Univ. of Minn.
`Bio-Medical
`Library
`
`661
`
`• Articles
`Trends in Heart Disease Deaths in Olmsted County, Minnesota, 1979-1994-V. L. Roger, S. J. Jacobsen,
`651
`S. A. Weston, K. R. Bailey, T. E. Kottke, and R. L. Frye
`658 Dermatologic Manifestations in HIV-Infected Patients: A Primary Care Perspective-]. H. Samet,
`P. Muz, P. Cabral, K. Jhamb, A. Suwanchinda, and K. A. Freedberg
`Preliminary Comparison of the Endoscopic Transnasal vs the Sublabial Transseptal Approach for
`Clinically Nonfunctioning Pituitary Macroadenomas-M. T. Sheehan, J. L. D. Atkinson, J. L. Kasperbauer,
`B. J. Erickson, and T. B. Nippoldt
`Pulmonary Arteriovenous Fistulas: Mayo Clinic Experience, 1982-1997-K. L. Swanson, U. B. S. Prakash,
`and A. W Stanson
`681 Detection of Preclinical Parkinson Disease in At-Risk Family Members With Use of [1231]~-CIT and SPECT:
`An Exploratory Study-D. M. Maraganore, M. K. O'Connor, J. H. Bower, K. M. Kuntz, S. K. McDonnell,
`D. J. Schaid, and W. A. Rocca
`
`671
`
`• Case Reports
`687 Tumor Imaging Via Indium 111-Labeled DTPA-Adenosylcobalamin..:_D. A. Collins, H. P. C. Hogenkamp,
`and M. W Gebhard
`692 Acute Hepatitis Due to Fluoxetine Therapy-Q. Cai, M. A. Benson, T. J. Talbot, G. Devadas, H. J. Swanson,
`J. L. Olson, and J. P. Kirchner
`695 Autonomic Failur.e and Proximal Skeletal Myopathy in a Patient With Primary Sjogren Syndrome-
`?. Sorajja, M. K. Poirier, J. B. Bundrick, and E. L. Matteson
`698 Bronchial Mucormycosis With Progressive Air Trapping-D. M . Collins, T. A. Dillard, K. W Grathwohl,
`G. N. Giacoppe, and B. F. Amold
`
`• Concise Review for Clinicians
`702 Treatment of Migraine Headaches-]. D. Bartleson
`
`• Subspecialty Clinics: Urology
`709
`Pharmacotherapeutic Advances in the Treatment of Erectile Dysfunction-A. Nehra, D. M. Barrett, and
`R. B. Moreland
`
`• Residents' Clinic
`723
`72-Year-Old Man With Exertional Chest Discomfort-K. R. Kozak, W. M. Hooten, and R. L. Click
`
`• Symposium on Antimicrobial Agents-Part X
`727
`The Tetracyclines-]. D. Smilack
`730 Trimethoprim-Sulfamethoxazole-1. D. Smilack
`
`• Historical Vignette
`735 Dr Dickinson Ober Wheelock-A Case of Sporadic Insulinoma or Multiple Endocrine Neoplasia Type 1?-
`J. A. van Heerden and M. M. Churchward
`
`• Editorial
`739 Determination of the Cause of Death: Its Relationship to Cardiac r: Dr. Reddy's Laboratories, Ltd., et al.
`v.
`J. E. Edwards
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1041
`7 46 Book Reviews
`748a Professional Opportunities
`
`• Other Features
`Full Table of Contents
`647
`649 Business Information
`650 Historical Profiles of Mayo
`
`686
`722
`740
`
`Stamp v:~nette
`Meet!ugs Schedulerl
`Information fo~ Authors
`
`

`
`661
`
`• Articles
`Trends in Heart Disease Deaths in Olmsted County, Minnesota, 1979-1994-V. L. Roger, S. J. Jacobsen,
`651
`S. A. Weston, K. R. Bailey, T. E. Kottke, and R. L. Frye
`658 Dermatologic Manifestations in HIV-Infected Patients: A Primary Care Perspective-]. H. Samet,
`P. Muz, P. Cabral, K. Jhamb, A. Suwanchinda, and K. A. Freedberg
`Preliminary Comparison of the Endoscopic Transnasal vs the Sublabial Transseptal Approach for
`Clinically Nonfunctioning Pituitary Macroadenomas-M. T. Sheehan, J. L. D. Atkinson, J. L. Kasperbauer,
`B. J. Erickson, and T. B. Nippoldt
`Pulmonary Arteriovenous Fistulas: Mayo Clinic Experience, 1982-1997-K. L. Swanson, U. B.S. Prakash,
`and A. W. Stanson
`681 Detection of Preclinical Parkinson Disease in At-Risk Family Members With Use of [123I] ~-CIT and SPECT:
`An Exploratory Study-D. M. Maraganore, M. K. O'Connor, J. H. Bower, K. M. Kuntz, S. K. McDonnell,
`D. J. Schaid, and W. A. Rocca
`
`671
`
`• Case Reports
`Tumor Imaging Via Indium 111-Labeled DTPA-Adenosylcobalamin-D. A. Collins, H. P. C. Hogenkamp,
`687
`and M. W. Gebhard
`692 Acute Hepatitis Due to Fluoxetine Therapy-Q. Cai, M. A. Benson, T. J. Talbot, G. Devadas, H. J. Swanson,
`J. L. Olson, and J. P. Kirchner
`695 Autonomic Failur.e and Proximal Skeletal Myopathy in a Patient With Primary Sjogren Syndrome-
`?. Sorajja, M. K. Poirier, J. B. Bundrick, and E. L. Matteson
`698 Bronchial Mucormycosis With Progressive Air Trapping-D. M. Collins, T. A. Dillard, K. W. Grathwohl,
`G. N. Giacoppe, and B. F. Arnold
`
`• Concise Review for Clinicians
`702 Treatment of Migraine Headaches-]. D. Bartleson
`
`• Subspecialty Clinics: Urology
`Pharmacotherapeutic Advances in the Treatment of Erectile Dysfunction-A. Nehra, D. M. Barrett, and
`709
`R. B. Moreland
`
`• Residents' Clinic
`723
`72-Year-Old Man With Exertional Chest Discomfort-K. R. Kozak, W. M. Hooten, and R. L. Click
`
`• Symposium on Antimicrobial Agents-Part X
`727
`The Tetracyclines-]. D. Smilack
`730 Trimethoprim-Sulfamethoxazole-1. D. Smilack
`
`• Historical Vignette
`735 Dr Dickinson Ober Wheelock-A Case of Sporadic Insulinoma or Multiple Endocrine Neoplasia Type 1?-
`J. A. van Heerden and M. M. Churchward
`
`• Editorial
`739 Determination of the Cause of Death: Its Relationship to Cardiac Disease and Autopsy Findings-
`]. E. Edwards
`
`• Other Features
`Full Table of Contents
`647
`649 Business Information
`650 Historical Profiles of Mayo
`
`Stamp Vignette
`686
`722 Meethtgs Schedulerl
`Information fo~ Authors
`740
`
`Letters to the Editor
`742
`146 Book Reviews
`7 48a Professional Opportunities
`
`Exh. 1041
`
`

`
`The Tetracyclines
`
`JERRY D. SMILACK, M.D.
`
`The tetracyclines, among the first of the antibiotics to
`become available 50 years ago, remain widely used. Tetra-
`cyclines have bacteriostatic activity against a wide variety
`of pathogens that are responsible for many common and
`some exotic infections. They are particularly valuable in
`the treatment of atypical pneumonia syndromes, chlamyd-
`ia! genital infections, rickettsial infection (Rocky Moun-
`tain spotted fever, typhus, Q fever), Lyme disease, and
`ehrlichiosis.. On the basis of pharmacokinetic consider-
`ations, doxycycline is the preferred agent among the tetra-
`
`cycline congeners. Minocycline may have a limited role in
`the treatment of methicillin-resistant staphylococcal dis-
`ease in situations in which an oral antimicrobial agent may
`be appropriate. The tetracyclines are generally contra-
`indicated during pregnancy and childhood because of
`their association with dental staining and interference with
`bone growth. Photosensitivity may occur with some tetra-
`cyclines, and several drug and food interactions may limit
`gastrointestinal absorption.
`Mayo Clin Proc 1999;74:727-729
`
`Discovered by Duggar1 50 years ago, the tetracyclines
`
`remain one of the most widely prescribed antibiotic
`classes in the world. Data collected in 1992 showed that, in
`the United States, tetracyclines were prescribed by office-
`based physicians more often than were penicillins, tri-
`methoprim-sulfamethoxazole, ciprofloxacin, or ampicillin;
`only amoxicillin and erythromycins were prescribed more
`frequently. 2 During a 12-month period ending in March
`1997, wholesale cost of all tetracycline prescriptions filled
`in US retail pharmacies totaled almost $400 million (Na-
`tional Prescription Audit. Unpublished data).
`
`AVAILABLE TETRACYCLINES-SIMILARITIES
`AND DIFFERENCES
`Five tetracyclines are available in the United States (Table
`1). The superior pharmacokinetic properties, lesser toxic-
`ity, and low cost of doxycycline make it the agent of choice
`among the tetracyclines. All but demeclocycline are avail-
`able generically at low cost, although minocycline is con-
`siderably more expensive than the other generic tetracy-
`clines. The cost of a course of doxycycline is roughly
`equivalent to that of tetracycline.
`
`Antimicrobial Activity
`The tetracyclines inhibit a wide array of aerobic and
`anaerobic bacteria, including many rickettsiae, chlamyd-
`iae, mycoplasmas, spirochetes, and even some protozoa
`and mycobacteria. 3-5 · These agents are generally bacterio-
`static but not bactericidal. Bacterial protein synthesis is
`
`From the Division of Infectious Diseases, Mayo Clinic Scottsdale,
`Scottsdale, Arizona.
`Individual reprints of this article are not available. The entire Sym-
`posium on Antimicrobial Agents will be available for purchase as a
`bound booklet from the Proceedings Editorial Office at a later date.
`Mayo Clin Proc 1999;74:727-729
`
`727
`
`inhibited by reversible binding on the 30 S ribosome and
`blocking the attachment of transfer RNA to an acceptor site
`on the messenger RNA ribosomal complex. 3
`Against certain pathogens, minocycline and doxycy-
`cline are more potent than the other tetracycline conge-
`ners. Minocycline has excellent in vitro inhibitory activity
`against both Staphylococcus aureus and coagulase-negative
`staphylococci (for example, S. epidermidis), particularly
`methicillin-resistant S. aureus and methicillin-resistant S.
`epidermidis strains.6-8
`In one study, all 102 isolates of
`methicillin-resistant S. aureus were inhibited by minocycline
`concentrations of 2 ~g/mL or lower.6 A larger study that
`included 723 S. aureus and 1,402 S. epidermidis isolates found
`minocycline susceptibility to be 96% and 98%, respectively.7
`Mycobacterium marinum is susceptible to minocycline,
`whereas other mycobacteria such as M. fortuitum and M.
`chelonei are more susceptible to doxycycline. 3
`
`Pharmacokinetic and Pharmacodynamic
`Considerations
`A comparison of pharmacologic properties of the tetra-
`cyclines is helpful because certain attributes can be advan-
`tageous9 (Table 2). Most tetracyclines should be avoided in
`patients with renal insufficiency; substantial increases in
`serum levels as a result of diminished renal filtration may
`lead to hepatotoxicity.
`In contrast, doxycycline and
`minocycline are eliminated through the hepatobiliary and
`gastrointestinal tracts. Doxycycline can be administered
`without modification in patients with renal failure. Be-
`cause experience is limited and data concerning pharmaco-
`kinetics are conflicting,5 minocycline should be avoided in
`the presence of renal failure.
`In light of the long elimination half-lives of doxycycline
`and minocycline, once- or twice-daily dosing is possible.
`© 1999 Mayo Foundation for Medical Education and Research
`
`Exh. 1041
`
`

`
`728
`
`The Tetracyclines
`
`Mayo Clin Proc, July 1999, Vol74
`
`Table 1.-Tetracyclines Available in the United States
`Generic name
`Trade names
`Preparations
`Demeclocycline
`Declomycin
`Oral
`Vibramycin, Doryx, Doxycin,
`Oral and parenteral
`Doxycycline
`Monodox, and others
`Minocin
`Terramycin
`Achromycin V, Panmycin, Robitet,
`Sumycin, Tetracyn, and others
`
`Oral and parenteral
`Oral and parenteral
`Oral and parenteral
`
`Minocycline
`Oxytetracycline
`Tetracycline
`
`Milk, antacids, iron supplements, and probably other
`substances with calcium, magnesium, aluminum, and iron
`decrease tetracycline gastrointestinal absorption consider-
`ably and should be ingested at least several hours before or
`after administration of tetracycline. Although doxycycline
`and minocycline absorption may be less affected by these
`divalent and trivalent cations,3•9 avoiding administration
`within 1 to 2 hours after ingestion of interfering food or
`medication is prudent.
`Several additional drug interactions involving the tetra-
`cyclines are infrequent but deserve mention.9 Anticon-
`vulsants (for example, barbiturates, carbamazepine, and
`phenytoin) induce hepatic microsomal metabolism of tetra-
`cyclines and consequently decrease tetracycline serum
`concentrations. If given concurrently, cholestyramine and
`colestipol may bind tetracycline and reduce gastrointestinal
`absorption. Oral contraceptive efficacy may be decreased
`with concurrent use of tetracyclines. Potentiation of war-
`farin-induced anticoagulation with tetracycline use neces-
`sitates close monitoring of a patient's prothrombin time.
`
`MAIN INDICATIONS
`The tetracyclines are considered the antimicrobial drugs of
`choice or acceptable alternative agents for a wide variety of
`infections. Some of the more important uses of the tetracy-
`clines are listed in Table 3. In most situations, any one of
`the tetracyclines can be selected without concern of a spe-
`cific antimicrobial advantage of one agent over another.
`Minocycline is the preferable tetracycline congener for
`methicillin-resistant staphylococcal therapy when vanco-
`
`mycin is not otherwise considered appropriateP Doxycy-
`cline is more active than tetracycline against Streptococcus
`pneumoniae13 and may be an acceptable alternative agent
`in the treatment of pneumococcal pneumonia, 14 but its use
`should be considered only when high-level penicillin resis-
`tance is unlikely.
`Certain tetracyclines have been useful in the treatment
`of several presumably nonmicrobial conditions. Through
`its inhibition of antidiuretic hormone-induced water
`reabsorption in the renal tubule and collecting ducts,
`demeclocycline is indicated for the treatment of the syn-
`drome of inappropriate antidiuretic hormone. 9 One pla-
`cebo-controlled, double-blind study demonstrated modest
`benefit of minocycline in patients with rheumatoid arthri-
`tis.15 Doxycycline may have value in preventing clogging
`of biliary tract stents.16 As sclerosing agents, the tetracy-
`clines are useful for the treatment of malignant and other
`refractory pleural effusions.
`
`TOXICITY AND CONTRAINDICATIONS
`Although the tetracyclines are generally well tolerated,
`certain adverse effects are important, two of which are
`photosensitivity and discoloration of developing teeth.5
`Photosensitive reactions can occur in patients taking any of
`the tetracyclines, although they may be less frequent with
`doxycycline17 and minocycline. 18 Tetracycline deposition
`in bone results in discoloration of primary dentition and
`may temporarily inhibit bone growth. 5 The tetracyclines
`are usually contraindicated during pregnancy and breast-
`feeding and in children younger than 8 years.
`
`Table 2.-Pharmacologic Characteristics of the Tetracyclines
`Elimination
`Effect of renal
`half-life
`insufficiency
`(h)
`on half-life
`10-17
`Prolonged
`12-22
`None
`11-23
`None
`6-10
`Prolonged
`6-11
`Substantially
`prolonged
`
`Effect of food
`on absorption
`Decreased
`None
`None
`Decreased
`Decreased
`
`Oral absorption
`(%)
`66
`90~100
`90-100
`58
`75
`
`Primary mode
`of elimination
`Renal
`Hepatobiliary
`Hepatobiliary
`Renal
`Renal
`
`Drug
`Demeclocycline
`Doxycycline
`Minocycline
`Oxytetracycline
`Tetracycline
`
`Data from the United States Pharmacopeia! Convention.9
`
`Exh. 1041
`
`

`
`Mayo Clin Proc, July 1999, Vol74
`
`The Tetracyclines
`
`729
`
`Table 3.-Major Clinical Conditions for
`Which Tetracyclines May Be Used*
`Respiratory infections
`Community-acquired pneumonia in an outpatient setting
`Atypical pneumonia (Mycoplasma pneumoniae, Chlamydia
`pneumoniae, psittacosis)
`Acute exacerbations of chronic bronchitis
`Legionellosist
`Genital infections
`Chlamydia trachomatis (nongonococcal urethritis, pelvic
`inflammatory disease, epididymitis, prostatitis,
`lymphogranuloma venereum)
`Granuloma inguinale
`Syphilist
`Systemic infections
`Rickettsiae (Rocky Mountain spotted fever, endemic and
`epidemic typhus, Q fever)
`Brucellosis (in combination with rifampin or streptomycin)
`Lyme borreliosis
`Ehrlichiosis
`Relapsing fever (Borrelia recurrentis)
`Vibrio (cholera, V. vulnificus, and V. parahaemolyticus)
`Tularemia t ·
`Bacillary angiomatosis (bartonellosis)t
`Leptospirosis t
`Other (local and systemic) infections
`Methicillin-resistant Staphylococcus aureus and S.
`epidermidist (minocycline) when vancomycin or other
`agents are not considered appropriate
`Pasteurella multocidat
`Mycobacterium marinumt
`Helicobacter pylori (in combination with bismuth
`subsalicylate and metronidazole or clarithromycin)
`Yersinia pestist
`Other conditions
`Acne vulgaris
`Prophylaxis
`Mefloquine-resistant Plasmodium falciparum malaria
`*Tetracyclines are the drug of choice for the infections that are in
`boldface.
`tinfections for which a tetracycline is an acceptable alternative to
`standard agents.
`Data from referencys 3, 5, _and 9 through 11.
`
`Hepatotoxicity, specifically acute fatty necrosis, may oc-
`cur in pregnant women and in patients with renal impair-
`ment, as well as in those receiving high-dose tetracycline
`therapy.9
`Esophageal ulceration ·has been reported with use of
`doxycycline but can be minimized with adequate fluid
`intake when a capsule or tablet is given orally.19-21 Certain
`vestibular side effects, including dizziness, ataxia, and ver-
`tigo, occur in association with minocycline use, but the
`reported frequency varies widely.18 Minocycline use has
`been associated with skin and mucous membrane pigmep-
`tation.9 Blue or blue-black oral pigmentation was seen in
`
`10% of patients taking minocycline for at least 1 year; the
`rate increased to 20% after 4 years of continuous use. 22
`Infrequent or relatively minor side effects associated with
`tetracycline treatment include gastrointestinal intolerance,
`diarrhea, and fungal superinfection.9 Lupuslike symptoms
`associated with minocycline therapy have recently been em-
`phasized.23 Pseudotumor cerebri is an extremely rare ad-
`verse effect of tetracycline use. Nephrogenic diabetes
`insipidus may result from demeclocycline therapy.
`
`9.
`
`REFERENCES
`1. Duggar BM. Aureomycin: product of continuing search for new
`antibiotics. Ann NY Acad Sci 1948;51:177-181
`2. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing
`among office-based physicians in the United States (published erratum
`appears in JAMA 1998;279:434]. JAMA 1995;273:214-219
`3. Williams DN. Tetracyclines. In: Gorbach SL, Bartlett JG, Blacklow NR,
`editors. Infectious Diseases. 2nd ed. Philadelphia: Saunders; 1998.
`pp 227-231
`4. Smilack JD, Wilson WR, Cockerill FR 111. Tetracyclines, chloram-
`phenicol, erythromycin, clindamycin, and metronidazole. Mayo C/in
`Proc 1991;66:1270-1280
`5. Kucers A, Crowe SM, Grayson ML, Hoy JF. The Use of Antibiotics: A
`Clinical Review of Antibacterial, Antifungal and Antiviral Drugs. 5th ed.
`Oxford (England): Butterworth-Heinemann; 1997. pp 719-762
`6. Qadri SM, Halim M, Ueno Y, Saldin H. Susceptibility of methicillin-
`resistant Staphylococcus aureus to minocycline and other antimicrobi-
`als. Chemotherapy 1994;40:26-29
`7. Yuk JH, Dignani MC, Harris RL, Bradshaw MW, Williams TW Jr.
`Minocycline as an alternative antistaphylococcal agent [letter]. Rev
`Infect Dis 1991;13:1023-1024
`8. Archer GL, Climo MW. Antimicrobial susceptibility of coagulase-nega-
`tive staphylococci. Antimicrob Agents Chemother 1994;38:2231-2237
`USP Dl: Drug Information for the Health Care Professional. Vol I. 13th ed.
`Rockville (MD): US Pharmacopeia! Convention; 1993. pp 2610-2620
`10. The choice of antibacterial drugs [published erratum appears in Med
`Lett Drugs Ther 1998;40:54]. Med Lett Drugs Ther 1998;40:33-42
`11. Advice for travelers. Med Lett Drugs Ther 1996;38:17-20
`12.
`Lewis S, Lewis B. Minocycline therapy of resistant Staphylococcus
`iwreus infections [abstract].
`Infect Control Hasp Epidemiol
`1993;14:423
`13. Shea KW, Cunha BA, Ueno Y, Abumustafa F, Qadri SM. Doxycycline
`activity against Streptococcus pneumoniae [letter]. Chest 1995;
`108:1775-1776
`14. Bartlett JG, Breirrian RF, Mandell LA, File TM Jr. Community-acquired
`pneumonia in adults: guidelines for management. Clin Infect Dis
`1998;26:811-838
`15. Tilley BC, Alarcon GS, Heyse SP, Trentham DE, Neuner R, Kaplan DA,
`et al (MIRA Trial Group). Minocycline in rheumatoid arthritis: a 48-
`week, double-blind, placebo-controlled trial. Ann Intern Med 1995;
`122:81-89
`16. Smit JM, Out MM, Groen AK, Huibregtse K, Jansen PL, van Marie J, et
`al. A placebo-controlled study on the efficacy of aspirin and
`doxycycline in preventing clogging of biliary endoprostheses. Gastro-
`intest Endosc 1989;35:485-489
`17. Cunha BA. New uses for older antibiotics: the 'rediscovery' of four
`beneficial and cost-effective antimicrobials. Postgrad Med 1997 Apr;
`101:68-70; ·73-7 4; 79-80
`18. Allen JC. Minocycline. Ann Intern Med 1976;85:482-487
`19.
`Lanza FL. Esophageal ulceration produced by doxycycline: review of
`the literature and comparison of the injury from doxycycline hyclate and
`hydrochloride with that from doxycycline monohydrate. Curr Ther Res
`C/in Exp 1988;44:4 75-484
`20. Schneider R. Doxycycline esophageal ulcers. Am J Dig Dis 1977;22:
`805-807
`21. Shiff AD. Doxycycline-induced esophageal ulcers in physicians [letter].
`JAMA 1986;256:1893
`22. Eisen D. Minocycline-induced oral hyperpigmentation [letter]. Lancet
`1997;349:400
`23. Singer SJ, Piazza-Hepp TD, Girardi LS, Moledina NR. Lupuslike reaction
`associated with minocycline [letter]. JAMA 1997;277:295-296
`
`Exh. 1041