BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE

FEBRUARY 1978

VOL. 54, No. 2

A SYMPOSIUM ON THE TETRACYCLINES: A MAJOR APPRAISAL* Introduction HAROLD C. NEU, M.D. Professor of Medicine and Pharmacology Head, Division of Infectious Diseases Columbia University College of Physicians and Surgeons New York, New York

THE tetracyclines were isolated in 1948 from a strain of Streptomyces taureofaciens. The first member of the series was called chlrtetracycline. In 1950 oxytetracycline, which comes from S. rimosus, was discovered, followed by methacycline, doxycycline, and minocycline. This symposium was planned to reevaluate these compounds. STRUCTURE AND MECHANISM OF ACTIVITY

The basic tetracycline structure consists of four benzene rings with various substituents on each of the rings (Figure 1). Changes in positions one and six significantly alter the compound's pharmacological properties, although its antibacterial activity changes minimally. At position six of the *Sponsored by the New York Academy of Medicine in cooperation with Science and Medicine Publishing Co., Inc. under a grant from Pfizer Laboratories, New York, N.Y., and held at the Academy October 15,1977.

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Me

WeNM2

OH -7 6 5a

4a

ha 12 OH

0

OH

12a

OH

1

CONH2

0

Tetracycline NMe2

Me

Doxycyclin.

a6deoxy-5hydroxytetracycline

H

OH

H

H

Minocyclin.

6-demethyl-6deoxy7-dimethylaminotetracycline Fig. 1. Tetracycline and two analogues

C ring, doxycycline has a methyl group and a hydroxyl group at the same position on the beta ring, in distinction to tetracycline hydrochloride. Otherwise, the compounds structurally are very similar. ' The basis of the antimicrobial activity of the tetracyclines is shown in Figure 2. These bacteriostatic compounds inhibit protein biosynthesis at the 30S ribosomal level. Protein biosynthesis starts as the DNA strands open by nuclease cleavage. A strand of DNA is then copied, and a messenger RNA is made with a DNA-directed RNA polymerase. At the same time, 5S, 30S, and 50S ribosomes are produced. The 30S ribosome comes from the ribosome pool and makes contact with the messenger RNA. Then, in the presence of GTP and F-formyl methionine transfer RNA, the 30S ribosome forms an initiation complex. If tetracycline is present, it blocks this step, thereby interrupting the initiation process and, consequently, no initiation complex is formed. All tetracyclines appear to bind to the same receptor site. There is no evidence, as with the aminoglycosides, for a specific receptor protein for each tetracycline.2 The compounds are bacteriostatic, that is, they are taken up by the cell Bull. N.Y. Acad. Med.

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nalidixic acid DNA

KXDZXZ

-Op DNA

rifampin

30 S pool

protein

kanamycin gentamicin

AAtRNA(

erythromycin lincomycin

complex Fig. 2. Protein biosynthesis illustrating sites of action of agents that inhibit protein synthesis

and interfere with protein synthesis. However, if the bacterium is in an area in which there is no further DNA, RNA, or protein synthesis and the bacterium is not phagocytosed, the organism can subsequently start growing again if the tetracycline leaks out of the cell because tetracyclines are not permanently bound to ribosomes. There has been a great deal of discussion whether bactericidal agents offer any advantage over bacteriostatic agents in the chemotherapy of Vol. 54, No. 2, February 1978

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TABLE I. ACTIVITY OF TETRACYCLINES AGAINST GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA Minimum inhibitory concentration (,ug.Iml.) Doxycycline Minocycline Tetracycline Median Range Median Range Range Median Gram-positive bacteria Staph. pyogenes Strep. pyogenes (Group A) Strep. pneumoniae (Dip. pneumoniae) Strep. viridans spp. Strep. faecalis (Enterococcus, Group D)

1.6 0.19

->100 - 50

3.1 0.78

0.39 0.09

->100 - 25

1.6 0.39

0.39 0.09

- 12.5 - 25

0.78 0.39

0.2 3.9

- 100 - 100

0.8 3.1

0.1 0.09

- 12

- 50

0.2 0.39

0.1 0.09

- 25 - 50

0.2 0.39

6.3

->100 > 100

1.6

->100

50

1.6

->100

100

Gram-negative bacteria Escherichia coli Enterobacter Klebsiella Serratia Proteus mirabilis Neisseria gonorrhoeae Neisseria meningitidis Hemophilus influenzae Shigella Pseudomonas aeruginosa

- 500 12.5 - 50 25 - 500 50 200 200 50 ->100 >100 0.39 - 6.3 0.78 - 3.1 0.8 0.3 0.8 - 3.1 1.6 1.6 ->500 100 50-300 200

- 500 12.5 - 25 25 - 300 50 50 50 ->100 >100 50 0.39 0.09 - 3.1 - 6 0.8 1.6 - 3.1 0.8 1.6 1.6 - 500 100 25-300 100

6.3 12.5 25 25 50 ->100 >100 0.39 0.19 - 3.1 - 1.6 0.8 1.6 - 3.1 0.8 1.6 100 1.6 - 500 100 100-200

Mycoplasma and Chlamydia M. pneumoniae T. mycoplasma Chlamydia

1.6 0.2 0.5

1.6 0.05 0.5

1.6

3.1 6.3 6.3

- 3.1 - 0.8 - 4.0

1.6 0.4 2.0

1.6 12.5 6.3

- 0.2 - 4.0

1.6 0.1

3.1 6.3 3.1

0.5

- 500 - 12.5 - 500 25

1.6 - 4.0

infection. The only cases in which bactericidal agents have been shown to be significantly more important are those in which the patients had a leukocyte count less than 500 white cells per mm3 e.g., a leukemic patient undergoing chemotherapy, or a patient with bacterial endocarditis. Indeed, in the treatment of pulmonary and urinary tract infections or in such problems as otitis media, sinusitis, etc., improvement has never been demonstrated in morbidity or mortality when bactericidal rather than bacteriostatic agents are used. Although tetracyclines are bacteriostatic, the same is true for chloramphenicol, erythromycin, and the lincinoid compounds (e.g., lincomycin or clindamycin), and all of the macrolide agents, such as tylosin and oleandomycin. The resistance of bacteria to the compounds is based on either the presence of a plasmid, which causes decreased uptake of tetracycline while elimination of the compound by the microorganism continues, or an altered ribosome. The latter circumstance is probably less common. Plasmids

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conferring resistance to tetracycline have been found in staphylococci, streptococci, and most of the Enterobacteriaceae as well as the pseudomohads, such as Pseudomonas aeruginosa.3 The tetracyclines have a broad range of antibacterial activity against both Gram-positive and Gram-negative organisms (Table I), both aerobic and anaerobic species.4'5 Considering tetracycline as representative of tetracycline, oxytetracycline, and chlortetracycline, the median MIC against Staphylococcus pyogenes is 3.1 ug./m ., with a fairly broad range (1.6 to 100 ,ug./ml.). Doxycycline has a similar broad range (0.39 to more than 100 ,g./ml.), although the median is lower (1.6 ,tg./ml.). Minocycline has a more circumspect range (0.39 to 12.5 gg./ml.), with an even lower median (0.78 pug./ml.). With Streptococcus pyogenes and S. viridans, the activity of the older tetracyclines is again somewhat lower than that of doxycycline and minocycline. In general, the newer compounds are more active against the Gram-positive organisms. With regard to pneumococci, most of the tetracycline resistance reported during the late 1950s and early 1960s is difficult to document today.6 Indeed, blood cultures from our own institution and several others showed that most S. pneumoniae organisms are quite sensitive to tetracyclines, particularly to doxycycline. Although the range of activity of the tetracyclines against Hemophilus influenzae, both typable and nontypable strains, is wide, doxycycline is the most active compound against the organisms encountered in respiratory infections and sinusitis. On the other hand, minocycline is more active against staphylococci, particularly S. aureus.7 None of the tetracyclines is highly effective against the various enterococci, such as S. faecalis, S. feciumn, etc. Tetracyclines are active against Neisseria, both N. gonorrhoeae and N. meningitidis.89 In recent years the level of tetracycline required to inhibit N. gonorrhoeae has increased; this is not usually due to plasmids but to alteration of cell-wall structure. There are inadequate studies of the exact MIC values of doxycycline and minocycline against tetracycline-resistant N. gonorrhoeae strains. To date there are no N. meningitidis strains resistant to the tetracyclines. Against the members of the Enterobacteriaceae, the median MICs of the three compounds are quite similar. None is effective against Proteus mirabilis, primarily because of failure of uptake because of changes in the cell wall. This is analogous to the situation that exists for the detergent

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TABLE II. EFFECT OF NEWER TETRACYCLINES UPON BACTERIA RESISTANT TO TETRACYCLINE HCl

Organism Strep. pneumonae

Staph. aureus Strep. faecalis Enterobacteriaceae E. coli, etc. Proteus Klebsiella Bacteroides fragilis

Compound effective Most resistant, some inhibited by doxycycline Minocycline, many inhibited Doxycycline, some inhibited All resistant All resistant

Doxycycline, many inhibited

antibiotics (e.g., the polymyxins), which are also ineffective against P. mirabilis. Against Escherichia coli, Klebsiella, and Enterobacter there is a wide range of activity of all of the tetracyclines, and the median MIC values would depend upon the number of resistant isolates encountered in a particular locality.4 All of the tetracyclines have some activity against P. aeruginosa but only at a high level. Chlortetracycline may be the most effective tetracycline against Pseudomonas, but none of the tetracyclines are approved for clinical use against Pseudomonas infections. All of the tetracyclines are effective against Chlamydia (the organisms responsible for psittacosis and trachoma) and against Mycoplasma pneumoniae. 10-12 By and large, the two newer compounds (doxycycline and minocycline) are similar to the older ones (Table II). The differences relate to the ability of the microorganisms to rid themselves of the antibiotic and not to a lack of a protein that binds the antibiotic. If an organism such as S. pneumoniae or S. faecalis is resistant to tetracycline hydrochloride, it is usually resistant to all of the tetracycline compounds. On the other hand, many organisms (e.g., S. aureus) are susceptible to minocycline as well as to doxycycline. For example, such an organism might have an MIC of 100 ,ug./ml. to tetracycline, whereas its MIC to doxycycline or minocycline might be 3 or 6 ,ug/ml. The Enterobacteriaceae, unfortunately resistant on the basis of a plasmid, which confers the ability to rid themselves of tetracycline hydrochloride, also can rid themselves of minocycline and doxycycline. Conversely, many strains of Bacteroides fragilis resistant to tetracycline hydrochloride are inhibited by doxycycline. The mechanism that controls the latter process, however, is not well understood."3 Bull. N.Y. Acad. Med.

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TABLE III. PHARMACOKINETIC PROPERTIES OF TETRACYCLINES

Excretion Effect upon absorption

Compound Tetracycline hydrochloride Oxytetracycline Doxycycline Minocycline Demethylchlortetracycline

after

Dose Half-life parenteral binding absorbed in serum injection

Protein

Food Ca++ Fe++ % + + + + ++ 55-65 + + + + + 25-35 +1- + ++* 80-95 +1- + ++ 80-95 + + + + + 80-90

% 77 58 93 98 66

T112, h 10 9 15-22 11-17 15

% 60 70 35 10 40

*Occurs even if given intravenously.

PHARMACOLOGY All tetracyclines are quite well absorbed when taken orally, except chlortetracycline. Moreover, peak levels can be achieved one or two hours after administration of doses of 250 mg. (Table III)."4,15 Interfering substances, particularly food of any type, markedly reduce absorption of tetracycline hydrochloride, oxytetracycline, and chlortetracycline. The tetracyclines have a high affinity for divalent cations, particularly those found in substances such as the antacids (the cations aluminum, calcium, magnesium); tetracyclines bind and chelate with these compounds and thus are excreted in the feces.16 Approximately 20 to 50% is unabsorbed and eliminated through the gut or the biliary tract. After an enterohepatic circulation the drug is chelated with the divalent cations in the stool and excreted. A certain amount of the drug is handled by glomerular filtration. The metabolism of all of the tetracycline compounds (except chlortetracycline) is minimal. Chlortetracycline does not accumulate to the same degree as the other, older tetracyclines because it is indeed metabolized, provided there is good liver function. If a patient ingests the drug on an empty stomach, about 77% of tetracycline hydrochloride is absorbed, as is only 58% of oxytetracycline or 66% of demeclocycline. Minocycline and doxycycline are absorbed in amounts greater than 90%. The presence of food, calcium, and iron can interfere with absorption. On a scale of 1+ to 3+, food has a 2 + interference with tetracycline hydrochloride absorption. Less clear is the extent to which food interferes with the absorption of doxycycline or minocycline because studies have been fairly contradictory; Vol. 54, No. 2, February 1978

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TABLE IV. Distribution of tetracyclines*

A.

Compounds Tetracycline hydrochloride Minocycline Doxycycline B.

Compounds Doxycycline Tetracycline hydrochloride Oxytetracycline C.

Compounds Tetracycline hydrochloride Oxytetracycline Minocycline Doxycycline

Lung ++ ++ ++

Liver ++ +++ +++

Kidney ++ + +++

Brain + +++ +++

Sputum + +++ +++

Saliva + +++ +

Ratio of antibiotic level in bile to serum Ratio 20 5 6

Tetracyclines' penetration into CSF % of serum level 10 10 10-20 25

*Tissue penetration is regarded as essential to therapeutic efficacy, but specific antibiotic tissue levels have not been directly correlated with specific therapeutic benefits.

overall, the blood levels with and without food are similar. The presence of calcium has less effect on doxycycline and minocycline than on other tetracyclines, but iron does have an effect. Even if iron is given intravenously-because of doxycycline's excellent absorption from the intestine (from the proximal part of the jejunum and particularly from areas in the duodenum where iron is absorbed"-its absorption is decreased.17 The half-lives of the tetracyclines vary. 13 The average half-life of tetracycline is about 10 hours (range, seven to 12 hours); it must be remembered that many of these half-lives were determined during an earlier era, and perhaps less attention was paid to the actual creatinine clearances. The half-lives of minocycline and doxycycline lie between the range of 11 to 17 hours and 18 to 22 hours, respectively. It is important to realize that simultaneous therapy with antiepileptic drugs such as diphenylhydantoin and carbamazepine can result in a 50% decrease in the half-life of drugs such as doxycycline. Approximately 55 to 65% of tetracycline is bound to protein. Oxytetracycline is the least protein-bound of all the tetracyclines. Minocycline and doxycycline vary in their binding from 80 to 95%, depending on the study. 15,18 Bull. N.Y. Acad. Med

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TISSUES All of the tetracyclines are well distrbuted in man; for example, they produce good concentrations in lung tissue. Some of the best studies have been with doxycycline and minocycline (Table IV). Very high concentrations are achieved in the bile as well as in liver parenchymal cells. The concentration in kidney tissue varies from one tetracycline to another. These drugs penetrate the eye very well; some also concentrate in prostatic tissue; and minocycline and doxycycline easily reach the brain. Tetracyclines do produce a problem, however, in that they cross the placental barrier and can accumulate in fetal bone, where they produce toxicity. They also are excreted in breast milk. The accumulation of tetracyclines differs somewhat in sputum and saliva. Minocycline, in particular, produces very high concentrations in saliva and lacrimal secretions. Doxycycline and minocycline produce higher concentrations in sputum and saliva than do the other compounds.19 The tetracyclines achieve a very high blood level rapidly after either oral or parenteral administration and reach almost equal levels in lung parenchyma and serum. The tetracyclines do not reach bronchial secretions and sputum early; it takes about 48 hours, and then they achieve only a fairly low level. For example, if the serum level is 3 gg./ml., the level in bronchial secretions and sputum might be only 0.1 to 1.0 4g./ml.20 However, in contrast to the low levels in bronchial secretions and sputum, the levels in bronchial mucosa are achieved rapidly and appear to equal the levels in serum. If the site of infection in chronic bronchitis is assumed to be just below the surface of the bronchi, high concentrations of tetracyclines in bronchial epithelium may contribute to their effectiveness in bronchitic infections. These compounds achieve very high concentrations in the bile; for example, the bile/serum ratio of doxycycline is 20:1, which is four times the level seen with tetracycline and oxytetracycline. With drugs such as the penicillins, the bile/serum ratio is often only 2:1 or 3:1.21 Tetracyclines cross into the cerebrospinal fluid; in an inflammatory situation the level of tetracycline or oxytetracycline is about 10 to 20% that in the serum.22 IN

TETRACYCLINE EXCRETION Tetracyclines differ rather widely in the amount excreted in the urine after parenteral injection. For example, 60% of tetracycline hydrochloride, Vol. 54, No. 2, February 1978

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TABLE V. MAJOR ADVERSE EFFECTS OF ALL THE TETRACYCLINES

Skin

Side effects Phototoxicity, onycholysis, rash

Allergic

Rash, urticaria, anaphylactic reaction, angioneurotic edema

Teeth

Staining, dysgenesis, fluorescence

Gastrointestinal

Nausea, vomiting, diarrhea, proctitis, glossitis, stomatitis

Hepatic toxicity

Abnormal liver-function tests, lethal hepatic toxicity

Superimposed infections

Candida, resistant staphylococci, and Gram-negative bacilli

Metabolic

Catabolic effect

Renal

Azotemia, Fanconi syndrome (due to outdated tetracycline), nephrogenic diabetes insipidus-

demethylchlortetracycline

Hematologic

Anemia, neutropenia, eosinophilia (rare)

Miscellaneous

Increased intracranial pressure, vertigo due to minocycline

70% of oxytetracycline, 40% of demeclocycline, only 10% of minocycline, and 35% of doxycycline is excreted.23 ADVERSE REACTIONS

What are the problems encountered with the tetracyclines? Phototoxicity, onycholysis, and rash have been reported with all of them (Table V).24 Urticaria and, very rarely, an anaphylactic reaction or angioneurotic edema have occurred; demethylchlortetracycline may be associated with a lupus erythematosus type of syndrome. In young children tetracyclines can produce staining of the teeth, which can occur if given during the last half of pregnancy or the first eight years of life.25 Perhaps more significant are some of the gastrointestinal superinfections and hepatic effects. Patients have complained of glossitis or stomatitis, cheilosis at the edge of the mouth, nausea, vomiting, and diarrhea (common particularly with 2-gm. doses of tetracycline hydrochloride). Proctitis Bull. N.Y. Acad. Med.

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TABLE VI. TETRACYCLINES Adverse effects compared Antianabolic

Phototoxicity

Accumulate renal failure

effect

Vestibular toxicity

Tetracycline hydrochloride

++

+++

+ ++

0

Oxytetracycline

++

+++

+ ++

0

Demeclocycline

++++

+++

+++

0

Doxycycline

++

0

0

0

Minocycline

+

+

+++

+++

Compound

is not uncommon with some of the older tetracyclines. Abnormal liverfunction tests, which can be particularly difficult problems, have occurred in individuals in low-perfusion states who have received an excess of 2 gm. of tetracycline hydrochloride, chlortetracycline, or oxytetracycline. Candida infections occur with relative frequency-perhaps more with the older drugs, because they are not absorbed as well and thus alter the bowel flora. In addition, there are Gram-negative superinfections with organisms such as P. mirabilis and, occasionally, staphylococci. These occurred primarily during the late 1950s, when tetracyclines were used to treat staphylococcal infections. Metabolic effects occur because the drugs to some degree are antianabolic: they produce a catabolic effect and increase the blood urea nitrogen. Outdated tetracyclines have produced a type of Fanconi syndrome with an amino acid loss, phosphaturia, etc.26 Doxycycline, which does not degrade to the epianhydro form, has not caused this. Uncommonly, neutropenia, anemia, and eosinophilia are observed after their administration. The miscellaneous effects listed in Table V are rarely seen today because we no longer give tetracyclines to children. However, when they were used in children, particularly during an early period of life, they could cause a bulging fontanelle, some meningeal irritation, increased intracranial pressure, and pseudotumor cerebri.27 Vertigo due to minocycline is also a familiar symptom.28 These side effects are produced by the older tetracyclines. With the newer compounds, side effects are perhaps less common (Table VI). Vol. 54, No. 2, February 1978

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TABLE VII. CLINICAL USE OF TETRACYCLINES A. Treatment of choice Rickettsial infections Rocky Mountain spotted fever Typhus, murine and epidemic Rickettsialpox Q fever Chlamydial infections Venereal, conjunctival Psittacosis Brucellosis Tularemia Mycoplasma pneumonia Relapsing fever (Borrelia) Melioidosis Cholera B. Effective but other agents available Pneumococcal pneumonitis Anaerobic infections Listeria infections Gas gangrene Hemophilus infections Anthrax Gonorrhea Shigellosis Nocardiosis C. Syndromes of use Bronchitis Sinusitis Acne Malabsorption Urinary infection Acute exacerbations of chronic bronchitis D. Generally ineffective or less effective than other agents Pharyngitis Endocarditis Serious staphylococcal infections Leptospirosis Osteomyelitis Meningitis Gram-negative bacteremia

USE OF TETRACYCLINES

Where would one use a tetracycline? In some areas these agents are generally ineffective, or at least less effective than other antibiotics (Table VII). Tetracyclines are not the drugs of choice for pharyngitis and, unfortunately, cannot be used in endocarditis. The use of tetracyclines for serious staphylococcal infections, particularly the older tetracyclines, at the beginning of the 1960s was also disappointing. Leptospirosis was once Bull. N.Y. Acad. Med.

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thought to be effectively treated with the tetracyclines, but since we now realize that the secondary stage of the disease is an antigen-antibody reaction, these agents probably are not useful. There are few data about the use of tetracyclines in osteomyelitis, although sometimes they appear to be effective. They are not considered useful in meningitis, although they certainly have been used in Gram-negative meningitis, and I would not consider them the drug of choice in Gram-negative sepsis. Sometimes they are not the first choice for therapy but are nevertheless effective. In patients with pneumococcal pneumonitis in an outpatient setting, tetracyclines work quite well, although they are not the drugs of choice. Kirby studied tetracyclines during the mid-1950s and showed that tetracyclines were as effective as penicillin G in treating pneumococcal pneumonia, provided the patient had no serious underlying disease that compromised immunological function. The use of tetracyclines in anaerobic infections needs to be qualified. Anaerobic infections above the diaphragm are susceptible to penicillin, but tetracyclines are also very useful for these infections. For anaerobic infections below the diaphragm, I would not use the older tetracyclines. Other data indicate that doxycycline, because it is effective against tetracycline hydrochloride-resistant B. fragilis, is effective in those infections. With Listeria, again, other agents could be used, although tetracyclines have proved successful. They have been used in gas gangrene, although I prefer penicillin. For Hemophilus infections in the respiratory tract, tetracyclines are as effective as ampicillin, although few data substantiate this; their use in gonorrhea is discussed in this issue by Dr. William M. McCormack. The tetracyclines were once very effective for shigellosis, but, unfortunately, because of the widespread appearance of the plasmid-mediated tetracycline resistance in Shigella, this is no longer true for Shigella sonnei, Shigella flexneri, or Shigella dysenteriae. The tetracyclines are an alternative treatment in Nocardia infections, although sulfonamides are the drugs of choice. Tetracyclines are certainly very useful for bronchitis, sinusitis, and acne. A nonapproved but important use of the drug is certain malabsorption problems such as Whipple's disease or the blind loop syndrome.In cities with a large population from Puerto Rico,Santo Domingo,or the Far East-areas of the world where malabsorption is common-the disorder can be cured by the tetracyclines. These drugs have also been found to be effective in selected urinary tract infections and they have been used for years with great success to Vol. 54, No. 2, February 1978

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treat acute exacerbations of chronic bronchitis. The tetracyclines have proved efficacious in a variety of unusual infections. For instance, Rocky Mountain spotted fever, not an uncommon disease in New York State, responds to the tetracyclines. Although Q fever is not common here and rickettsialpox is quite rare, the tetracyclines are effective. Chlamydial infections are relatively common in New York City. We see three or four cases of psittacosis every year, for which tetracyclines are drugs of choice. Brucellosis and tularemia are not comnmon, but M. pneumoniae, a major cause of pneumonitis in the young, is common, and the tetracyclines can be used in all of these infections. Relapsing fever (caused by Borrelia), melioidosis, and cholera are less common, but, again, the tetracyclines are the drugs of choice.

SUMMARY The tetracyclines have a number of interesting and useful antibacterial properties as well as excellent pharmacological aspects. I avoid minocycline or chlortetracycline in urinary tract infections, but doxycycline is useful. Its use as chemotherapy will have to be evaluated more closely, although it seems obvious that because doxycycline does not accumulate in patients with renal failure, it would be the tetracycline of choice in a patient with renal failure. The question of patient compliance in taking tetracycline is worthy of review and will be discussed later in this issue. It is clear, however, that when one carefully reviews the uses of tetracyclines, they are not drugs to be discarded but are drugs with distinct advantages over other agents.

1.

2.

3.

4.

REFERENCES pathogenic bacteria to seven tetracycline Neu, H. C.: Molecular Modifications of antibiotics in vitro. Am. J. Med. Sci. Antimicrobial Agents to Overcome Drug 255:179, 1968. Resistance. In: Antibiotics and 5. Garrod, L. P., Lambert, H. P., and Chemotherapy. Basel, Karger, 1976, vol. 20, pp. 87-1 1. O'Grady, F.: Antibiotic and Chemotherapy. London, Churchill LivingGale, E. F., Cundiffe, E., Reynolds, P. stone, 1973, pp. 151-152. E., et al.: The Molecular Basis of Anti6. Holt, R., Evans, T. N., and Newman, biotic Action. New York, Wiley, 1972, R. L.: Tetracycline-resistant pneumopp. 315-322. cocci (letter). Lancet 2:545, 1969. Benveniste, R. and Davies, J.: Mecha7. Fedorkof, J., Katz, S., and Allnoch, H.: nisms of antibiotic resistance in bacteria. In vitro activity of minocycline, a new Annu. Rev. Biochem. 42:471, 1973. tetracycline. Am. J. Med. Sci. 255:252, Steigbigel, N. J., Redd, C. W., and Fin1968. land, M.: Susceptibility of common Bull. N.Y. Acad. Med.

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Vol. 54, No. 2, February 1978