Combination Therapy: New Approach To Cure Invasive Fungal Infections

Shweta Singh, Zeeshan Fatima and Saif Hameed* Amity Institute of Biotechnology, Amity University Haryana, Gurgaon (Manesar) - 122413

2017-04-06 09:00:52



Fungi are among the most versatile group of microorganisms which exists as a normal part of microflora in the surroundings and within the humans but it can cause mild to severe deadly infections. In this era, the increasing rate of mortality is due to the upcoming cases of invasive fungal infections (IFI) has attracted considerable interest for researchers and henceforth resulting in a major global health problem. When fungi invade the deep tissues and enter in the blood it causes IFI which are very hard to treat and leads to prolonged illness. The most prevailing IFI are caused by Candida species known as candidiasis and particularly Candida albicans, as they are opportunistic fungi which become pathogenic in immunocompromised patients. The cutaneous infections are although treatable in comparison with the IFI.

The conventional drugs belonging to the class of azoles, polyenes, allylamines and echinocandins are available in the market for the antifungal treatment. But due to the prolonged use of drugs, there is emergence of drug resistance due to which the same drugs are now ineffective. Hence there is an urgent need to either search for newer drugs or enhance the efficiency of current antifungal drug regimen. Since, the introduction of new drugs from labs to clinics is a cumbersome and time consuming process, working towards later option is more feasible. One of the most promising such approach is the use of multiple drugs for the treatment of IFI (Fig. 1). Traditionally, there is a practice to use a single drug for the infections, but due to the failure of the single drug, use of multiple drugs is followed by a method known as combination drug therapy (CDT).


Nowadays, CDT is becoming a popular and promising therapy for combating IFI. It focuses on using the best combination of drugs and reducing the side effects of the combined drugs at the same time. The potential of inhibiting the growth of the microorganism by any drug is calculated in terms of minimum inhibitory concentration (MIC). The degree of synergy for the combined drugs is expressed in terms of fractional inhibitory concentration index (FIC). FIC is the MIC of drugs in combination divided by the MIC of drug acting alone. The range from 0.5 to 4 is used to define additively results in interactions in most combination studies of antifungal agents. The possible outcome of the combination therapy could be:

1) Synergistic effect: When the interaction of the drugs result in the increase in the effects of one or both the drugs then it is called synergistic effect. In other words 1+1 becomes greater than 2. The FIC index for synergistic effect should be less than 0.5. The recently studied combination of drugs which shows synergy are:

·         Terbinafine and azoles which are found to inhibit the ergosterol synthesis targeting the cell membrane.

·         Azoles and polyenes which are inhibiting the cell membrane.

·         Echinocandins, azoles and polyenes where polyenes causes cell lysis, echinocandins are known to destroy fungal cell wall, whereas azoles impairs the cell membrane.

2) Antagonistic effect: When the interaction of the drugs result in the decrease of the individual effects of one or both the drugs then it is called antagonistic effect. In other words 1+1 becomes less than 2. The recently studied combination of drugs which shows antagonism are:

·         Azoles inhibit the ergosterol synthesis whereas, it is important for polyenes to act as an antifungal.

·         Azoles acts on ergosterol synthesis for which the action of amphotericin B becomes dysfuntional.

3) Additive effect: When the addition of the compound to the drug results in the increase in the antifungal effect, it is said to be additive effect. In other words 1+1 is only equal to 2.


CDT against Candida infections

The combination of azoles drugs with tacrolimus (FK506), cyclosporine A, amiodarone and retigeric acid B has shown promising results against C. albicans strains. In a recent study, it has been shown that the combination of micafungin, ethanol and doxycycline inhibits C. albicans and mixed C. albicans–Staphyloccoccus aureus biofilms. The monotherapy treatment of invasive Candida infections with flucytosine leads to the occurrence of resistant species. This issue has been overcome by adding the amphotericin B to flucytosine. Even the use of combination of caspofungin with amphotericin B can be used for the treatment of persistent candidemia in a small group of neonates. Ibuprofen is a known potent anti-inflammatory and analgesic drug which shows synergy with fluconazole and blocks efflux pumps of Candida, hence can be used for azole resistant candidiasis. Similarly posaconazole has been used in combination with other antifungal agents..The Candida biofilms are very hard to treat and are becoming a major cause of mortality in the catheter related blood stream infections in hospital acquired infections. The medical indwelling devices used like catheters are preoccupied by fungal growth in the form of biofilm. The use of single drugs is not sufficient to cure the biofilms. The use of combination of lipopeptide bacillomycin D with amphotericin B has shown promising result for inhibiting the Candida biofilms. The CDT is not successful for all the sites in the body. Like, CDT is not recommended for the treatment of candidemia. Contrary, CDT is considered useful for the candidal endocarditis, endophthalmitis, hepatosplenic candidiasis, meningitis and peritonitis.


Parameters for combination therapy

The use of more than two drugs is dependent on many factors. Many parameters have been studied to combine the drugs for the treatment. It is important to study the synergistic, antagonistic nature of the drugs, so that the best combination is chosen. The antifungal drugs which are used have different mechanisms of action. Azoles (itraconazole, fluconazole) alter the cell membrane of fungi. Echinocandins (micafungin, caspofungin) act by inhibition of cell wall by inhibiting the action of 1,3-β-glucan synthase. Flucytosine is an antimetabolite which inhibits the protein synthesis in the fungal cell. Thus it is pertinent to know the mechanism of action of the drugs combined to reduce the harmful side effects. On the other hand, some drug administration has been restricted to the age factors. Like itraconazole is not permitted for children. For the recommendation of combination of the drug, it is mandatory to validate the in-vitro studies and clinical experience.

Benefits of combination therapy

The combination therapy has a bright future because of the following resons:

·         There is a possibility of shorter treatment durations and lower doses.

·         There could be a reduced risk of development of drug resistance.

·         Broader coverage of wider infections.

·         The amplified action of antifungal drugs is achieved by finding the new molecular targets in fungi.

·         Cost of treatment could be reduced.

·         Mortality rates can be controlled.


Although there is a need for more studies in order to validate the use of CDT for many IFI. Major improvements are still awaited for CDT. There is need to study the more combinations of drugs and their respective mechanism of action with the possible outcomes.

Source: Expert Rev Anti Infect Ther. 2013;11(5):523-35, Med Mycol. 2011;49(6):561-80.