Fixed combinations of antibiotic drugs used in Central America

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F

IXED

COMBINATIONS OF ANTIBIOTIC DRUGS

USED IN CENTRAL AMERICA1

Fededco Guerrero-M&ox2 and M. L. GzGerrero3

I

NTRODUCTION

Antibiotics are among the drugs most prescribed by physicians in medical practice. It is also true, however, that increasing bacterial resistance to many of these drugs has been observed in recent years, a phenomenon that appears ascribable to extensive use, misuse, and overuse of antibiotics (1-j). There- fore, it is important that physicians in countries where antibiotic use is regulated become more cautious about issu- ing prescriptions; and it is important that countries where antibiotics are sold over the counter consider countermeasures ca- pable of correcting obvious abuses-especially since lack of effective regulation (4) can encourage distribution of obsolete, marginally appropriate, or inappro- priate drug combinations.

The study reported here re- viewed the sources of 77 different ftied combinations of antimicrobial drugs registered for marketing in Central America and listed in the manufacturer’s book, Diccionanb de especiaZidad& farma- c&&as (5). It also sought to compare

I This article will also be published in Spanish in the Bo- ieth de Za O$cina Samtank Panameticana.

2 Physician, Neuropharmacology Section, Department of Pharmacology, University of Panama, Panama City, Panama.

3 Professor of Pharmacology, Division of Neuropharma- cology, School of Medicine, University of Panama, Pan- ama City, Panama.

the information provided about these combinations (especially indications, contraindications, and side-effects) in the manufacturer’s book for Central America as compared to that contained in the Physician’s Desk Reference (G) employed in the United States.

S

URVEY DATA

All 77 of these formulations consisted of one or more antibiotics com- bined in some cases with additional medications including enzymes (trypsin, streptokinase, chymotrypsin), analgesics, antihistamines, vitamins, and others. No preparations intended for otic, ophthal- mic, or dermal application were included in the survey. At the time of the survey (1984), the antibiotic combinations studied were being marketed in Costa Rica, El Salvador, Guatemala, Hondu- ras, Nicaragua, Panama, and the Do- minican Republic.

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(9%) were made by U.S. laboratories. The distribution of those manufactured by European and Latin American laboratories within the seven countries covered in this survey is shown in Table 1.

Despite a wide range of different drug dosages and forms involved, most of the 77 combinations studied were registered for use in Central Amer- ica. Regarding those manufactured by Latin American laboratories, the largest numbers were found to be registered for marketing in Guatemala, Nicaragua, and El Salvador, while somewhat smaller numbers were so registered in Costa Rica, Honduras, the Dominican Repub- lic, and Panama. Also, the highest per- centages of these antibiotic combinations

were being manufactured in Costa Rica, Guatemala, Mexico, and El Salvador. However, most of the laboratories involved were owned by multinational cor- porations based in the United States, only a few having local owners.

Regarding the antibiotic combinations manufactured in Europe, many of these laboratories offered a fmed combination of penicillin and strepto- mycin, despite reports indicating that such combinations have no therapeutic advantage (7). None of these European laboratories is mentioned in the Physi- cians’ Desk Reference employed in the United States. Indeed, only one of the 77 drug combinations studied was listed in the Physicians’ Desk Reference, this being a Bristol Laboratories product re- ferred to as Azotrex@ in the Physicians Desk Reference and Uropol by the Dic- cionario de especiaZidade5 farnzac&icas.

TABLE 1. Distribution to five Central American countries, Panama, and the Dominican Republic of the antibiotic drug combinations studied that were manufactured by European laboratories (43 products) and Latin American laboratories (27 products).

DWJ Countries of distribution

Pmducing products Costa El Dominican

laboratOrieS No. (%) Rica Salvador Guatemala Honduras Nicaragua Panama Republic

1. Eumpean

lzbofatoties in:

Spain 25 (57) 12 20 18 14 19 8 18

Germany 6 (14) i 5 6 6 6 5 6

Switzerland 6 (14) 5 3 5 5 2 4

Austria 2(5) 1 1 : 1 2 1

Denmark 2(5) 1 2 2 2 2 ;

lay 2(5) 2 2 2 2 2 2 2

Portugal 1 ( 2) 2: 3; 1 1 1 1 1

subtotal 44 (100) 33 31 37 21 35

It. Latin Amerkan labmtoties in:

Costa Rica 8 ( 30) 8 8 8 8 8 7 7

Guatemala 6 ( 22) 5

Mexico ₆ ₍ ₂₂₎ i i 6" : i ;

El Salvador 5 ( 1% : 4 4 2 5 2 2

Honduras 1 ( 4) .o 0 1 0 0

Panama _{1 ( 4)}

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In this case the information contained in the latter publication, as compared to the former, is very sketchy. Specifically, portions of the Physicians ’ Desk Reference text are as follows:

“Description:

“Each capsule contains Tetrex@ (tetracycline phosphate complex) equivalent to tetracycline HCl activity . . . 125 mg Sulfarnethizole . . . . . . _ 250 mg Phenazopyridine HCl . . . 50 mg

“Indications:

“Based on a review of this drug by the National Academy of Sciences-Na- tional Research Council and/or other information, FDA has classified the indications as follows:

“Lacking substantial evidence of effectiveness for the labeled indications.

“Final classification for the less- than-effective indications requires further in- vestigation. . . .

“It may be used in mixed infections where the invading organisms are more sensitive to the combination than to either antibacterial agent alone and is not intended for the treatment of infections where complete response to either component might be expected.

“It is indicated in the treatment of cystitis, urethritis, pyelonephritis, ure- teritis, and prostatitis due to bacterial infection, prior to and following genitourinary surgery and instrumentation, prophylacti- cally in patients with urethrostomies and cord bladders.

“In geriatrics this drug is particu- 2 _o\ larly useful when exacerbations of infection _{occur in such conditions as cystocele, pro-} Y

e stat+ and nonspecific urethritis.

s “Infections caused by beta-he- 2 molytic streptococci should be treated for at -& least 10 days to help prevent the occurrence

P,

a _a of rheumatic fever or acute glomeru- 2

lonephritis.

108

“Contraindications:

“The drug should not be used in patients with a history of sensitivity to one of the components; or in prematures, neonates, pregnant females at term; or in patients with chronic glomerulonephritis, uremia, severe hepatitis, hepatic or renal failure, or severe pyelitis of pregnancy.

“Warnings:

“Certain hypersensitive individ- uals may develop a photodynamic reaction precipitated by direct exposure to natural or artificial sunlight. . . .”

Comparable portions of the Diccionario de especiahdades farma- c.hticas, quoted in part, provide the following information about Uropol:

“Indicati0nS:

“Cystitis, urethritis, pyelone-

phritis, pyelitis, and prostatitis due to bacterial infection. . _ .

“Contraindications:

“The drug should not be used in chronic glomerulonephritis, uremia, severe hepatitis, hepatic or renal failure, or severe pyelitis of pregnancy.”

The information provided by the Diccionario did not include the “lacking substantial evidence of effectiveness for the labeled indications” cited in the Physicians’ Desk Reference. Also, the latter publication briefly de-

scribes the properties of each compound included in the formulation while the Diccionario does not. And finally, unlike the Diccionario, the Physicians’ Desk Reference gives information about the risk of side-effects this antibiotic combi-

nation might produce. Clearly, such in-

formation needs to be included in the Diccionarib, both to guide physicians and to provide a sound basis for marketing and regulating antibiotics in Central America.

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However, the faed combinations of antibiotics that these Latin American branches manufacture are not usually included in the Physicians Desk Refer- ence. For instance, Upjohn has registered a combination of novobiocin and tetracycline in Central America under the brand name “Albamicin,” and this is ac- cordingly included in the Diccionanb de especiaZia%zdes farmact?zcticas. However, Upjohn does not have this formulation listed as one of its products in the Physi- cians ’ De.& Reference, where it merely lists products containing one or the other of these drugs. Similarly, Lederle has registered a combination of tetracycline, sa- licylamide, acetophenetidine, phenyl- ephrine, and chlorpheniramine in Cen- tral America under the brand name “Acropon,” and it has registered tetracycline alone under the brand name “Ach- romycin.@” However, while both products are listed in the Diccionmb de esp&didades farmach&as, only Ach- romycin@ is included in the Physicians’ De& Referewe.

D

ISCUSSION AND

CONCLUSIONS

The foregoing suggests that most or all of the 77 fured Central Ameri- can antibiotic combinations studied are unnecessary or obsolete (8). Our findings also show that the pharmaceutical companies involved are not using proper standards of advertising in all countries. That is, it appears that the companies are only very cautious about advertising in those countries that have specific regula-

tions against the sale of drugs without prescription and against the inclusion of more than one drug in a single prescribed product. In general, they appear to pay little attention to such matters in countries without regulations governing the manufacture, sale, and use of antibiotics .

In this vein, it seems reason- able to ask why multinational pharmaceutical laboratories located in Costa Rica or Guatemala that are branches of U.S. firms are manufacturing fixed combinations of antibiotics that are not included in the American Physicians Desk Refer- ence. It is a well-known fact that there are no regulations governing sales of antibiotics in Central America, and that

one can buy these drugs over the counter s with no prescription. The obvious con- 2 elusion is that the pharmaceutical labora- 2 tories are aware of this state of affairs, t and that policies designed to take advantage of it are encouraging misuse of anti- ii biotics in the region.

This is especially worrisome 6 because resistance to antibiotics is 5 mounting, even in countries where these 2 drugs are carefully regulated; because re- a sistant bacteria have shown a marked

ability to travel within and between $ countries, and because misuse of antibi- 2 R otics or use of unnecessary or obsolete

combinations of them cannot help but 5 _. aggravate the resistance problem. For

these reasons, in addition to the desire to i? 8 ensure the welfare of individual patients,

it would seem important for each Minis- 9 try of Health in Central America to con- h sider the role it plays in dispensing anti- P biotics without prescription and to 2 consider possible ways of modifying that 4

role. i?

Along these lines it is worth, 8 noting that every two years the World $ Health Organization publishes a report listing those drugs considered essential

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published in 1979 included only 13 essential antibiotics, four complementary antibiotics, and one fured combination (sulfamethoxazole and trimethoprim).

It would seem appropriate for the health authorities of each Central American country to consider these peri- odic WHO reports on essential drugs and to use them as a basis for devising regulations governing the introduction of antibiotics to the market. It would also seem important for each country to regularly reevaluate previously established regula- tory criteria derived from its drug policies.

By way of taking a small step forward, each health ministry should re- quire all pharmaceutical laboratories to place in the Diccionario de especiaLi- dades farmac&icas all the information about each of their antibiotics that is contained in the Physicians ’ Desk Refer- ence. Beyond that, in the long run it would seem desirable for each health ministry to seek complete control of antibiotics by demanding better manufacturing standards and restricting easy over-the-counter access, two measures that could yield great potential benefits for health care in Central America as a whole.

S

UMMARY

k

2 _{antibiotic drug combinations registered}A survey was made of 77 fured e.

e in Central America and the Dominican G Republic and listed in the drug manufac- .g turers’ book, the Diccionario de espe- d _a cialidades farmace’zcticas (5). A search

2

was made for the same or similar drug

3

combinations in the Physicians’ Desk Reference (6); the site of each drug manufacturer was examined; and available information about certain combinations

110 was noted.

The results of this survey indicated that only one of the 77 combinations was listed in the Physicians’ Desk Reference; that the information contained in the Diccionario de especiali- dades farmac~uticas by itself tended to be less than satisfactory; that most of the combinations were manufactured by Eu- ropean pharmaceutical companies or by Latin American branches of U.S. or Eu- ropean firms; that all or nearly all of the 77 drug products were unnecessary or obsolete; and that the prevailing unregu- lated use of these drug combinations cannot but promote bacterial resistance to a wide range of worthwhile drugs. The authors therefore suggest that manufac- turers be required to place in the Dic- cionario all information about each of their antibiotics that is contained in the Physicians’ Desk Reference. They also recommend that the health authorities involved devise regulations to improve manufacturing standards and regulate access to these drugs, measures that could yield great benefits for health care in Central America as a whole.

RE

FERENCES

Veterans Administration. Ad hoc interdisciplin- ary advisory committee on antimicrobial drug usage.JAMA 237(14):1481-1484, 1977.

Worldwide antibiotic misuse (conference). Lan-

cet 2:299, 1981.

Saving antibiotics from themselves. Nature 292:661, 1981.

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5 Panamericana de Libros de Medicina (ed.). Die- cionario de especz&Ues farnzac~uticas: Cen-

tro-amhi?a-Reprib Dominicana (12th

ed.). Panama City, Panama, 1980.

6 Medical Economics Company. PhyszZ~m’ Desk Reference (33rd ed.). Oradell, New Jersey, 1979.

7 National Academy of Sciences-National Re-

search Council, Division of Medical Sciences.

Fixed combination of antimicrobial agents

(drug efficacy study). N EngL J Mea’ 280: 1149-

1154, 1969.

8 Gus&son, L. L., and K. Wide. Marketing of obsolete antibiotics in Central America. Luncet

1:31-33, 1981.

9 World Health Organization. The Selection of

Ersentid Dncgs. WHO Technical Report Series,

Nos. 615 and 641. Geneva, 1977 and 1979. See

also World Health Organization. The Use ofEs-

se&z/ Dncgs. WHO Technical Report Series,

Nos. 685 and 722. Geneva, 1983 and 1985.

.

Congenital

Syphilis

in the

uniled states

After eight years of steady decline (in 1971- 1978), the number of reported cases of congenital syphilis among infants under one year of age in the United States rose in the period 1978- 1985 from 108 to 268 per annum.

The incidence of congenital syphilis generally re- flects the incidence of primary and secondary syphilis among women of childbearing age, as well as the diagnosis and treatment of syphilis in prenatal care programs. In 1985, congenital syphilis rates were highest in areas with high incidences of primary and secondary syphilis. Between 1978 and 1983, primary and secondary syphilis rates for women also increased-to a peak of 7.6 cases per 100,000 women in 1983.

Surveillance data available for the 1983-1985 period indicate that the demographic character- istics of mothers of infants with congenital syph- itis dii not change appreciably in this period. The mean age for a mother at the time of birth of the infected infant was 24 years (range, 14-43 years); and 133 (30%) of the mothers were under 20 years of age.

In the general population, 95% of all pregnant women have at least one prenatal medical visit; in contrast, only 52% of the mothers of infants with congenital syphilis in 1983-1985 reported having at least one prenatal visit. Among those

mothers rece‘kring prenatal care, the mean ges-

tational age at which they were Rrst seen for prenatal care was 22 weeks-late in the second trimester.

Preventable failure to diagnose or treat infected mothers who did receive prenatal care contrib- uted to the occurrence of the disease. Among women who received prenatal care, congenital syphilis cases were attributed to failure to screen for syphilis in 18 women (8%); failure to treat 32 pregnant women (14%) with a reactive serologic test for syphilis; and failure to screen 58 women (25%) in the third trimester of pregnancy who lied in an area with a high preva- lence of congenital syphilis.

Source: U.S. Centers for Disease Contml, Morbidity

and Mortal& Weekly Report 35(40), 1996.