drugs to which resistance has not yet developed, and above all by following treatment sched ules that will induce a high and stable con centration of the drug sufficient to act even on partially sensitive strains of the agent. On the basis of studies of the pharmacodynamics of antibiotics, the following regi men is recommended : four to six times daily applications of the drug at regular intervals (every three or every five hours) from 7 to 8
A.M. to 10 or 11 P.M., the last application to be made before the patient falls asleep. In this way a uniform concentration can be maintained in the conjunctival sac during the daytime, and retention of the drug through out the night is favored. For example, tetra cycline introduced according to this proce dure remains at or above 20 μg/ml (Fig. 6 ) , which is significantly higher than the concen tration that assures an antichlamydial effect at the site of reproduction of the trachoma agent. As stated above, the use of PVA as the vehicle in the preparation of the antibiotics prolongs their action. This permits their ap plication at longer intervals (three to four applications daily), and reduces the risk of allergic reactions. Our clinical observations of more than 2000 trachoma patients treated with various antibiotics have demonstrated the advantages of using PVA as the vehicle and of applying the drugs at regular inter vals. For the mass treatment of trachoma and associated bacterial conjunctivitis, a program calling for the intermittent treatment of the entire population, family by family, has in our experience proven to be the most practi cal and economical method. We noted with considerable regularity that if tetracycline was administered shortly before the patient
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retired for the night, it tended to be retained throughout the night. This prompted us to suggest the following schedule for mass treatment campaigns in the Sudan: (1) tetracycline (in suspension or in a polymeric solution) to be administered once daily in the evening25 on six consecutive days, this to constitute one cycle of treatment; and (2) one cycle to be carried out once each month for six months, this to constitute one course of treatment. A total of 10,074 inhabitants were treated in this way, family by family. The preva lence of active trachoma dropped from 39.9 to 8.9% after the first course of treatment, then to 5.6% by the end of the first year of observation. When a second course was given to recalcitrant cases, the 5.6% preva lence was reduced twofold. The incidence of fresh infections declined from 8.9% (during the first six months) to 0.7% (during the first year), and the incidence of relapses dropped from 5.0 to 0.5%. To step up the concentration of the drug in the ocular tissues in the morning so as to
701
make it comparable to the evening levels, two or three instillations can be made at short in tervals early in the day. It has been sug gested that three instillations of 10 %sulfapyridazine solution in PVA be made during one hour in the morning and one instillation in the evening.26 An analysis of the pharmacodynamics of the drugs in the ocular tissues makes it pos sible to interpret results obtained in clinical trials of various treatment procedures. For example, a study in Sudan of two methods of intermittent treatment in primary schools (2032 school children), in which one daily instillation for 36 days (Group 1) was com pared with two daily instillations for 36 days (Group 2)—that is, 36 or 72 instillations— showed the two regimens to be equally effica cious. Six months after completion of the treatment course, the percentage of cured subjects was 82.6% in Group 1 and 84.1% in Group 2. The efficacy of the two regimens was also identical in two other respects : they were equally effective for the treatment of conjunctivitis patients (the cure rate was
TiuSATHIOT
·«-
-Ϊ&-
MO
TDtE
Fig. 6 (Maichuk). Pharmacodynamics of tetracycline in conjunctival sac of trachoma patients treated six times daily at regular intervals. Antibiotic levels (μξ/αύ) shown at left.
702
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER, 1972
■cuwauan A».
O.U-
A
X •a 4 B
\
I* a 3
, -1—
u ΧΊ 9 Fig. 7 (Maichuk). Antibiotic pharmacodynamics in conjunctival sac after instillation of 1% tetracycline suspension once or twice daily. Hours are shown by numbers at bottom of graph. i
H
88.8% in Group 1 and 86.5% in Group 2) ; and the same length of time was required for the elimination of pathogenic flora from the conjunctival sac. In studying the levels of drug concentra tion, we found that the application of a tetra cycline suspension twice daily with a threehour interval between instillations resulted in a short-term enhancement of the antibiotic activity, which was not the case when one daily instillation was made (Fig. 7). By virtue of the prolongation of the anti biotic effect brought about by the use of a polymeric vehicle, the concentration of the antibiotic in the conjunctival sac 24 hours after the instillation of 1% tetracycline HC1 in PVA was still 1.25 ± 0.2 pg/ml. The drug was introduced once daily, and prefer ence was given to the family method which facilitated treatment in the evening. The to tal treatment course included 36 instillations. Among 155 trachoma patients, cure was achieved in 82.7% and alleviation of clinical symptoms in another 8.3%. Of 311 subjects with bacterial conjunctivitis, 82.4% were
cured after six days of treatment. KochWeeks bacillus was eliminated in all cases and Morax-Axenfeld diplobacillus in most cases. SUMMARY
On the basis of an analysis of the pharma codynamics of a drug in the ocular tissues, and a correlation of the results with the sen sitivity of trachoma agent to the drug in question, a variety of treatment regimens for trachoma can be developed from which the regimen best suited to the clinical course of the case to be treated can be selected. Impor tant factors in such rational chemotherapy of trachoma are the choice of the drug, the form in which it is prepared, its route of ad ministration, the frequency of its applica tion, and the treatment schedule to be followed. REFERENCES
1. WHO : Expert Committee on Trachoma, Third Report. Geneva, WHO Technical Report, 1962. 2. WHO: Fourth WHO Scientific Group on
VOL. 74, NO. 4
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Trachoma Research. Geneva, WHO Technical Re port, 1966. 3. Dudina, Z. T. : Organized control of trachoma. In Textbook of Eye Diseases, vol. 2. Moscow, Medgiz, 1960, p. 115. 4. Daghfus, T. : Organization of the fight against trachoma and purulent ophthalmia in Tunisia. New Delhi, Int. Cong. Ophth., 1962. 5. Erwinn, S. : A statement on trachoma in In donesia. WHO Inter-regional Conf. on Trachoma, 1962. 6. Kamel, S.: Trachoma and acute ophthalmias in Egypt. Arch. Ophth. 69:117, 1963. 7. Litricin, O. : Trachom u Jugoslavia. Narodno Zdrav. 8:223, 1963. 8. Rostkowcki, L. : Trente ans de la lutte métho dique contre le trachome en Pologne. Rev. Int. Trach. 40:270, 1968. 9. Gupta, U. C. : Trachoma in India. Rev. Int. Trach. 42:102,1965. 10. Safonov, A. G. : Ways and means for consol idating the results of trachoma control in the USSR. Vesta. Oftal. 1:3, 1969. 11. Chumakov, M. P. : Synthomycin therapy of trachoma. In Antibiotic Therapy of Trachoma. Moscow, Medgiz, 1955, p. 4. 12. Vassilieva, A. D., and Shoulpenkova, A. Z. : Trachoma Relapses. Some of the Problems of In fectious Eye Diseases. Moscow, Chuvashizdat, 1968, pp. 28, 36. 13. Maichuk, Y. F . : Clinical picture of lacrimal pathology in trachoma patients. Proc. XXI Conf. Moscow Helmholtz Inst. Eye Dis. Moscow, Chu vashizdat, 1961, p. 120. 14. : Significance of secondary bacterial infection in the persistent forms of trachoma. Some
703
of the problems of infectious eye diseases, 1968, p. 131. 15. Lenkevich, M. M., and Kournosova, L. M. : Pharmacological analysis of inhibitions of metabo lism in trachoma agents. Pharm. Toxicol. 27:584, 1964. 16. Tarizzo, M. L., and Nabli, B. : The effect of antibiotics on the growth of TRIC agents in embryonated eggs. Am. J. Ophth. 63:1585, 1967. 17. Tarizzo, M. L. : Discussion in trachoma and allied diseases. Am. J. Ophth. 63:1585, 1967. 18. Shiao, L. C , Wang, S. P., and Grayston, J. T.: Sensitivity and resistance of TRIC agents to peni cillin, tetracycline, and sulfa drugs. Am. J. Ophth. 63:1558,1967. 19. Maichuk, Y. F. : Polyvinyl alcohol as medici nal basis for antibiotics in practice of ophthalmol ogy. Oftal. Zn. 5:350, 1964. 20. : Ditetracycline—a long-acting antibi otic for the treatment of trachoma and conjunctivi tis. Progress in Antimicrobial and Anticancer Che motherapy, 1970, p. 953. 21. Grayston, J. T.: Discussion. Am. J. Ophth. 63:1583,1967. 22. Thygeson, P. : Discussion. Am. J. Ophth. 63 : 1585, 1967. 23. Dawson, C. R. : Discussion. Am. J. Ophth. 63:1585,1967. 24. Tarizzo, M. L., and Nataf, R. : The treatment of trachoma. Rev. Int. Trach. 47:72, 1970. 25. Maichuk, Y. F . : Treatment of patients suf fering from trachoma and conjunctivitis in Sudan. Vesta. Oftal. 79:31, 1966. 26. Posdniyakov, V. I. : Polymeric basis for pro longation of sulfapyridazine. Moscow, Proc. Conf. of MONIKI, 1967, p. 712.
O P H T H A L M I C MINIATURE
T h e r e h e was, in a town all noisy with letters and words, in a carriage full of men reading the news of the world in their newspapers, in a Lon don full of printed stuff, of boards and placards each giving its tidings. Yet he was travelling like a blind man, asking his way, asking help as he went. Another must expound to him the meaning of the plates with the word Monument painted on them. T h e n he would get out of the train and look cunningly to see by which of the staircases men were mounting to the street, for the words W a y O u t tell him naught. I n the course of the day he must have asked many questions and told many men that he could not read. Macdonald Critchley Developmental Dyslexia W m . Heinemann, 1968