[Postgraduate Medicine]

[SYMPOSIUM]

New uses for older antibiotics

The 'rediscovery' of four beneficial and cost-effective antimicrobials

Burke A. Cunha, MD

VOL 101 / NO 4 / APRIL 1997 / POSTGRADUATE MEDICINE


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This is the first of three articles on antimicrobial therapy

Preview: For years, the antibiotic marketplace has been in a state of eruption, sending forth an impressive array of -cillins, -mycins, and other familiar options. But in this era of managed care, many physicians are re-examining some of the old standbys, especially since these agents share an important trait: cost-effectiveness. In this article, Dr Cunha reviews established and growing uses for doxycycline, minocycline hydrochloride, trimethoprim-sulfamethoxazole, and metronidazole.


Several antibiotics that have been around for years are now the subject of renewed interest and are enjoying a dramatic increase in use. Several factors account for this comeback. For one thing, more cases are emerging of certain infectious diseases against which these older agents are especially effective, such as ehrlichiosis, Lyme disease, and methicillin-resistant Staphylococcus aureus (MRSA) infection. Other factors are the agents' beneficial pharmacokinetic profiles and their generic availability, which makes them extremely cost-effective compared with their newly released counterparts.

Another feature of the older agents that is very important in light of the economic pressures arising from managed care is that oral administration is as effective as intravenous administration for a wide variety of infectious diseases. Intravenous therapy can be largely eliminated except in the most critically ill patients, and even patients who are started on an intravenous regimen can be switched to oral therapy as soon as clinical improvement occurs, which is usually within 3 days. The cost savings of this factor alone are tremendous for the institution and the healthcare system. Patients who start on oral therapy or switch to it soon after admission avoid infections originating at the intravenous line and have a shorter hospital stay, which means less likelihood of contracting phlebitis or nosocomial infections.

This article describes traditional applications as well as new uses for four of the older antibiotics: doxycycline (Doryx, Vibramycin), minocycline hydrochloride (Minocin), trimethoprim-sulfamethoxazole (TMP-SMX) (Bactrim, Cotrim, Septra), and metronidazole (Flagyl, Protostat).

Doxycycline

Of all the older antibiotics, doxycycline has the greatest potential for expanded use. The spectrum of activity determines, in large part, the application of an antibiotic, and doxycycline's lipid solubility and intracellular mode of action give it an unusually wide spectrum of activity. Its long half-life permits once- or twice-daily dosing. It has excellent bioavailability, and blood and tissue levels are equivalent whether the drug is administered orally or intravenously. Recently, doxycycline has been found to be effective for unusual diseases that are being seen with increasing frequency and for diseases that have just been discovered in the last few decades.

Unusual infections
A traditional use for doxycycline has been prophylaxis and treatment of traveler's diarrhea, but it also has long been used for unusual organisms, such as Pseudomonas pseudomallei and the rickettsia that causes Rocky Mountain spotted fever. The emergence of ehrlichiosis (another rickettsial infection) along the eastern seaboard with the same prevalence as Rocky Mountain spotted fever is of growing concern; doxycycline has been found to be as effective against both human granulocytic ehrlichiosis and human monocytic ehrlichiosis as it is against Rocky Mountain spotted fever.

Doxycycline is also highly effective against a wide variety of zoonotic infections; in a recent outbreak of plague in India, it was used for both prophylaxis and treatment.

Lyme disease
Recently, doxycycline has been used widely to treat all phases of Lyme disease, including erythema migrans. Doxycycline is active against Borrelia burgdorferi (the spirochete that causes Lyme disease), and it penetrates, in concentrations sufficient for eradication, virtually all body tissues that the organism may reach via hematogenous dissemination. Oral doxycycline has been shown to be as effective as parenteral ceftriaxone sodium (Rocephin) in treatment of central nervous system (CNS) Lyme disease (ie, neuroborreliosis) (1). This has tremendous cost-saving implications. In the New York area, a 3-week course of parenteral ceftriaxone for CNS Lyme disease, including administration by home care, costs between $5,000 and $7,000. In comparison, a 3-week course of oral doxycycline treatment costs only a few hundred dollars.

In addition, treatment failure in Lyme disease is seldom, if ever, seen with properly administered doxycycline regimens, whereas failures are common with erythromycin therapy.

Pneumonia
Doxycycline is highly effective against all of the common pathogens that cause upper respiratory tract infections. It is especially useful in treating community-acquired pneumonias, both cases caused by typical bacterial pathogens (with the exception of Klebsiella, which occurs primarily in alcoholics) and cases caused by atypical pathogens.

Despite its effectiveness, doxycycline has been used relatively infrequently to treat bacterial community-acquired pneumonias because many physicians believe that it is not active against Streptococcus pneumoniae--the main cause of bacterial pneumonia. The source of this misunderstanding is the fact that conventional tetracycline hydrochloride does miss many strains of S pneumoniae. However, doxycycline not only is uniformly active against S pneumoniae, but also is highly active against penicillin-resistant pneumococci. Therefore, doxycycline monotherapy may be used with confidence for bacterial community-acquired pneumonias, either parenterally or as part of an intravenous-to-oral antibiotic switch program. Pneumonia of mild to moderate severity may be treated entirely with oral doxycycline.

Sexually transmitted disease
Another factor contributing to the growing widespread use of doxycycline is its effectiveness against a wide variety of pathogens that cause sexually transmitted disease. Its antichlamydial activity in particular has made doxycycline a favorite choice because of the rising prevalence of chlamydial genitourinary infections. However, doxycycline is not active against penicillinase-producing Neisseria gonorrhoeae.

Animal bites
Doxycycline is often used in emergency departments to treat patients seeking attention for animal bites. Many animal bites contain unusual organisms (eg, Pasteurella multocida, DF-2 [dysgonic fermenter type 2]) against which doxycycline is highly active. This use of doxycycline continues to increase, especially in penicillin-allergic patients, because animal bites are an important cause of morbidity and mortality throughout the world.

Malaria
Falciparum malaria is becoming an increasingly widespread problem. Doxycycline is certain to have a prominent role in treatment of this difficult infectious disease because it is useful in cases that are resistant to chloroquine hydrochloride (Aralen HCl).

Additional infections
Doxycycline is particularly useful in treatment of legionnaires' disease and mycoplasma and mycobacterial infections and has many advantages over the erythromycin preparations often used for these infections. Doxycycline is less expensive than erythromycin, causes fewer gastrointestinal side effects, and does not cause phlebitis when administered intravenously (2-5). Even in life-threatening legionella infections, addition of rifampin (Rifadin, Rimactane) is not needed. Doxycycline is also useful against most nontuberculous acid-fast mycobacteria (ie, Mycobacterium fortuitum, Mycobacterium chelonei).

Another disease against which doxycycline has activity is toxoplasma infection. Doxycycline has been useful in treating some cases of vancomycin (Lyphocin, Vancocin, Vancoled)­resistant enterococci (VRE) infections, although it is not active against non-VRE enterococci.

Traditional as well as new and increased uses for doxycycline are summarized in table 1 (2-6).

Table 1. Therapeutic uses of doxycycline (Doryx, Vibramycin)

Traditional uses
Actinomycosis
Amebiasis
Anthrax
Balantidiasis
Brucellosis
Chancroid
Chlamydial infection
Cholera
Gonorrhea
Granuloma inguinale
Leptospirosis
Lymphogranuloma venereum
Melioidosis
Mycoplasma pneumoniae infection
Nocardiosis
Plague
Psittacosis
Q fever
Relapsing fevers
Rickettsialpox
Rocky Mountain spotted fever
Sexually transmitted disease
Shigella infections
Sinusitis
Syphilis
Trachoma
Traveler's diarrhea
Tropical sprue
Tularemia
Typhus (louse-borne, murine, and scrub)
Ureaplasma urealyticum infection
Yaws
Zoonotic infections


New or increased uses
Animal bites
Atypical pneumonias
Chlamydial infection
Ehrlichiosis
Enterococcus infections resistant to vancomycin (Lyphocin, Vancocin, Vancoled)
Falciparum malaria resistant to chloroquine HCl (Aralen HCl)
Human granulocytic and monocytic ehrlichiosis
Legionella infections
Lyme disease
Mycobacterium chelonei infection
Mycobacterium fortuitum infection
Penicillin-resistant Streptococcus pneumoniae
Toxoplasmosis


Tips for use
Doxycycline does not cause the photosensitizing reaction that may occur with conventional tetracycline. Divalent cations, gluten products, and calcium do not materially interfere with its absorption.

Since doxycycline is a highly lipid-soluble antimicrobial, a loading dose is necessary for optimal results. Therefore, for moderate or severe infections, the usual dose, given intravenously or orally, should be doubled for 72 hours and then reduced to the usual dose (ie, 200 mg every 12 hours reduced to 100 mg every 12 hours). The entire dose (intravenous or oral) may be given once daily.

Doxycycline should be taken with food and should not be given to pregnant patients or young children.

Minocycline

Minocycline is a second-generation, long-acting tetracycline that was introduced in the same era as doxycycline. The two drugs have many common attributes: long half-life, once- or twice-daily administration, excellent bioavailability, and equivalent blood and tissue levels whether administered intravenously or orally. However, the two drugs differ in several important respects.

CNS infection
Pharmacokinetically, minocycline and doxycycline are both highly lipid-soluble. However, compared with conventional tetracycline, minocycline is ten times more lipid-soluble whereas doxycycline is only five times more lipid-soluble. The clinical importance of this characteristic is that minocycline has particularly good tissue penetration and excellent CNS penetration; although doxycycline does penetrate the CNS, it does not do so to the degree that is achievable with minocycline.

Staphylococcal infection
Minocycline's antimicrobial spectrum is very similar to that of doxycycline with one important addition: It has much more antistaphylococcal activity. Minocycline is one of the few drugs that is clinically active against MRSA infection, and it has been used successfully to treat both colonization and infection. Vancomycin is effective against MRSA infection; however, it is not effective in eliminating the carrier state.

Additional infections
Minocycline may be used to treat legionnaires' disease, Lyme disease, and zoonotic infections.

Traditional as well as new and increased uses for minocycline are summarized in table 2 (1,7-9).

Table 2. Therapeutic uses of minocycline hydrochloride (Minocin)
Traditional uses
Actinomycosis
Acute sinusitis
Amebiasis
Anthrax
Balantidiasis
Brucellosis
Chancroid
Chlamydial infections
Cholera
Gonorrhea
Granuloma inguinale
Leptospirosis
Lymphogranuloma venereum
Melioidosis
Mycoplasma pneumoniae infection
Nocardiosis
Plague
Psittacosis
Q fever
Rickettsialpox
Rocky Mountain spotted fever
Severe acne
Shigella infections
Syphilis
Trachoma
Tularemia
Typhus (louse-borne, murine, and scrub)
Yaws

New or increased uses CNS infection with susceptible organisms CNS Lyme disease Legionnaires' disease MRSA infection Staphylococcus aureus infection


CNS, central nervous system; MRSA, methicillin-resistant Staphylococcus aureus.


Tips for use
Minocycline is usually well tolerated and is an excellent choice for use in outpatients. Food and divalent cations interfere minimally or not at all with oral absorption, and photosensitizing reactions are rare.

Because of its high lipid-solubility, the drug is maintained in high concentrations in middle ear fluid; thus, it has been implicated in vestibular side effects. It should not be given to pregnant patients or young children.

TMP-SMX

TMP-SMX is a broad-spectrum antibiotic that is active against S aureus, virtually all aerobic gram-negative bacilli except Pseudomonas aeruginosa and, to a lesser extent, streptococci. It is variably active against enterococci; however, it has little or no activity against Bacteroides fragilis and other anaerobes. Many physicians do not realize that TMP-SMX covers precisely the same spectrum as the third-generation cephalosporin ceftriaxone. Therefore, when ceftriaxone is used for initial intravenous therapy, TMP-SMX is a logical and appropriate choice for transition to an oral agent.

TMP-SMX has traditionally been used to treat urinary tract infections and upper respiratory tract infections (ie, otitis, sinusitis, and bronchitis) and to prevent and treat traveler's diarrhea. Its equivalent effectiveness whether given orally or intravenously makes it an obvious choice for prolonged prophylaxis or therapy.

Pneumocystic infections
In recent years, TMP-SMX's excellent tissue penetration has made it a popular agent for certain diseases. For example, it is used extensively for prophylaxis and treatment of Pneumocystis carinii pneumonia, and it is also effective against other AIDS-associated pathogens (eg, Listeria, Nocardia). It provides protection against pneumocystic infections throughout the entire body, unlike aerosolized pentamidine isethionate (NebuPent). For this reason, extrapulmonary pneumocystosis is not found in patients after prophylactic or therapeutic regimens using TMP-SMX. The only limitation on more widespread use of TMP-SMX against pneumocystic infections is the high incidence of sulfa allergies that occurs in AIDS patients.

Nonaeruginosa pseudomonads
Another important current use of TMP-SMX is for nosocomial infections caused by nonaeruginosa pseudomonads. These pathogens are waterborne and therefore are fairly often the source of infection after irrigation-associated surgical procedures, infection in intravenous lines, and urinary tract infection. TMP-SMX provides optimal therapy against these emerging nosocomial pathogens.

Additional infections
Because of its excellent penetration into the cerebrospinal fluid and brain, TMP-SMX is being used increasingly to treat listerial and nocardial infections. Another important current use is for gram-negative bacteremia (when P aeruginosa is not an issue) because of the drug's unusually broad spectrum of activity. (TMP-SMX is useful even if initial therapy was with a third-generation cephalosporin or a combination regimen.) TMP-SMX is being used in regimens that take advantage of its long serum half-life and is being combined with metronidazole to provide cost-effective therapy for intra-abdominal or pelvic sepsis.

Traditional as well as new and increased uses for TMP-SMX are summarized in table 3 (10-14).

Table 3. Therapeutic uses of trimethoprim-sulfamethoxazole (Bactrim, Cotrim, Septra)

Traditional uses
Acute sinusitis
Aeromonas infections
Brucellosis
Bordetella pertussis infection
Chancroid
Chronic bronchitis
Chronic granulomatous disease
Citrobacter infections
Enteric fevers
Enterobacter infections
Escherichia coli infection
Falciparum malaria resistant to chloroquine HCl (Aralen HCl)
Haemophilus influenzae infection
Hidradenitis suppurativa
Lymphogranuloma venereum
Melioidosis
Neisseria gonorrhoeae infection
Otitis media
Plesiomonas infections
Proteus infections
Providencia infections
Salmonella infections
Serratia infections
Shigella infections
Staphylococcus aureus infection
Streptococcus pneumoniae infection
Traveler's diarrhea
Urinary tract infection
Vibrio cholerae infection


New or increased uses
Gram-negative bacteremias, excluding Pseudomonas aeruginosa
Gram-negative meningitis caused by susceptible organisms
Legionella infections
Listeria infections
Nocardia infections
Pneumocystis carinii infection
Pseudomonas cepacia infection
Xanthomonas maltophilia infection


Tips for use
TMP-SMX should not be used in patients who are pregnant or have a known or suspected sulfa allergy or in neonates.

Metronidazole

Metronidazole is an established component in cost-effective antianaerobic treatment of intra-abdominal and pelvic infections, especially when combined with a once-a-day antibiotic, such as ceftriaxone or levofloxacin (Levaquin). However, it should not be added to drugs that have a high degree of activity against B fragilis, such as imipenem-cilastatin (Primaxin), ampicillin sodium­sulbactam sodium (Unasyn), piperacillin sodium­tazobactam sodium (Zosyn), or meropenem (Merrem IV), since it has no advantage and adds needless cost.

Clostridium difficile diarrhea
Widespread administration of antibiotics has resulted in a growing incidence of diarrhea and colitis caused by C difficile infection, an infection for which metronidazole is commonly used. Thus, interestingly, metronidazole can be both a cause of and a cure for this infection.

Oral metronidazole and vancomycin have been shown to be equally efficacious in treatment of C difficile diarrhea. I have not found metronidazole to be as consistently effective as vancomycin for this use, but it is less expensive.

Intravenous metronidazole is the mainstay of treatment for established C difficile colitis because it penetrates into the mucosa of the intestine. Intravenous vancomycin does not penetrate the gastrointestinal tract in sufficient concentrations to be useful in this serious situation.

Traditional as well as new and increased uses for metronidazole are summarized in table 4 (15-19).

Table 4. Therapeutic uses of metronidazole (Flagyl, Protostat)

Traditional uses
Bacteroides fragilis infection
Entamoeba histolytica infection
Hepatic amebiasis
Intra-abdominal infections
Pelvic infections


New or increased uses
Antibiotic-associated colitis
Antibiotic-associated diarrhea
Clostridium difficile infection


Tips for use
Metronidazole causes virtually no allergic hypersensitivity reactions. It should not be given to pregnant patients.

Summary

Because of its intracellular mechanism of activity, excellent safety profile, and low cost, doxycycline is one of the most extensively used antibiotics in the world, and its use will increase as new applications are found. One of its most important uses is in treatment of bacterial community-acquired pneumonias, but it is also useful against atypical pneumonias and sexually transmitted disease. As zoonotic infections continue to increase around the world, doxycycline will occupy an increasingly prominent place.

Minocycline shares doxycycline's favorable attributes and also has tissue-penetration characteristics that are important when therapeutic alternatives are few, as in MRSA.

TMP-SMX is widely used to treat urinary and respiratory tract infections and for prophylaxis and treatment of P carinii infection. As the AIDS epidemic continues, its use will continue to grow, because it is also effective against other pathogens associated with AIDS. TMP-SMX is relatively underused for treating gram-negative bacteremias, especially nosocomial infections caused by nonaeruginosa pseudomonads.

Metronidazole is a cost-effective antianaerobic component in treatment of intra-abdominal and pelvic infections, especially when it is combined with a once-a-day antibiotic.

References

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Dr Cunha is chief, infectious disease division, Winthrop-University Hospital, Mineola, New York, and professor of medicine, State University of New York at Stony Brook School of Medicine. Correspondence: Burke A. Cunha, MD, Infectious Disease Division, Winthrop-University Hospital, 259 First St, Mineola, NY 11501.


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