Tetracyclines

ANTIMICROBIAL THERAPY II

0025~7125/95

$0.00 + .20

TETRACYCLINES Natalie C. Klein, MD, PhD, and Burke A. Cunha, MD

The tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity against gram-positive, gram-negative, aerobic, and anaerobic bacteria as well as Mycoplasma, Chlamydia, Rickettsiae, spirochetes, and some protozoa. Chlortetracycline, the first tetracycline isolated in 1948 by Duggan, was followed 2 years later by the production of oxytetracycline. 1 In 1953, tetracycline was released followed by demeclocycline in 1959; rolitetracycline, a soluble derivative of tetracycline in 1960; and in 1961, methacycline, a derivative of oxytetracycline. The so-called long-acting second-generation tetracyclines, doxycycline and minocycline, were synthesized in 1966 and 1972. 01 The second-generation tetracyclines, with their long half-life, efficient oral absorption, and hepatic excretion, are ideal therapeutic agents for a variety of infections. The basic tetracycline structure consists of a hydronaphthacene nucleus containing four fused rings. The tetracycline analogs differ by substitutions on the fifth, sixth, or seventh position of the basic structure (Table 1). The mechanism of action of tetracyclines, similar to aminoglycosides, is by inhibiting protein synthesis by binding to the 30S ribosomal subunit. Tetracyclines gain access to the bacterial ribosomes via a two-step process, first by passive diffusion through hydrophilic pores in the outer cell membrane, then by an energy-dependent active transport through the inner cytoplasmic membrane. 12 Once inside the cell, tetracyclines bind to the 30S ribosomal subunit blocking the binding of aminoacyl tRNA to the acceptor site on the messenger RNA-ribosome complex. 51

From the Infectious Disease Division, Winthrop-University Hospital, Mineola; and the State University of New York School of Medicine, Stony Brook, New York

MEDICAL CLINICS OF NORTH AMERICA VOLUME 79· NUMBER 4· JULY 1995

789

790

KLEIN & CUNHA

Table 1. STRUCTURES OF SELECTED TETRACYCLlNES Substituent(S) AT Tetracycline

5th

Chlortetracycline

-H

-CH3 --OH

-Cl

Oxytetracycline

--OH

-CH3 --OH

---H

Tetracycline

-H

-CH3 --OH

-H

Demeclocycline

---H

--OH

-Cl

6th

7th Position

Methacycline

--OH

-CH 2

-H

Doxycycline

--OH

-CH3

-H

Minocycline

-H

-H

-N(CH 3 )2

ANTIMICROBIAL SPECTRUM

The tetracyclines exhibit broad-spectrum activity against many gram-positive and gram-negative bacteria as well as Mycoplasma, Chlamydia, Rickettsiae, and amoebae (Table 2). Although bacteriostatic in vitro, when present in high concentrations, they are frequently bacteriocidaPl The tetracyclines have greater activity in vitro against grampositive than gram-negative bacteria. Minocycline and doxycycline are more active against Staphylococcus aureus and various streptococci than tetracycline (Table 2). Minocycline is one of the most potent antistaphylococcal antibiotics and may be used for serious S. aureus infections. Group B streptococci and enterococci are resistant to doxycycline and minocycline. The use of tetracyclines for infections caused by Streptococcus pyogenes or Streptococcus pneumoniae frequently results in the emergence of plasmid-mediated resistance and, therefore, should be avoided. The tetracyclines are active against most gram-positive bacilli, including Actinomyces israelii, Arachnia, Bacillus anthracis, Listeria monocytogenes, most clostridia, and Nocardia. The gram-negative spectrum of activity is limited by the emergence of resistant strains. Penicillin-sensitive Neisseria gonorrhoeae and meningococci are sensitive to tetracycline, doxycycline, and minocycline; however, penicillin-resistant gonococci tend also to be resistant to tetracyclines. Tetracyclines have limited usefulness in the treatment of infection caused by Salmonella or Shigella and have no activity against Proteus mirabilis, Providencia, or Pseudomonas aeruginosa. Most community-acquired Escherichia coli, Xanthomonas maltophilia, and Pseudomonas pseudomallei, however, are sensitive to tetracyclines, as are most vibrios, Campylobacter, Helicobacter, Plesiomonas shigelloides, Aeromonas hydrophila, Pasturella multocida, Brucella, and some Haemophilus species. The second-generation tetracyclines, doxycycline and minocycline, are more active against anaerobic bacteria (Bacteroides fragilis and clostridia) than tetracycline. IS Tetracyclines have excellent activity against Mycoplasma pneumoniae, Chlamydia, and Rickettsiae. Borellia burgdorferi, the

TETRACYCLINES

791

Table 2. ANTIBIOTIC SENSITIVITIES OF TETRACYCLINE, DOXYCYCLINE, AND MINOCYCLlNE Mean Minimal Inhibitory Concentration (l-lg/mL) Organism Gram-positive bacteria Staphylococcus aureus Streptococcus pyogenes Streptococcus pneumoniae Viridans group streptococci Enterococcus faecalis Gram-negative bacteria Escherichia coli Enterobacter spp Klebsiella spp Serratia marcescens Proteus mirabilis Neisseria gonorrhoeae Neisseria meningitidis Haemophilus influenzae Legionella pneumophi/a Shigella Bacteroides fragilis Mycoplasma/chlamydia Mycoplasma pneumoniae Ureaplasma urealyticum Chlamydia spp

Tetracycline

Doxycycline

Minocycline

3.1 0.78 0.8 3.1 >100

1.6 0.39 0.2 0.39 50

0.78 0.39 0.2 0.39 100

12.5 25 50 200 >100 0.78 0.8 1.6 5.2 1-2 0.52-2

12.5 25 50 50 >100 0.39 1.6 1.6 1.0 4-128 0.1-8

6.3 12.5 25 25 >100 0.39 1.6 1.6 0.43 2-128 0.1-16

1.6 0.4 0.6

1.6 0.1 0.06

1.6 0.13 0.02

Oata from Axelsson A, Brorson JE: Concentration of antibiotics in sinus secretions. Ann Otol 82:44, 1973.

agent of Lyme disease; Entamoeba histolytica; some malaria species; and Mycobacterium marinum are also sensitive to tetracyclines, especially dox-

ycycline. It is not widely appreciated that doxycycline and minocycline are highly active against S. pneumoniae. Resistance against S. pneumoniae is minimal with doxycycline and minocycline (:::;5%) in contrast to conventional tetracyclines (20%-30%) (Cunha BA, personal communication). For this reason, doxycycline monotherapy remains useful in the treatment of community-acquired pneumonias whereas conventional tetracyclines should be avoided. RESISTANCE PATTERNS

The emergence of resistance to tetracyclines has been a problem worldwide. The addition of tetracyclines to animal feed has been an important factor for the spread of plasmid-mediated resistance. Resistance to tetracyclines is primarily due to inhibition of transport of the drug into the cell or by increasing antibiotic efflux. Most acquired resistance to tetracyclines by gram-positive and gram-negative bacteria is plasmid mediated. 36 Resistance may occur by chromosomal alteration

792

KLEli\i & CUNHA

as well. I'> Strains of tetracycline-resistant group A streptococci were first noted in 1954. 37 By 1975, 36'/0 of group A streptococci in Britain were resistant, whereas a survey of group A streptococci in Scotland from 1978-80 revealed 30% to 40'X, of isolates resistant to tetracyclines. 6 , 48 Group B streptococci resistance to tetracycline is even more common, with up to 87% of isolates in one series." Tetracycline-resistant pneumococcus, first reported from Australia in 1962, is now found worldwide with an incidence of from 3% to 23%.22. 36 Staphylococcal strains resistant to tetracycline are common, but many strains remain sensitive to doxycycline. Thirty-three percent of coagulase-negative Staphylococcus was tetracycline resistant in an Ohio series. 56 Minocycline is the tetracycline with the highest degree of antiS. aureus activity. It is as potent and effective against S. aureus as anti staphylococcal penicillins or vancomycin. Minocycline is one of the few antibiotics that is effective against both MRSA colonization and infection. Tetracycline resistance is widespread among both aerobic and anaerobic gram-negative bacilli, especially among hospital-acquired isolates of Enterobacteriaceae. In one Boston hospital, 97% of Serratia, 91% of Proteus, 62%, of Klebsiella, and 61% of E. coli isolates were tetracycline resistant. 49 Resistance to tetracycline often associated with multiple antibiotic resistance is also common among Shigella and Salmonella isolates. 2,29 Outbreaks of cholera caused by Vibrio cholerae 01 biotype El Tor resistant to tetracycline have occurred in Tanzania and Bangladesh, whereas tetracycline-resistant N. gonorrhoeae isolates are present in Europe, Southeast Asia, and the United States. 9 , lll. 40 Resistance to tetracyclines has developed in strains of Haemophilus inJluenzae, Haemophilus ducreyi, Bacteroides, and Pseudomonas pseudomallei often accompanied by multiple antibiotic resistance. CLINICAL PHARMACOKINETICS Absorption, Metabolism, Excretion

The tetracyclines are incompletely absorbed from the gastrointestinal tract primarily from the stomach and the small intestine. Tetracycline drugs are better absorbed in the fasting state except for doxycycline and minocycline, which are well absorbed orally in the presence or absence of food (Table 3).24 On an empty stomach, the percentage of an oral dose absorbed is lowest for chlortetracycline (25% to 30%); intermediate for oxytetracycline, demeclocycline, and tetracycline (58% to 80%); and highest for doxycycline and minocycline (93°;;) to 100%).14,23.51 Tetracyclines are well absorbed in elderly patients with achlorhydia. 34 There was no difference in rate and extent of absorption in elderly patients from a control group given 250 mg tetracycline. 34 The use of iron preparations, aluminum hydroxide gels, sodium bicarbonate, and calcium and magnesium salts, and the use of milk and milk products, however, decrease absorption of tetracyclinesY· 42, 51 The administration of 500 mg tetracy-

793

TETRACYCLlNES

Table 3. ORAL ABSORPTION AND EXCRETION OF TETRACYCLlNES % Absorbed

Drug

Tetracycline Doxycycline Minocycline Chlortetracycline Oxytetracycline Demethylchlortetracycline

Fasting State

Effect with Food/Milk

77-80 93 100 25-30 58 66

Decreased Insignificant Insignificant NA Decreased Decreased

Effect with Ferrous Sulfate

Decreased Decreased Decreased Decreased Decreased Decreased

% Excretion in Urine

20 35-40 4-9 20 60 10

NA = Not available. Data from references 2, 5, 15 and 22.

cline or 200 mg of doxycycline or minocycline orally produces peak serum concentrations of 3 to 5 JJvg/mL after 2 hours. l7,54 The half-life of doxycycline (14 to 22 hours) and minocycline (11 to 13 hours) is much longer than tetracycline (8.5 hours) (Table 4).16,51 For practical purposes, doxycycline is the only intravenous tetracycline used because the other parenteral tetracyclines are associated with thrombophlebitis and hepatic toxicity. Because the absorption of doxycycline is so complete, serum levels after orally or intravenously administered doxycycline are equivalent, making doxycycline a convenient drug to use in patients when venous access is a problem. Distribution

The tetracyclines vary in their degree of protein binding dependent on the methods used for determination (see Table 4). Protein binding is Table 4. PHARMACOKINETICS OF TETRACYCLlNES Tetracycline

Serum half-life (h) Serum Binding % Protein Calcium Lipid solubility compared with tetracycline Apparent volume of distribution (L) Penetration into' Prostate Female reproductive organs Lung Sputum Saliva Bile

Doxycycline

Minocycline

6-12

14-22

11-33

20-65 39.5

60-95 19

55-75

1 108

5 50

10 60

+ ++ ++ + + +

+++ +++ +++ +++ ++ +++

+++ +++ +++ +++ +++ +++

= Slight; + + = moderate; + + + = excellent. NA = Not available. Data from references 5, 23-25.

*+

NA

794

KLEIN & CUNHA

highest with doxycycline, intermediate with minocycline, and lowest with tetracycline. 16,51 Tetracyclines penetrate fairly well into tissues and body fluids. Tetracyclines differ in their lipid solubility, and this is directly related to tissue penetration, Both doxycycline and minocycline are lipid soluble, accounting for their superior tissue penetration. Doxycycline is 5 times more lipid soluble than tetracycline, whereas minocycline is 10 times more lipid soluble than tetracycline. 17 Tissue penetration of doxycycline is unaffected by age. Serum levels in geriatric patients were similar to levels in young adults given 200 mg doxycycline. 53 The enhanced lipid solubility of the second-generation tetracyclines allows for rapid penetration into secretions of the respiratory tract, prostate, female genital tract, lung tissue, and bile (see Table 4).16,24-26, ss The lipid solubility of doxycycline and rapid and complete gastrointestinal absorption result in excellent tissue penetration as well as persistence in secretions of the respiratory tract and prostate, making doxycycline an ideal drug for typical and atypical pneumonia and acute prostatitis. Tetracyclines cross the placenta, accumulate in fetal bone and teeth, and are found in relatively high concentrations in human milk. 54 Although tetracyclines (except minocycline) slowly penetrate the cerebrospinal fluid in patients with both inflamed and noninflamed meninges, the levels achieved are low. 33 Minocycline has been used to treat eNS infections due to susceptible organisms. Excretion

Tetracycline is eliminated primarily in the urine by glomerular filtration, with more than 50% excreted in the urine after an oral dose and 70% excreted following parenteral administration. 36 Doxycycline is eliminated primarily through the digestive tract, with up to 90% excreted in the feces as an inactive conjugate or as a chelate, and has an enterohepatic circulation. Approximately 19% to 23% is excreted by glomerular filtration.23, 39 Therefore, no alteration in doxycycline dose is needed in patients with renal insufficiency or hepatic failure (Table 5). Because only 4% to 9% of orally or parenterally administered minocycline is Table 5. ADULT DOSING RECOMMENDATIONS WITH NORMAL AND ABNORMAL RENAL AND HEPATIC FUNCTION Hemodialysisl Peritoneal Dialysis

HepatiC Failure

Avoid

Avoid

Avoid

Doxycycline* 100 mg orally/IV every 12 h

100 mg orally/IV every 12 h

100 mg orally/IV every 12 h

100 mg orally/IV every 12 h

Minocycline*

100 mg orally/IV every 12 h

100 mg orally/IV every 12 h

100 mg orally/IV every 12 h

Drug

Tetracycline

Normal Renall Renal Hepatic Function Insufficiency

500 mg orally/IV every 6 h

100 mg orally/IV every 12 h

*200-mg loading dose.

TETRACYCLINES

795

excreted in the urine, the dose of minocycline for renal failure is also unchanged. 33, 36 The amount of minocycline excreted in the feces is low compared with other tetracycline drugs. Minocycline undergoes considerable metabolism and does not appear to accumulate in hepatic failure. 51 ADVERSE DRUG REACTIONS

As a group, tetracyclines are considered to be relatively safe drugs; however, a number of adverse effects can occur (Table 6). Gastrointestinal irritation can occur with all tetracycline drugs, especially oxytetracycline and doxycycline. The administration of food along with doxycycline prevents much of these symptoms. Tetracycline and doxycycline may cause esophageal ulcerations or strictures, which can be prevented by taking the medication with copious water and not immediately before going to bed,s, 57 Diarrhea occurs more often with poorly absorbed tetracyclines and rarely with wellabsorbed doxycycline. Diarrhea caused by Candida over growth or pseudomembranous colitis secondary to Clostridium difficile may also occur. Acute fatty necrosis of the liver is a rare complication associated with Table 6. ADVERSE EFFECTS OF TETRACYCLlNES Adverse Effect

Gastrointestinal Esophageal ulcerations/strictures Nausea, vomiting, epigastric discomfort Diarrhea Pancreatitis Hepatoxicity Skin/hypersensitivity reactions Rashes Photosensitivity/phototoxic reaction Nail, skin, scleral pigmentation Teeth/bones Discoloration of teeth/hypoplasia of enamel Kidneys Renal failure Nephrogenic diabetes insipidus Fanconi-like syndrome

Drug

Tetracycline, doxycycline Tetracycline, doxycycline, minocycline Tetracycline Tetracycline Intravenous tetracycline in pregnant women Tetracycline, doxycycline, minocycline Tetracycline, doxycycline, minocycline Minocycline Tetracycline, doxycycline, and minocycline in children os 8 years of age Tetracyclines may worsen renal function Demeclocycline Outdated tetracycline

Central nervous system Vertigo Pseudotumor cerebri

Minocycline Tetracycline, doxycycline, minocycline

Phlebitis

Tetracycline, doxycycline, minocycline

796

KLEIN & CUNHA

parenterally administered tetracycline. Most cases of severe hepatotoxicity have occurred in pregnant women receiving more than 2 g of tetracycline per day. Hypersensitivity reactions, including urticaria, morbilliform rashes, and anaphylaxis, are rarely seen with tetracycline drugs. Doxycycline and demeclocycline may produce a mild-to-severe reaction in sun-exposed skin, called a photo toxic reaction, sometimes accompanied by onycholysis. 51 Minocycline administration for prolonged periods may cause nail, skin, and scleral pigmentation. 3 Photosensitivity may occur with all tetracycline drugs. In children under the age of 8, tetracyclines cause a brown-to-yellow discoloration of teeth sometimes associated with hypoplasia of the enamel. The discoloration of permanent teeth by tetracyclines appears to be dose related and does not occur in adults. Tetracyclines except for doxycycline are antianabolic and contraindicated in renal failure. Tetracycline worsens azotemia in patients with chronic renal failure by inhibiting protein synthesis so that the kidneys excrete an additional load from amino acid metabolism. A Fanconi-like syndrome with renal tubular acidosis has been reported with outdated tetracycline. Demethylchlortetracycline can produce nephrogenic diabetes insipidus. Minocycline is frequently accompanied by a reversible vestibular toxicity characterized by tinnitus, lightheadedness, dizziness, and loss of balance. Vertigo is seen more frequently in women than in men. Pseudotumor cerebri has been reported in both adults and infants taking tetracyclines. 54 Phlebitis is a common complication of intravenously administered tetracyclines but occurs less frequently with doxycycline.

DRUG INTERACTIONS

A number of drugs may interact with tetracycline absorption or metabolism (Table 7). The concomitant administration of antacids containing calcium, magnesium, or aluminum; ferrous sulfate; sodium bicarbonate; or cimetidine may impair the oral absorption of tetracyclines? 41 Doxycycline may be less effective in patients receiving long-term anticonvulsant therapy with phenytoin or carbamazepine because the halflife of doxycycline is shortened by 50% owing to enhanced hepatic metabolism. 44 Barbituates and long-term alcohol consumption also reduce the half-life of doxycyclineY· 45 Severe renal failure has occurred in patients receiving tetracyclines after methoxyflurane anesthesia from the formation of calcium oxalate crystals. 13. 35 Intravenous tetracycline may enhance effects of anticoagulants by reducing plasma prothrombin activity.52 Tetracycline bacteriostatic drugs may interfere with penicillin bactericidal activity.31 Finally, the concomitant use of tetracyclines with oral contraceptives may reduce conjugated estrogen levels, decreasing efficacy of the contraceptive pill,5

TETRACYCLINES

797

Table 7. DRUG INTERACTIONS WITH TETRACYCLlNES Drug

Calcium-, magnesium-, and aluminumcontaining antacids Ferrous sulfate Sodium bicarbonate Cimetidine Anticonvulsants (carbamazepine, diphenylhydantoin) Barbiturates Chronic alcohol consumption Methoxyflurane anesthesia Anticoagulants Penicillin Oral contraceptives

Effect

Impaired absorption of tetracyclines Impaired absorption of tetracyclines Impaired absorption of tetracyclines Impaired absorption of tetracyclines Shortens half-life of doxycycline Shortens half-life of doxycycline Shortens half-life of doxycycline Renal failure after tetracycline use Intravenous tetracycline may cause enhanced anticoagulation Tetracyclines may interfere with bactericidal action of penicillin Tetracyclines may reduce conjugated estrogen level

CLINICAL USE

Tetracycline drugs are used to treat a variety of infections, including atypical pneumonia, diarrheal diseases, and acne (Table 8). Tetracyclines are considered the drugs of choice for the treatment of a number of less commonly encountered pathogens, including brucellosis, Chlamydia, cholera, lymphogranuloma venereum, granuloma inguinale, leptospirosis, Borrelia burgdorferi, melioidosis, Mycobacterium marinum, Borrelia recurrentis, and Vibrio vulnificus (Table 8). Problems with the development of tetracycline resistance, however, have decreased the usefulness of tetracyclines to some degree. PROPHYLACTIC USE

A single daily dose of doxycycline has been used to prevent traveler's diarrhea caused by enterotoxigenic E. coli and to prevent chloroquine-resistant malaria. Minocycline has been used for meningococcal prophylaxis, although rifampin is the drug of choice. TREATMENT Respiratory Tract Infections

Tetracyclines are useful drugs in the management of lower respiratory tract infections. Doxycycline has been found to be equally efficacious as ampicillin in the treatment of acute infective exacerbations in patients with chronic bronchitis. 1, 11, 19 Doxycycline has also been shown

798

KLEIN & CUNHA

Table 8. CLINICAL INDICATIONS FOR TETRACYCLlNES Pathogen/Syndrome

Alternative Therapy

Rickettsial infections' Brucellosis Borrelia recurrentis (relapsing fever) Mycobacterium marinum Early Lyme disease' Melioidosis Mycoplasma pneumoniae Syphilis Traveler's diarrhea' Pelvic inflammatory disease Legionnaires' disease Leptospirosis Tularemia Chlamydial infections' Vibrio vulnificus Amebiasis Actinomycosis Nocardiosis Whipple's disease Acne Meningococcal prophylaxist Chloroquine-resistant malaria' VRE (susceptible strains) MRSAt S. aureust

Chloramphenicol Streptomycin, TMP-SMX Erythromycin, chloramphenicol Rifampin, ethambutol, TMP-SMX Amoxicillin Chloramphenicol Erythromycin Benzathine penicillin Ciprofloxacin, TMP-SMX Ceftriaxone, azithromycin, ofloxacin Erythromycin Penicillin Streptomycin Azithromycin TMP-SMX Metronidazole Penicillin TMP-SMX Penicillin, streptomycin Erythromycin, clindamycin Rifampin Mefloquine Chloramphenicol Vancomycin Antistaphylococcal penicillins

"Doxycyline is the preferred tetracycline. tMinocycline is the preferred tetracycline. TMP-SMX· ~ Trimethoprim-sulfamethoxazole.

to be effective in treatment of lower respiratory tract infections in patients with no underlying lung disease. 38 The increasing rates of tetracycline resistance to H. inJluenzae and S. pneumoniae, however, make second-generation or third-generation cephalosporins the preferred agent for most patients with lower respiratory tract infections. The tetracyclines have excellent activity against pathogens causing atypical pneumonia, including Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia psittaci, Francisella tularensis, and Coxiella burnetti. 18• 32 Doxycycline has been shown to be effective in reducing the number of febrile days and improving symptoms of patients with M. pneumoniaeY· 30 Doxycycline penetrates well into sinus secretions and has been shown to be effective in the therapy of sinusitis. 4• 28 Sexually Transmitted Diseases

Tetracyclines remain excellent drugs for the treatment of nongonococcal urethritis caused by Chlamydia trachomatis or Ureaplasma urealyticum. Tetracyclines are effective therapy for non-penicillinase-producing

TETRACYCLINES

799

strains of gonorrhea, lymphogranuloma venereum, granuloma inguinale, and some cases of chancroid. Tetracyclines are the alternative therapy for syphilis in a penicillinallergic patient. Tetracycline or doxycycline combined with ceftriaxone for gonorrhea is standard therapy for pelvic inflammatory disease. Doxycycline, because of its ability to penetrate a noninflamed prostate, has been used successfully to treat chronic prostatitis. Gastrointestinal Infections

Tetracyclines are effective in eradicating the cholera carrier state, for prophylaxis, and for decreasing duration and volume of diarrhea, although rehydration remains the primary therapy.2o, 47 Tetracyclineresistant strains of V. cholerae, however, are increasing in prevalence. Single-dose tetracycline therapy has been effective in adult shigellosis. 46 Daily doxycycline is one agent used for traveler's diarrhea prophylaxis.50 SUMMARY

Tetracyclines are relatively safe drugs with a broad antimicrobial spectrum. Doxycycline remains the preferred tetracycline agent for most indications. Doxycycline has a long half-life, which makes convenient twice-a-day dosing possible. It is well absorbed orally even in the presence of food, has excellent tissue penetration, and does not require a dose adjustment in renal insufficiency. Doxycycline is a useful agent for the treatment of atypical pneumonias, sexually transmitted diseases, traveler's diarrhea, rickettsial infections, and Lyme disease. Minocycline is the preferred drug for MRSA colonization/infection. References 1. Aitchison WRC, Grant IWB, Gould JC: Treatment of acute eacerbations in chronic bronchitis. Br J Clin Pract 22:343, 1968 2. Anderson DM: Plasmid studies of Salmonella typhimurium phage type 179 resistant to ampicillin, tetracycline, sulphonamides, and trimethoprim. J Hyg Camb 85:293, 1980 3. Angeloni VL, Salasche SI, Ortiz R: Nail, skin and scleral pigmentation induced by minocycline. Cutis 40:229, 1987 4. Axelsson A, Brorson JE: Concentration of antibiotics in sinus secretions. Ann Otol 82:44, 1973 5. Bacon JF, Chenfield GM: Pregnancy attributable to interaction between tetracyclines and oral contraceptives. BMJ 280:293, 1980 6. Baker CJ, Webb BI, Barrett FF: Antimicrobial susceptibility of group B streptococci isolated from a variety of clinical sources. Antimicrob Agents Chemother 10:128, 1976 7. Barr WH, Adir JA, Barrettson L: Decrease of tetracycline absorption in man by sodium bicarbonate. Clin Pharmacol Ther 12:779, 1971 8. Bonavina L, De Meester TR, McChesney L, et al: Drug-induced esophageal strictures. Ann Surg 206:173, 1987 9. Centers for Disease Control: Vibrio cholerae-Bangladesh. MMWR 29:119, 1980

800

KLEIN & CUNHA

10. Centers for Disease Control: Tetracycline-resistant Neisseria gorlOrrhaeac-Georgia, Pennsylvania, New Hampshire. MMWR 34:563,1985 11. Chodosh S, Baigelman W: Doxycycline compared with amoxicillin in acute bacterial exacerbations of chronic bronchitis: Preliminary report of a double-blind crossover study. In Finegold SM (ed): Doxycycline (Vibramycin): Recent Investigations and Clinical Experience. New York, Excerpta Medica, 1977, p 1 12. Chopra 1, Howe TGB: Bacterial resistance to the tetracyclines. Microbiol Rev 42:707, 1978 13. Cousins ML Mazze RI: Tetracycline, methoxyflurane anesthesia, and renal dysfunction. Lancet 1:751, 1972 14. Cunha BA, Sibley C, Ristuccia A: Doxycycline. Ther Drug Monit 4:115, 1982 15. Cunha BA: Clinical uses of the tetracyclines. In Hlavka JL Boothe JH (eds): The Tetracyclines. Berlin, Springer-Verlag, 1985, p 393 16. Cunha BA, Corner JB, Jonas M: The tetracyclines. Med Clin North Am 66:293, 1982 17. Cunha BA, Garabedian-Ruffalo SM: Tetracyclines in urology: Current concepts. Urology 36:548, 1990 18. Cunha BA, Jonas M: Legionnaires' disease treated with doxycycline. Lancet 2:1107, 1981 19. Dalal A: Chronic bronchitis-a clinical trial of vibromycin and ampicillin. Med Digest 14:449,1969 20. De SA, Chauduri A, Duta 0, et al: Doxycycline in the treatment of cholera. Bull WHO 54:177, 1976 21. Duggar BM: Aureomycin: A product of the continuing search for new antibiotics. Ann NY Acad Sci 51:177, 1948 22. Evans W, Hansman 0: Tetracycline-resistant pneumococcus. Lancet 1:451, 1963 23. Fabre L Milek E, Kalfopoulos P, et al: Kinetics of tetracycline in man. n. Excretion, penetration in normal and inflammatory tissues, behavior in renal insufficiency and hemodialysis. Schweiz Med Wochenschr 101:625, 1971 24. Fabre J, Milek E, Kalfopoulos P, et al: Kinetics of tetracycline in man. 1. Digestive absorption and serum concentrations. Schweiz Med Wochenschr 101:593, 1971 25. Games HA: Doxycycline levels in serum and prostatic tissue in man. Urology 1:205, 1973 26. Gartmann J: Doxycycline concentrations in lung tissue, bronchial wall and bronchial secretions. Schweiz Med Wochenschr 102:1484, 1972 27. Gooch WM, Mogabgab WJ: Therapeutic effect of doxycycline upon Mycoplasma pneumoniae pneumonia. Antimicrob Agents Chemother 10:291, 1971 28. Gnarpe H, Lundberg C: L-phase organisms in maxillary sinus secretions. Scand J Infect Dis 3:257, 1971 29. Hansson JB, Walder M, Juklin I: Susceptibility of shigellae to mecillinam, nalidixic acid, trimethoprim and five other antimicrobial agents. Antimicrob Agents Chemother 19:271, 1981 30. Izumikawa K: Doxycycline treatment of mycoplasma! pneumonia. Postgrad Med Suppl 1:51, 1979 31. Jawetz E: The use of combinations of antimicrobial drugs. Annu Rev Pharmacol 8:151, 1968 32. Johnson OH, Cunha BA: The atypical pneumonias. Postgrad Med 93:69, 1993 33. Klein NC, Cunha BA: Tetracyclines in antimicrobial therapy in the elderly patient. Tn Yoshikawa T, Norman DC (eds): Antimicrobial Therapy in the Elderly Patient. New York, Marcel Dekker, 1994, p 323 34. Kramer PA, Chapron DJ, Benson L et al: Tetracycline absorption in elderly patients with achlorhydria. Clin Pharmacol Ther 23:467, 1978 35. Kuzacu EY: Methoxyflurane, tetracycline, and renal failure. JAMA 211:1162, 1970 36. Finch RG, Mandragos K: Antibiotic and chemotherapy. In Lambert HP, O'Grady FW (eds): Tetracyclines, ed 6. New York, Churchill Livingstone, 1992, p 277 37. Lowbury EJL, Hurst L: Atypical anaerobic forms of Streptococcus pyogenes associated with tetracycline resistance. J Clin Pathol 9:59, 1956 38. Lyons HA, Thomas JS, Hewrich AE, et al: Efficacy of doxycycline in acute infections of the lower respiratory tract. Curr Ther Res Clin Exp 19:24, 1976

TETRACYCLlNES

801

39. Merier C, Lawrencet FL, Rudhardt M, et al: Behaviour of doxycycline in renal insufficiency. Helv Med Acta 35:124, 1969/1970 40. Mhitlu FS, Mmari PW, Ijumba J: Rapid emergency of El Tor Vibriio cholerae resistant to antmicrobial agents during first six months of fourth cholera epidemic in Tanzania. Lancet 1:345, 1979 41. Neuvonen PJ: Interactions with absorption of tetracyclines. Drugs 11:45, 1976 42. Neuvonen PI, Cothoni C, Hackman R, et al: Interference of iron with the absorption of tetracyclines in man. BMJ 4:532,1970 43. Neuvonen PI, Pentilla 0: Interaction between doxycycline and barbiturates. BMJ 1:535,1974 44. Neuvonen PI, Pentilla 0, Lehtovaara R, et al: Effect of anti-epileptic drugs on the elimination of various tetracycline derivatives. Eur J Clin Pharmacol 9:147, 1975 45. Neuvonen PI, Pentillo 0, Roose M, et al: Effect of long-term alcohol consumption on the half life of tetracycline and doxycycline in man. Int J Clin Pharmacol 14:303, 1974 46. Pickering LK, DuPont HL, Olarte J: Single dose tetracycline therapy for shigellosis in adults. JAMA 239:853,1978 47. Rahman MM, Majid MA, Alam AK, et al: Effects of doxycycline in actively purging cholera patients: A double blind trial. Antimicrob Agents Chemother 10:610, 1976 48. Report of Ad-Hoc Study Croup on Antibiotic Resistance: Tetracycline resistance in pneumococci and group A streptococci. BMJ 1:131, 1977 49. Sabath LD: Current concepts: Drug resistance of bacteria. N Engl J Med 280:91, 1969 50. Sack DA, Kamiinksy DC, Sack RB, et al: Prophylactic doxycycline for travelers diarrhea. Results of a prospective double-blind study of Peace Corps volunteers in Kenya. N Engl J Med 298:758, 1978 51. Sande MA, Mandell CL: Antimicrobial agents. In Coodman LS, Cilman A (eds): The Pharmacological Basis of Therapeutics, ed 7. New York, Macmillan, 1985, p 1170 52. Searcy RL, Simms MN, Foreman jA, et al: Evaluation of the blood clotting mechanism in tetracycline-treated patients. Antimicrob Agents Chemother 4:179, 1964 53. Simon C, Malercyzk V, Engelke H, et al: The pharmacokinetics of doxycycline in kidney insufficiency in geriatric patients compared to younger adults. Schweiz Med Wochenschr 105:1615, 1975 54. Standi ford HC: Tetracyclines and chloramphenicol. In Mandell CL, Douglas RC, Bennett JE (eds): Principles and Practice of Infectious Diseases, ed 3. New York, Churchill Livingstone, 1990, p 284 55. Thadepalli 1, Huang JT: Treatment of anaerobic lung infections with intravenous doxycycline. Curr Ther Res 21:849, 1977 56. Watanakunakorn C: Antimicrobial susceptibility of 200 blood isolates of coagulasenegative staphylococci to 20 antimicrobial agents. Scand J Infect Dis 16:345, 1984 57. Winckler K: Tetracycline ulcers of the oesophagus; endoscopy, histology, and roentgenology in two cases and review of the literature. Endoscopy 13:225, 1981

Address reprint requests to Natalie C. Klein, MD, PhD Infectious Disease Division Winthrop-University Hospital 259 First Street Mineola, NY 11501