Drug of last resort explained

Drug of last resort should not be confused with Heroic medicine.

A drug of last resort (DoLR), also known as a heroic dose,^[1] is a pharmaceutical drug which is tried after all other drug options have failed to produce an adequate response in the patient. Drug resistance, such as antimicrobial resistance or antineoplastic resistance, may make the first-line drug ineffective, especially in case of multidrug-resistant pathogens and tumors. Such an alternative may be outside of extant regulatory requirements or medical best practices, in which case it may be viewed as salvage therapy.

Purposes

The use of a drug of last resort may be based on agreement among members of a patient's care network, including physicians and healthcare professionals across multiple specialties, or on a patient's desire to pursue a particular course of treatment and a practitioner's willingness to administer that course. Certain situations such as severe bacterial related sepsis or septic shock can more commonly lead to last resorts.

Therapies considered to be drugs of last resort may at times be used earlier in the event that an agent would likely show the most immediate dose-response related efficacy in time-critical situations such as high mortality circumstances. Many of the drugs considered last resorts fall into one or more of the categories of antibiotics, antivirals, and chemotherapy agents. These agents often exhibit what are considered to be among the most efficient dose-response related effects, or are drugs for which few or no resistant strains are known.

With regard to antibiotics, antivirals, and other agents indicated for treatment of infectious pathological disease, drugs of last resort are commonly withheld from administration until after the trial and failure of more commonly used treatment options to prevent the development of drug resistance. One of the most commonly known examples of both antimicrobial resistance and the relationship to the classification of a drug of last resort is the emergence of Staphylococcus aureus (MRSA) (sometimes also referred to as multiple-drug resistant S. aureus due to resistance to non-penicillin antibiotics that some strains of S. aureus have shown to exhibit). In cases presenting with suspected S. aureus, it is suggested by many public health institutions (including the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) in the United States) to treat first with empirical therapies for S. aureus, with an emphasis on evaluating the response to initial treatment and laboratory diagnostic techniques to isolate cases of drug resistance.

Due to the possibility of potential severe or fatal consequences of resistant strains, initial treatment often includes concomitant administration of multiple antimicrobial agents that are not known to show cross-resistance, so as to reduce the possibility of a resistant strain remaining inadequately treated by a single agent during the evaluation of drug response. Once a specific resistance profile has been isolated via clinical laboratory findings, treatment is often modified as indicated.

Vancomycin has long been considered a drug of last resort, due to its efficiency in treating multiple drug-resistant infectious agents and the requirement for intravenous administration. Recently, resistance to even vancomycin has been shown in some strains of S. aureus (sometimes referred to as vancomycin resistant S. aureus (VRSA) or vancomycin intermediate-resistance S. aureus (VISA)) often coinciding with methicillin/penicillin resistance, prompting the inclusion of newer antibiotics (such as linezolid) that have shown efficacy in highly drug-resistant strains. There are also strains of enterococci that have developed resistance to vancomycin referred to as vancomycin resistant enterococcus (VRE).

Agents classified as fourth-line (or greater) treatments or experimental therapies could be considered by default to be drugs of last resort due to their low placement in the treatment hierarchy. Such placement may result from a multitude of considerations, including greater efficacy of other agents, socioeconomic considerations, availability issues, unpleasant side effects or similar issues relating to patient tolerance. Some experimental therapies might also be called drugs of last resort when administered following the failure of all other currently accepted treatments.

Although most of the notable drugs of last resort are antibiotics or antivirals, other drugs are sometimes considered drugs of last resort, such as cisapride.^[2]

Examples

Antimicrobials

• Aminoglycosides — their use is extremely restricted due to risk of hearing loss and kidney damage.
• Amphotericin B — used for life-threatening fungal infections and primary amoebic meningoencephalitis;^[3] its side effects are often severe or potentially fatal.
• Carbapenems (such as imipenem/cilastatin) — used as a drug of last resort for a variety of different bacterial infections.
• Ceftobiprole and ceftaroline — fifth-generation cephalosporins active against methicillin-resistant Staphylococcus aureus (MRSA); use is limited to prevent development of drug resistance.
• Cefiderocol — a cephalosporin used to treat complicated urinary tract infections (cUTI) caused by multi-drug resistant Gram-negative bacteria in patients with limited or no alternative options.
• Chloramphenicol — formerly first-line therapy for Rocky Mountain spotted fever (until doxycycline became available).^[4] Also first-line therapy (used topically) for bacterial conjunctivitis, and systemically for meningitis when allergies to penicillin or cephalosporin exist. Unacceptably high risk of irreversible, fatal aplastic anemia and gray baby syndrome causes intravenous chloramphenicol to be a drug of last resort.^[5]
• Colistin — used against certain life-threatening infections, such as those caused by Pseudomonas; carries risk of kidney and nerve damage.
• Fostemsavir (an HIV attachment inhibitor) and lenacapavir (an HIV capsid inhibitor) are indicated in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations.^{[6] [7]}
• Melarsoprol — a highly toxic antiprotozoal typically reserved for use only in late stages of the T. b. rhodesiense type of African trypanosomiasis, wherein it remains the only treatment. Its toxicity often results in polyneuropathy and reactive encephalopathy, resulting in death in around 5% of patients.^[8]
• Linezolid — use is limited due to high cost and risk of vision loss or myopathy (due to mitochondrial damage).
• Tigecycline — used to kill Acinetobacter and Legionella species; this drug is limited by high cost and risk of liver injury.

Other drugs

• Alosetron — used in the management of severe chronic diarrhea-predominant irritable bowel syndrome (IBS-D) in females not responsive to conventional therapy. Its use is restricted due to serious gastrointestinal adverse reactions, e.g. ischemic colitis and complications of constipation.^[9]
• Cisapride — used for severe gastroesophageal reflux disease (GERD); carries risk of heart arrhythmias.
• Clomethiazole — a sedative/hypnotic agent used in the treatment of alcohol withdrawal when benzodiazepines are not effective.
• Clozapine — used in treatment-resistant schizophrenia not responsive to at least two different antipsychotics; the main reason for such restriction is agranulocytosis and other severe side effects including seizures and myocarditis.^[10]
• Felbamate — an anticonvulsant used in refractory epilepsy. Its use is associated with an increased risk of aplastic anemia and liver failure.^[11]
• Isotretinoin — when all topical treatments or antibiotics against acne have failed, many dermatologists resort to isotretinoin, which is an oral treatment that permanently dries out the sebum production of the skin and is often a permanent solution against acne. It can cause severe nosebleeds, causes birth defects when taken while pregnant, is said to cause depression, hair loss and can permanently dry out the skin all over the body and is therefore not the first treatment.^[12]
• Levosimendan — used in acutely decompensated severe chronic heart failure in situations where conventional therapy is not sufficient.
• Oral minoxidil for hypertension,^{[13] [14]} however topical minoxidil is a first-line drug for hair loss.
• Monoamine oxidase inhibitors — due to potentially lethal dietary and drug interactions which may trigger hypertensive crisis and/or serotonin syndrome,^[15] they are generally used only when other classes of antidepressants (e.g., SSRIs or SNRIs) don't work.^{[16] [17] [18]}
• Thalidomide — withdrawn in 1961 owing to widespread incidence of severe birth defects (phocomelia or tetraamelia) after prenatal use by pregnant women, US Food and Drug Administration approved thalidomide for erythema nodosum leprosum (ENL) in 1998, and 2008 for new cases of multiple myeloma (administered with dexamethasone). A large "off-label" business in thalidomide began for rare cancers even while it was only FDA-approved for erythema nodosum leprosum.
• Tolcapone — used in patients with Parkinson's disease who are not appropriate candidates for other adjunctive therapies. Use is restricted due to hepatotoxicity.
• Vigabatrin — used only in extreme treatment-resistant epilepsy due to the risk of permanent vision loss.^[19]

See also

• Heroic measure

Notes and References

1. Book: The American Heritage Stedman's Medical Dictionary. registration. Houghton Mifflin Company. 2004. 9780618428991.
2. FDA tells doctors to use heartburn drug as last resort . BMJ . 320 . 7231 . 336 . 5 February 2000. 1173548. 10.1136/bmj.320.7231.336. Ciment . J. .
3. Grace. Eddie. Asbill. Scott. Virga. Kris. Naegleria fowleri: Pathogenesis, Diagnosis, and Treatment Options. Antimicrobial Agents and Chemotherapy. November 2015. 59. 11. 6677–6681. 10.1128/AAC.01293-15. 26259797. 4604384.
4. Web site: Rocky Mountain Spotted Fever (RMSF) - Symptoms, Diagnosis, and Treatment . US Centers for Disease Control . 12 March 2014.
5. RMSF
6. Web site: June 2020 . Rukobia (fostemsavir) Extended-Release Tablets, for Oral Use. Full Prescribing Information. . U.S. Food and Drug Administration.
7. Web site: December 2022 . Sunlenca (lenacapavir) Tablets, for Oral Use; Sunlenca (lenacapavir) Injection, for Subcutaneous Use. Full Prescribing Information. . U.S. Food and Drug Administration.
8. Web site: Pepin . J . Infectious Disease & Antimicrobial Agents - Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (African Trypanosomiasis) . antimicrobe.org . 27 July 2024 . https://web.archive.org/web/20240207082619/http://www.antimicrobe.org/b54.asp . 7 February 2024 . 2014 . live.
9. Web site: Lotronex (alosetron hydrochloride) Tablets. Full Prescribing Information. Prometheus Laboratories Inc., 9410 Carroll Park Drive, San Diego, CA 92121. 2019-12-21. 2016-02-22. https://web.archive.org/web/20160222142743/https://www.lotronex.com/hcp/_docs/Lotronex_PI.pdf. dead.
10. Schulte. P.. 25525638. What is an adequate trial with clozapine?: therapeutic drug monitoring and time to response in treatment-refractory schizophrenia.. Clinical Pharmacokinetics. 2003. 42. 7. 607–618. 12844323. 10.2165/00003088-200342070-00001.
11. Web site: Felbamate. MedlinePlus : U.S. National Library of Medicine. 19 May 2013.
12. Costa. Caroline S. Bagatin. Ediléia. Martimbianco. Ana Luiza C. da Silva. Edina MK. Lúcio. Marília M. Magin. Parker. Riera. Rachel. 2018-11-24. Oral isotretinoin for acne. The Cochrane Database of Systematic Reviews. 2018. 11. CD009435. 10.1002/14651858.CD009435.pub2. 1469-493X. 6383843. 30484286.
13. An Americal View of Minoxidil — a Powerful 'Last Resort' Antihypertensive. InPharma. March 1, 1980. 229. 1. 2. 10.1007/BF03292651. 198213029.
14. Book: Mann, Samuel J.. Hypertension and you : old drugs, new drugs, and the right drugs for your high blood pressure. 2012. Rowman & Littlefield Publishers. Lanham, Md.. 978-1-4422-1517-7. 90. registration.
15. Grady. MM. Stahl. SM. Practical Guide for Prescribing MAOIs: Debunking Myths and Removing Barriers. CNS Spectrums. 26 April 2012. 17. 1. 2–10. 10.1017/S109285291200003X. 22790112. 206312008.
16. Book: Turkington. C. Harris. JR. The Encyclopedia of the Brain and Brain Disorders. limited. 2009. Facts On File. New York. 978-0816063956. 238. 3rd.
17. Krings-Ernst. Ilana. Ulrich. Sven. Adli. Mazda. Antidepressant Treatment with MAO-Inhibitors During General and Regional Anesthesia: a Review and Case Report of Spinal Anesthesia for Lower Extremity Surgery Without Discontinuation of Tranylcypromine. International Journal of Clinical Pharmacology and Therapeutics. 1 October 2013. 51. 10. 763–70. 10.5414/CP201898. 23993253.
18. Web site: Marplan (isocarboxazid) Tablets. Full Prescribing Information. Validus Pharmaceuticals. 22 May 2017. 2, 5. 18 August 2017. https://web.archive.org/web/20170818214332/http://marplan.com/wp-content/uploads/sites/6/2014/06/marplan-prescribing-info.pdf. dead.
19. Web site: Sabril (vigabatrin) Tablets for Oral Use, Powder for Oral Solution. Full Prescribing Information. Lundbeck.