Immunomodulatory Effects of Antimicrobial Agents. Part I

Antibacterial and Antiviral Agents

Marie-Thérèse Labro

Disclosures

Expert Rev Anti Infect Ther. 2012;10(3):319-340. 

In This Article

Abstract and Introduction

Abstract

Despite impressive therapeutic progresses in the battle against infections, microorganisms are still a threat to mankind. With hundreds of antibacterial molecules, major concerns remain about the emergence of resistant and multidrug-resistant pathogens. On the other hand, the antiviral drug armamentarium is comprised of only a few dozens of compounds which are highly pathogen specific, and resistance is also a concern. According to Arturo Casadevall (Albert Einstein College of Medicine, NY, USA), we have now entered the third era of anti-infective strategy, which intends to favor the interplay between active molecules and the immune system. The first part of this review focuses on the potential immunomodulating properties of anti-infective agents, beginning with antibacterial and antiviral agents.

Introduction

After millenniums of fatal infections and devastating epidemics, in the last two centuries, the causative agents have been progressively identified and a large armamentarium has been constructed. Infectious pathogens cover a broad range of organisms, from viruses, only visible in the electron microscope, to worms easily visible to the naked eye. Since the mid 19th century, the battle against infectious diseases, has been strengthened by the expanding knowledge in microbiology, immunology and by the development of powerful weapons (vaccines, antibacterials) resulting in approximately 80% of the rise in life expectancy. Then, in the 1950s, the 'wonder drugs' (penicillin, streptomycin, chloramphenicol, and a growing list of other antibiotics) promised an end to bacterial infections. Viruses have offered fewer routes to remedies, except for vaccines: in 1979, smallpox became the first disease to be eradicated from the world. In these euphoric times, the US Surgeon, General William H Stewart told Congress in 1969 that time was ripe to "close the book on infectious disease".[1]

However, despite all these extraordinary developments and the numbers of antimicrobial molecules, the battle is not won. Approximately 15 million people die each year due to infectious diseases – nearly all live in developing countries.[201] The greatest killer is by AIDS (2,600,000 deaths/year) and respiratory infection in children (3,500,000 deaths/year), followed by TB (1,500,000 deaths/year), malaria (1,100,000 deaths/year) and measles (900,000 deaths/year). The incidence and prevalence of serious mycoses continues also to be a public health problem and an important cause of morbidity and mortality, especially in immunocompromised patients.

In addition, owing to their extreme power of evolution, microorganisms tend to improve their survival by generating resistance mechanisms and exchanging data and solutions. The increase in the number of patients whose natural defenses have been obliterated either by therapeutics (transplantation, cancer and so on) or by another infection, or because of an underlying acquired or genetic immune disease, also explains the increased prevalence of severe infections in these patients. This last observation leads to the widely acknowledged evidence that the host immune defenses and antimicrobial drugs must act synergistically to successfully combat infections.

Casadevall recently outlined that we have entered the third era of antimicrobial treatment.[2] The first era (the first milleniums) was based upon symptomatic treatment rather than etiologic treatment, and occasionally on enhancement of host defenses, particularly after the identification of phagocytes by Metchnikoff.[3] The second era was the fantastic hope generated by the rapid development of therapeutic, pathogen-targeted molecules, which unfortunately, for the reasons cited above, remains an endless run. The third, modern, era intends to join both therapeutics arms: active molecules and modulation of (cooperation with) the immune system.

Many immunomodulating drugs are now on the market and are given in combination with antimicrobial agents. The purpose of this review concerns how antimicrobial agents can, by themselves, interfere with the host system. This aspect has been frequently addressed, mainly with regards to antibacterial agents. There exist many pathways for antimicrobial drugs to modify the immune response (Figure 1). Two areas will be covered here: the immune adverse events triggered by the antimicrobial drugs and the direct modulation of immune effectors, with therapeutic prospects, whenever possible. Alteration of microbial targets (indirect effects) and antimicrobial synergy, which includes the cellular uptake of drugs, will not be approached here.

Figure 1.

Immunomodulatory pathways of antimicrobial agents. (1) Modulation of genes involved in immune reactions, or of the neurohormonal system which regulates immune functions. (2) Toxic or immunotoxic effects (allergic reactions or destruction of immune effectors, e.g., neutropenia). (3) Direct modulation of immune effectors (lymphocytes, phagocytes) including oxidant scavenging; (4) synergy with host mechanisms to kill intra- or extra-cellular pathogens. (5) Modification of antimicrobial agents by host factors (enzymes, oxidants), leading to alteration of its antimicrobial activity or of its toxic, immunotoxic potential. (6) Indirect effects following the alteration of the pathogen by the drug (altered susceptibility to host factors, release of toxic compounds, e.g., lipopolysaccharides). Ab: Antibody; AB: Natural antibiotics of phagocytes; C: Complement. Adapted with permission from [47].

This review will include two parts: part I will focus on molecules, targeted to bacteria and viruses, which affect people in high income countries and are a strong stimulus for industry and research. Part II will be devoted to molecules targeted to parasites and fungi, which mainly affect poverty stricken individuals in third-world countries, and, for a long time, have not led to deep interest in the pharmaceutical industry. However, developments are taking place in this area and antifungal and antiparasitic drugs are becoming the new challenge for the future.

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