Drug repositioning, a new alternative in infectious diseases.

Dear Editor:

There has been a significant decrease in the number of approved antibiotics in the last two decades, and in parallel, a steady increase of multidrug resistant bacteria (MDR) has been occurring. Thus, MDR have become a global issue of public health, and with this threat, the challenge to develop new antibiotics has emerged in all areas: governmental, scientific, and the private pharmacological industry. In this sense, drug repositioning has arisen as an alternative approach for the faster identification of drugs that are effective against infectious diseases.

The expressions “Drug repositioning” and “drug repurposing” was first described by Ashburn and Thor (2004) in their paper “Drug repositioning: identifying and developing new uses for existing drugs”. According to the authors, this is the process to find new uses for clinically approved drugs, and this is also known as redirecting and reprofiling.

Several studies have signalled that drug repositioning has advantages compared to the traditional way of seeking for active substances,[2], [4], [5], [6], [7] since pharmacological, toxicological and bioavailability data, among others, are already available. Thus, less time is spent in their development, leading to a significant reduction in costs, and it proves to be a preferred and advantageous alternative strategy to discover drugs more quickly. Other encouraging data are the success rates for repositioned drugs, which are higher when compared to new drugs, reaching 30% in the last few years. Also, together with the positive aspects of repositioning is its recent approval by the Food and Drug Administration (FDA).

Comparing repurposing and use off-label, there is a similarity between these practices: a new indication of the drug, other than the usual one. However, the use outside the label goes beyond this, since it may include different age groups, dosage or route of administration. Although this is considered a legal and common application, it is often performed in the absence of adequate scientific data, and may expose patients to unrestricted and ineffective experimentation of drugs with unknown health risks.

In Table 1, we present a summary of the repositioning of drugs for antibacterial treatment: examples of studies that investigate the antimicrobial activities of several pharmacological classes, including psychotropics, local anaesthetics, tranquilizers, cardiovascular drugs, antihistamines, anti-inflammatories, being these called “non-antibiotic drugs”.[10], [11], [12], [13], [14]

Table 1

Studies of repositioning non-antibiotic drugs with antibiotic effect.

Drug	Original indication	New indication		Reference
AAS	Non-steroidal Anti-inflammatory	MRSA		Chan et al., 201710
Amitriptiline	Antidepressant		Staphylococcus spp.Enterococcus faecalisMicrococcus luteusBacillus spp.Shigella spp.Salmonella spp.Vibrio choleraeVibrio parahaemolyticusEscherichia coliKlebsiella pneumoniaPseudomonas spp.Proteus spp.Citrobacter spp.Providencia spp. Enterobacter cloacaeHafnia spp.Lactobacillus sporogenesMicrococcus flavusVibrio cholerae	Mandal et al., 201011Muthukumar and Janakiraman, 201422
Auranofin	Rheumatoidarthritis		MRSA	Harbut et al., 201523
Chlorpromazine	Anti-psychotic		Corynebacterium urealyticumEscherichia coliKlebsiella pneumoniaeCitrobacter freundiiMorganella morganiiAcinetobacter baumanniiHaemophilus influenzaeMoraxella catarrhalisCampylobacter jejuniStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaeStreptococcus pyogenesStreptococcus agalactiaeEnterococcus faecalisClostridium perfringensClostridium difficileBacreroides fragilisPrevotella spp.Brucella spp.	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 199612Munoz-Bellido, Munoz-Criado and García-Rodríguez, 200013
Clofazime	Tuberculosis		Mycobacterium leprae	Naylorand Schonfeld, 201424
Clomipramine	Antidepressant		Serratia marcescensMorganella morganiiAcinetobacter baumanniiHaemophilus influenzaCampylobacter jejuniStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaeStreptococcus pyogenesStreptococcus agalactiaeEnterococcus faecalisClostridium perfringensClostridium difficileBacteroides fragilisPrevotella spp.Brucella spp.	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 200013
Disulfiram	Alcoholism		MRSAPseudomonas aeruginosa	Phillips et al., 199125Velasco-García et al., 200626
Ebselen	Neuroprotector		MRSAVRSAStreptococcus spp.Enterococcus spp.	Thangamani, Younis e Seleem 2015[6], [7]
Escitalopram	Antidepressant		Klebsiella pneumoniaeProteus mirabilisEnterobactor cloacaeStaphylococcus aureus Pseudomonas aeruginosa	Akilandeswari, Ruckmani and Ranjith, 201327
Fluoxetine	Antidepressant		Corynebacterium urealyticumHaemophilus influenzaeMoraxella catarrhalesCampylobacter jejuni	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 199612Munoz-Bellido, Munoz-Criado and García-Rodríguez, 200013
Ibuprofen	Non-steroidalAnti-inflammatory		MRSA	Chan et al., 201710
Iproniazid	Antidepressant		Mycobacterium tuberculosis	López-Muñoz and Alamo, 200928
Loperamide	Diarrhoea		Salmonella enterica	Ejim et al., 201116
Sertraline	Antidepressant		Corynebacterium urealyticumEscherichia coliKlebsiella pneumoniaeEnterococcus cloacaeCitrobacter freundiiSerratia marcescensProteus mirabilisProteus vulgarisMorganella morganiiAcinetobacter baumanniiHaemophilus influenzaeMoraxella catarrhalisCampylobacter jejuniStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaeStreptococcus pyogenesStreptococcus agalactiaeEnterococcus faecalisClostridium perfringensClostridium difficileBacteroides fragilisPrevotella spp.Brucella spp.Staphylococcus spp.Micrococcus luteusBacillus subtilisShigella spp.Salmonella spp.Vibrio choleraeVibrio parahaemolyticusPseudomonas aeruginosaProvidencia spp.Lactobacillus sporogenes	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 199612Munoz-Bellido, Munoz-Criado and García-Rodríguez, 200013Samanta et al., 201229
Paroxetine	Antidepressant		Corynebacterium urealyticumHaemophilus influenzaeMoraxella catarrhalesCampylobacter jejuni	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 199612Munoz-Bellido, Munoz-Criado and García-Rodríguez, 200013
Risperidone	Anti-psychotic		Corynebacterium urealyticum	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 199612Munoz-Bellido, Munoz-Criado and García-Rodríguez, 200013
Simvastatin and Atorvastatin	Cardiovascular diseases		Staphylococcus epidermidisStaphylococcus aureusSalmonella spp.Pseudomonas aeruginosaMicrococcus luteusKlebsiella pneumoniaeEscherichia coliEnterococcus faecalisEnterobacter hormaecheiBacillus cereusStaphylococcus spp.Staphylococcus coagulase negativeMRSA	Rampelotto et al., 2018 in press14Graziano et al., 201530
Thalidomide	Anti-nausea		Mycobacterium leprae	Paravar and Lee, 200831

MRSA, methicillin-resistant Staphylococcus aureus; VRSA, vancomycin-resistant Staphylococcus aureus; AAS, acetylsalicylic acid.

The treatment of chronic bacterial infections in immunocompromised patients with synergistic drug combinations is well established, and this procedure has been used for several years. These synergistic combinations are used because of three main advantages: expansion of the antibiotic spectrum[16], [17]; overcoming resistance; and decrease of resistance to antibiotics through their careful use.[19], [20], [21]

Since repositioned non-antibiotic drugs have shown antibiotic effects among themselves as well as when used together with antimicrobials, these combinations presently consist of a useful option to overcome the problem of weak activity of individual drugs.[2], [10], [16]

Based on the several studies presented, it can be inferred that the repositioning of non-antibiotic drugs with known toxicity profiles represents a promising alternative for the treatment of bacterial infections. Nevertheless, it is a consensus in the global scientific community that it is only the starting point, and additional studies regarding mechanisms of action and in vivo studies, among others, are vital for the safe use of these drugs.

Conflicts of interest

The authors declare no conflicts of interest.