Paul Ehrlich, a prescient pioneer in the field of antimicrobial chemotherapy: what did he foresee a century ago?

Keywords::

• antibiotic resistance
• parasites
• pathogens
• pharmacodynamics
• therapeutic index

It is almost a century since Professor Paul Ehrlich of the Royal Institute for Experimental Therapy in Frankfurt (Germany) gave the address in Pathology on Chemotherapeutics: scientific principles, methods and results [1]. Many of the key points of Ehrlich’s treatise set the stage for modern therapeutics in the treatment of infectious diseases. Ehrlich et al. provided the foundation for much of what we practice today [1]. Perhaps, even more remarkable are several of his predictions about the emergence of antibiotic resistance occured some 25 years before the first modern antibacterial agent was reported. As well as the therapeutic index, structure–activity relationships, combination therapy, antibiotic synergism, the role of pharmacokinetics and pharmacodynamics in therapy, he also predicted the closing of tuberculosis sanitaria!

Fixation in chemotherapy

Ehrlich realized that “parasites are only killed by those materials to which they have a certain relationship, by means of which they are fixed”. He used the example of salvarsan, and its processing by the spirochete-infected host to create a chemical that kills the pathogen as opposed to salvarsan itself. Indeed, he described the investigations of ‘drug fast’ trypanosomes and fuchsin as one of the earliest examples of drug class cross-resistance.

Ehrlich paid tribute to the work by Langley in which he established the existence of chemoreceptors, and thus, when pathogens ‘adjust’, these highly drug-specific targets can nullify not just one drug but other similar agents. Ehrlich proposed that we target as large a number of different chemoreceptors as possible. However, he also stated that a “few hundred substances may fix themselves on a parasite and only a few are capable of bringing about its destruction”. This observation gives testimony to the attrition rate of antimicrobial drugs in development, of which only one in 10,000 make it to the clinic. In an attempt to avoid this redundancy, Ehrlich proposed that drugs be created in a complicated manner using a ‘poisoned arrow’ analogy. He described it as the fixing group of the drug anchors to the chemoreceptor being the point of the arrow, the binding member is the shaft of the arrow and the poison is fixed to the shaft of the arrow. Although this concept has been explored, there are few examples of its successful application. The use of liposomes to encapsulate the antifungal agent amphotericin to reduce adverse events and improve efficacy could be considered a form of poisoned arrow [2]. Of note, research is in progress looking at a ‘Trojan horse’ strategy of adding a siderophore to an aminopenicillin that could enable the antibiotic to penetrate Gram-negative pathogens [3].

Balance therapeutic & safety effects (therapeutic index)

Ehrlich reminded his audience that such agents must kill the parasites and not merely injure them. He referred to the work by Professor Hata, who had reported the significance of the ratio of organotropic to parasitotropic effects [1]. In other words, the ‘benefit versus risk’ to the infected host must be assessed. Ehrlich referred to these as the dosis tolerata and dosis toxica. He only considered substances to be therapeutic if the fraction of the dosis tolerata is sufficient to elicit a therapeutic effect. Paradoxically, two well-established agents/classes have seen their dosing regimen refined, vancomycin and the aminoglycosides (gentamicin). Specifically, the aminoglycosides were initially dosed three times per day in an effort to achieve bactericidal activity, but these doses led to nephrotoxicity or ototoxicity. More recently, understanding that maintenance of high trough levels contributed to these adverse effects, the implementation of once-daily dosing achieved excellent activity (on the basis of the bactericidal C_max mode of action), whereas lower trough levels reduced side effects.

Structure–activity relationships

Bearing in mind that Ehrlich et al. did not have the luxury of today’s sophisticated chemistry and imaging methods, they elegantly elucidated the impact of changing various groups on the core of phenylarsenic acid. By substituting chlorine, oxygen, hydrocyanic acid, sulfuric acid, ammonia and other molecules, they showed a difference in toxic effect that varied by 1500-fold. In addition, they observed that these different compounds also had a differential impact on the organs of the infected host. A well-known modern example of the impact of critical small structural changes could be the development of ketolide and fluoroquinolone antibiotics, where some molecular manipulations result in enhanced activity, whereas others are accompanied by unwanted toxicities [4,5].

Qualities of an ideal remedy

The basis of unique chemoreceptors being used to develop more specific agents that not only target particular pathogens but also have no toxic host effect was proposed by Ehrlich. He realized that moving from laboratory studies to clinical implementation was fraught with dangers. It was appreciated that Homo sapiens could exhibit certain specific idiosyncrasies or ‘supersensitivites’, which do not occur in laboratory animals. It was also noted that when pathogens were killed by certain therapeutic agents, the bodies of these invaders were capable of causing further host damage. Indeed, the bactericidal activity of today’s b-lactams against Gram-negative bacteria may elicit an endotoxic reaction due to the release of lipopolysaccharides from the destroyed cell wall [6,7].

It was evident at this time that Ehrlich was developing ‘therapeutic tactics’, of which ‘therapia sterilisans magna’ was the primary method to rid the host of invaders. Indeed, the term ‘frapper fort et frapper vite’ best describes this approach to ensure that the most appropriate agent is selected at the optimal dose and administered such that the drug has full access to the pathogens. Ehrlich fully appreciated that if the medicine destroyed only 95% of the pathogens then the remaining organisms could become resistant to the drug’s actions. He termed these isolates ‘relapsing crops of parasites’. He recognized that this propensity to ‘relapse’ was dependent on the specific pathogen. He concluded that “it is necessary to do one’s utmost to destroy the whole of the parasites (pathogens) all at once by means of drugs, as owing to their great power of adaptation a single germ surviving may perhaps be the cause of the infection breaking out afresh”. Today, we realize the importance of appropriate dosing strategies on the basis of pharmacodynamic modeling, not only to optimally kill bacteria, but also to minimize the selection of antibiotic-resistant bacteria [8,9].

Deficient sterilization

Ehrlich clearly acknowledged that there were two main reasons behind the failure of his ‘therapia sterilisans magna’: the ability of pathogens to infect body sites that were inaccessible to drugs and the concept of resistant germs. Efforts to overcome these problems included prolonged drug therapy over weeks rather than single doses, the use of very low volumes of drugs, the use of agents to enhance the penetration of drugs into areas such as the CSF, and the direct application of drugs into inaccessible areas. One of the most innovative approaches Ehrlich proposed was the use of combined therapy. He recognized the folly of adding two similar agents such as trypan red and trypan blue as they had similar receptors. Treatment of trypanosomiasis in mice was improved by adding parafuchsine and salvarsan. Ehrlich proposed that combinations could affect a cure with the least harmful dose and reduce the likelihood of resistance. Today, we are still exploring the optimal use of synergistic antibiotic combinations, not only to act at different sites in a metabolic pathway (as with trimethoprim–sulfamethoxazole) but also to block β-lactamase’s ability to destroy a β-lactam antibiotic with the use of an enzyme inhibitor or another β-lactam with higher affinity for the β-lactamase so that the active agent can still prevail (e.g., ampicillin–sulbactam, piperacillin–tazobactam or combinations of carbapenems to inhibit some metallo-β-lactamases in the treatment of multidrug-resistant Acinetobacter).

So where do we stand today with our quest for the ideal antimicrobial agent?

The last century has seen the development of several hundred antimicrobial agents that have had a positive effect on pneumonia-related mortality, reduced serious sequelae associated with meningitis, and improved outcomes in bacteremia and sepsis, among many other achievements. Yet the emergence of multidrug-resistant Gram-negative species is a major current challenge. Have we learned from Ehrlich’s century-old hypotheses? Ehrlich was a prescient scientist who provided us with many relevant and insightful clues to optimize the development of these essential agents. However, we have only really incorporated his hypotheses in the past decade or so. The drugs we strive to develop should be bactericidal, specifically target key pathogens to reduce possible collateral damage, have minimal ability to induce deleterious effects from bacterial cell death, achieve appropriate concentrations at the likely sites of infection, have a stimulatory effect on host defenses, have little to no resistance selection ability, and be well tolerated by the host. Perhaps, if we had sooner taken all of Ehrlich’s concepts to our research programs, we might be facing a more rosy future for antibiotic therapy.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.