Antibacterial agents: back to the future? Can we live with only colistin, co-trimoxazole and fosfomycin?

Authors

  • J. Carlet,

    1.  Consultant for the African Partnership for Patient Safety (APPS) project, WHO, and President of the World Alliance against Multi-resistant Bacteria, Paris
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  • J.-L. Mainardi

    1.  Centre de Recherche des Cordeliers, LRMA, Equipe 12, Université Paris Descartes, Sorbonne Paris Cité, Paris
    2.  Université Pierre et Marie Curie –Paris, Paris
    3.  INSERM, Paris
    4.  AP-HP, Hôpital Européen Georges Pompidou, Paris, France
      E-mail: jeancarlet@gmail.com
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Resistance to antibiotics is increasing dangerously worldwide [1,2]. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci have been spreading for many years, explaining the massive usage of vancomycin. Enterobacteriaceae harbouring extended spectrum β-lactamases (ESBL) have spread more recently, but quickly [3,4]. We have not been reactive enough with ESBL because it was evident that carbapenems would be the next target [5,6]. This class of drugs, which represents our last line of therapy, is needed not only to treat severe and nosocomial infections, but also, in several countries, to treat community-acquired infections. Resistance to this class of drug will increase rapidly, leaving us with almost nothing except the old, sometimes toxic, drugs that have been almost forgotten. There are numerous mechanisms for resistance to carbapenems [6], which can easily spread worldwide (e.g. KPC, OXA 48, NDM-1). NDM-1 recently received much media coverage because it was found in British people returning from India [7]. The way in which people live and travel today, massive immigration and troop mobilization all accelerate the spread of multi-resistant bacteria [8]. The screening of possible carriers, with the application of the Dutch ‘search and destroy’ strategy is difficult to establish on a large scale. Micro-organisms resistant to almost every antibiotic are already present in many countries, requiring the use of the old ‘toxic’ antibiotics, such as colistin. There are huge differences between countries, and Scandinavian countries, the Netherlands and Switzerland still have low levels of both methicillin-resistant Staphylococcus aureus and resistant Gram-negative bacteria. Resistance is not new, but we were ‘saved’ until recently by the regular introduction of new effective compounds, belonging to many different classes. This time, the pipeline is almost dry for drugs active against Gram-negative bacteria. There are a reasonable number of recent, effective compounds that are active against Gram-positive cocci, but no new antibacterial agent active against Gram-negative bacteria is expected in the next few years. Therefore, for Gram-negative bacteria, we are back 30 years, and the risk of large epidemic outbreaks, leading to a true pandemic with multi-resistant bacteria, is real. This is something of a return for bacteria, after a long period of viral supremacy. What are the causes of this dramatic situation? In most countries, people still use too many antibiotics, empirically, in particular to treat viral infections, such as pharyngitis, or bronchitis or urinary colonization, often without using the available and simple diagnostic tests. To treat severe infections, and for the sake of their patient, prescribers use broad-spectrum antibiotics to prevent treatment failures, but seldom re-evaluate this initial therapy, nor do they de-escalate treatment, even when it would be safe for the patients. Treatments are still far too long. In several countries, access to antibiotics is free, in the pharmacies, or over-the-counter. The problem is also dramatic in animals. A recent study, performed in the Netherlands shows that up to 80% of hens harbour ESBL Gram-negative bacteria [9]. Antibiotic consumption in animals worldwide is excessive, although huge differences are noted between European countries [10]. The Netherlands and France are the highest consumers.

At the same time, companies have de-invested the field of antibiotic therapy, which is considered to have a high cost and risk : benefit ratio, and a limited market for drugs because of their low price. Resistance increases sharply, and no new antibiotic appears on the horizon—a deadly duo!

Life, in the community and in hospitals is a succession of small or large and silent epidemic outbreaks with both susceptible and resistant micro-organisms. Infection control measures are still applied, but in most countries in a suboptimal way, and screening of carriers remains difficult and far too costly for most countries. So it is difficult to prevent the spread of a new mechanism of resistance, for example ESBL.

Can we survive without antibiotics? A large international meeting was organized in 2011 in France, by Biomérieux, with the title Ready for a world without antibiotics? The answer was obviously ‘NO’, or not at present. Antibiotics remain the key actor in the management of infections.

Can we survive with only a few old antibiotics? In this issue of Clinical Microbiology and Infection, three antibiotics are re-visited: colistin, co-trimoxazole and fosfomycin. The review by Raz [11] underlines the increased role of fosfomycin as a therapeutic option against multidrug-resistant pathogens, particularly those responsible for urinary tract infections. For co-trimoxazole, Goldberg and Bishara [12] summarize the accumulated evidence in the literature on the new, ‘unconventional’ clinical use of co-trimoxazole during the last three decades. Obviously, those compounds are still effective against both Gram-positive and Gram-negative organisms. Colistin remains efficient even for Gram-negative bacteria that harbour carbapenemases, or complex associated mechanisms, such as Pseudomonas aeruginosa. It is less toxic than anticipated. However, more strains are becoming resistant to colistin. Yahav et al. [13] in their review summarize the results of studies on the clinical use of colistin administered intravenously or as an aerosol. The article of Couet et al. [14] conducts a critical review with prospective thoughts and focuses on the most recent pharmacokinetic studies on colistin, published during the last few years or months, or not yet published but only presented at international meetings. Combination therapy (mandatory for fosfomycin administered intravenously) is often used to increase the efficiency of these three drugs, and limit the occurrence of resistance. However, the best partner remains to be determined even if aminoglycosides are often used when a combination of colistin and fosfomycin would be a reasonable therapy for infections caused by resistant Gram-negative bacteria.

It is important, sociologically, to better understand why people do not seem to be frightened by the problem of antibiotic resistance, although it could represent the next pandemic! It is not clear why such huge amounts of energy and resources have been put into the preparedness for H1N1 ‘micro-pandemia’, and why it is so difficult to motivate politicians or healthcare organizations, such as WHO, on antibiotic resistance, and to urgently set up a strong and coordinated programme, with precise and pragmatic actions. Probably people think that new antibiotics will appear, as happened in the past. It is time to react vigorously to protect and save antibiotics, and to try to stop the continuing spiral of resistance. For this to happen, a strong cooperation between healthcare professionals, in both human and animal medicine, and consumers is needed, and simple, but powerful and convincing, information must be given to the politicians and the public.

Some groups have been active for many years, trying to promote these actions. We could cite ReAct—Action on Antibiotic Resistance and APUA, the Alliance for the Prudent Use of Antibiotics, which were created in 1981. We created recently a World Alliance against Multi-resistant Bacteria [15]. Three hundred and twenty professionals, from many horizons in human and animal medicine support this alliance, as well as 35 medical specialties or professional bodies (including large European societies). Sixty-five well-known international experts constitute our international scientific advisory committee. More importantly, consumers (Le Lien, Le Collectif Interassociatif Sur la Santé) are fully involved in this alliance, and it is hoped that consumers from countries other than France will join. The Alliance proposes a combined programme, including four mandatory and simultaneous actions: the upgrade of infection control measures; the spread of antibiotic stewardship programmes, with active protection of antibiotics; the use and development of diagnostic tests; and the acceleration and facilitation of research and access to new antibiotics. Together, we can reach a positive outcome, and help to save antibiotics.

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