A History and Future of Tetracyclines and Their Effectiveness

A History and Future of Tetracyclines and Their Effectiveness

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Imagine this scenario if you will: you are on the outskirts of a city in Asia. People are fleeing by car, on foot, and on bicycle, some wearing masks, others holding pieces of cloth over their faces. The military checkpoints on the road are overwhelmed by the mass hysteria. Schools have been closed, and hospitals are on emergency standby for sick and dying patients. Pharmacies across the country have been cleaned out of the broad spectrum antibiotic known to treat the disease that is threatening to engulf the city.

Does this sound like a scene from a Hollywood movie? It may, but it was also what took place in 1994 in Surat, India, during an outbreak of pneumonic plague (Yersinia pestis). The drug that everyone was seeking to ward off death wasn’t some fancy new-fangled gorillacillin. It was tetracycline, an inexpensive and decades-old medication used to treat a host of common ailments.

Discovery of Tetracyclines

Chlorotetracycline (Aureomycin) was first discovered in 1945 by Dr. Benjamin Duggar of Lederle Laboratories, isolated from Streptomyces aureofaciens bacteria dwelling in soil. Terramycin followed soon after, isolated from S. rimosus. It was Robert B. Woodward of Harvard who first determined the structure of oxytetracycline, allowing Pfizer to produce tetracycline as a synthetic pharmaceutical product.

Little did these pioneering scientists know that tetracycline would go on to become one of the most used antibiotics of all time. It is still on the World Health Organization’s list of Most Essential Medicines. Second and third generation versions of tetracycline were later developed, but first generation tetracycline is still the primary drug used to treat a number of conditions.

Indications and Dosing

The list of indications for tetracycline and its derivatives is enormous, as it encompasses infections of the upper and lower respiratory tract, skin and soft tissue, and urinary tract. It is often used first line for Lyme disease, Rocky Mountain spotted fever (Rickettsia), psittacosis, chlamydia, and mycoplasma pneumoniae, as well as for more rare illnesses, such as plague and anthrax.

Most people know tetracycline best as the treatment of choice for acne, and it is used now for rosacea as well. Tetracycline is also sometimes used to augment other antibiotics and is used in place of certain antimicrobials when allergies or other tolerability issues arise.

The usual oral dose of tetracycline is  500 mg b.i.d. or 250 mg q.i.d. Doses of  500 mg q.i.d. may be needed for severe infections, infections unresponsive at lower doses, and certain diseases such as brucellosis and syphilis.

It is not recommended to give tetracycline to children under eight years of age. For children older than eight years of age, the usual dose is 10 to 20 mg/lb (25 to 50 mg/kg) body weight divided in four equal doses.

For long-term treatment of moderate to severe acne, the dosage is 1 gram per day in divided doses. The dosage can be reduced, if improvement is observed, to approximately 125 mg to 500 mg per day or every other day.

Oral tetracycline is usually given in capsule or tablet form, but it can compounded for liquid administration, as well (ideal for pediatric patients who may need smaller doses and improved palatability).

Members of the tetracycline family are also administered by IV and via topical liquid, cream, or ointment from a compounding pharmacy. Topical applications of tetracycline have gained popularity with dermatologists and infectious disease specialists, as they reduce the systemic effects of the drug, eliminate concern about drug-drug interactions, and target the area of infection more effectively.

During a recent tetracycline shortage, compounding pharmacies were often the only way to obtain the drug, and many physicians, especially dermatologists, relied on them to continue to provide treatment their patients needed. During any drug shortage or allocation period, turning to a compounding pharmaceutical provider may yield access to a drug believed to be unobtainable. In the case of tetracycline, it was a packaging issue with one of the few manufacturers, yet compounding pharmacies could still get the raw ingredients to make prescriptions. The FDA maintains an up-to-date list of all national drug shortages.

Tetracyclines do oxidize rather easily when exposed to light and air (depending on the formulation). Oxidized tetracyclines can lose potency and cause bluish-black pigmentation in patients’ skin. Patients should be cautioned to store their medications in ways that preserve their integrity. They should also be warned that tetracyclines should never be used past their expiration dates. While most other drugs simply lose their efficacy once past expiry, tetracyclines degrade into hepatotoxic compounds that can cause liver damage or failure.

Side Effects and Drug Interactions

In addition to the usual hypersensitivity and gastric upset that can be experienced with all antibiotics, tetracyclines can have a caustic effect on the esophagus. Patients taking oral tetracyclines should not lie down for one hour after taking their medication, and they should be sure to drink a full glass of water with it.

The two most notable and common side effects of tetracyclines are photosensitivity (worse with second generation tetracyclines) and bone penetration, which can cause tooth staining in developing teeth and fetal bone abnormalities. Thus, they are not given to pregnant women, nursing mothers, or children under the age of eight, unless no other agent is possible.

Patients on anticoagulant therapy may experience slowed protimes, and they may need to adjust their therapy accordingly. When tetracycline is taken with methoxyflurane, fatal renal toxicity may result, so the two should never be taken concurrently. While all tetracyclines carry a warning about rendering oral contraceptives less effective, minocycline has a higher rate of metabolism through the liver and would therefore have the greatest risk of CYP450 competition.

Tetracyclines bind with aluminum, calcium, magnesium, iron, zinc, and sodium bicarbonate. Therefore, they should not be ingested with these elements, including over-the-counter antacids and dairy products, lest they be rendered less effective.

Mechanism of Action and Resistance

Tetracycline binds to the 30S subunit of bacterial ribosomes, where it blocks attachment of charged aminoacyl-t-RNA to the ribosomal A site. This inhibits protein synthesis by preventing the production of new amino acids in the peptide chain. Therefore, it is bacteriostatic.

Tetracycline has a broad spectrum of activity, which is one of the reasons it has remained so popular for so many years. The only major intrinsic resistance is to Pseudomonas aeruginosa and Proteus spp.

Unfortunately, acquired resistance has developed to tetracycline, due to widespread use in both humans and livestock. An efflux pump is the mechanism by which resistance occurs. Changes to the bacterial cell envelope do not allow transport of the drug into the cell, and sufficient inhibitory concentrations are unable to accrue in the cytoplasm.

Because of the erosion of tetracycline’s activity, use of cultures and susceptibility testing is recommended. Resistance can vary widely between institutions and disease states.

Second and Third Generation Tetracyclines

No new first generation tetracycline has been approved by the FDA since 1971. However, the ability to create semisynthetic tetracyclines by chemically transforming isolated natural components allowed for the introduction of next generation tetracyclines. Doxycycline was developed and approved in 1967, and Minocycline was developed in 1967 and approved in 1972.

The hope with the new generation of tetracyclines was to get around some of the developing resistance to the first generation. While this essentially bought some time for improved activity, it wasn’t until the introduction of third generation tetracyclines (glycylcyclines) that the efflux pump was thwarted. Meanwhile, second generation tetracyclines were more lipophilic, which allowed for better absorption, and had slightly improved pharmacokinetics to garner a few new indications.

The release of tigecycline in 2005 saw an all new approach to the drug family.  Tigecycline avoids the acquired resistance efflux pump by binding in a different orientation to the ribosome than original tetracycline. Although it still has no activity against Pseudomonas, it has good activity against resistant pathogens, including MRSA (methicillin resistant Staphylococcus aureus) and Acinetobacter spp. Tigecycline is available only in intravenous formulation and is indicated for complicated intra-abdominal infections and skin and soft tissue infections, as well as community-acquired bacterial pneumonia.

Although tigecycline had good efficacy in clinical trials and in early use, it also had a higher mortality rate than its comparators, for unknown reasons. It now carries a black box warning that it should be given only when no other drug is an option.

Tetracyclines Today

Even with the resistance that has been seen with tetracyclines, they are still one of the most relied on antibiotics around the globe. In order to maintain the efficacy they have, we offer the following suggestions:

  1. Adopt a policy of prudent use for all anti-infectives. Recent campaigns to reduce automatic use of antibiotics for otitis media, for example, have been successful at letting natural immunity clear infections in many patients.
  2. Reduce use of antibiotics in animals, especially livestock raised for food. There are actually several mechanisms by which resistance could be generated by giving tetracycline to animal populations, and they can cause multi-drug resistance, not just lowered efficacy of tetracycline.
  3. Advocate for continued research into new alternatives. Preserving tigecycline for emergency situations will prolong its efficacy, but with a drug as effective as this against MRSA, it would be helpful to know the specifics of its higher mortality rate so it could gain greater use. Also, the Federal Government needs to address the lack of incentives for pharmaceutical companies to produce new antibiotics. It is simply too costly to research and bring drugs to market when they are only used for short time periods, versus drugs that will be used for years (e.g., antihypertensives, antidepressants, etc.).
  4. Develop better national and global strategies for dealing with dangerous outbreaks. Although the plague in India has passed, recent situations with SARS and Ebola have shown that we have grown no better at managing large scale health crises. An influenza epidemic like those that took place around World War I could cripple the national infrastructure and spread quickly to global disaster. The plague outbreak in India resulted in losses of hundreds of millions of dollars due to trade embargoes and effects on tourism during Diwali. The actual number of deaths in Surat? Less than 100.

Pharmaceutica North America is here as a resource to you to help you find quality compounding pharmaceutical ingredients and to guide you in the use of compounded medications. Contact us today to obtain quality medication ingredients for your patients’ needs.

 

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