The “golden era” of antibiotics started with the discovery of penicillin, streptomycin, chloramphenicol, and tetracycline [1]. However, their introduction into medical practice was associated with rapid appearance of resistance: 50 % of hospital Staphylococcus aureus isolates were resistant within 7 years of penicillin’s first use [1]. During the following years a huge number of newer antibiotics have been released but simultaneously more and more pathogenic bacteria developed resistance to nearly all antibiotic classes through intrinsic or acquired resistance mechanisms; this has created a global public health problem that affects all parts of the world (in 2004, more than 70 % of pathogenic bacteria were resistant to at least one of the currently used antibiotics) [2, 3]. Bacterial resistance mechanisms to antibiotics include their inactivation via hydrolysis, alteration or bypassing the drug target, preventing access of the drug to the target sites making the cells unrecognizable to the antibiotic, and active efflux out of the cell via membrane-bound efflux transporters. These resistance mechanisms primarily occur as a result of mutations of endogenous genes and/or lateral gene transfer of resistance genes from other pathogens [4]. Studies on genomics and metagenomics recently reported that diverse natural ecosystems (human gut, soil, etc.), the so-called resistomes, contain genes able to confer resistance to antimicrobials, in addition to some pathogens being considered as disseminated multicellular organisms having interactions mediated by complex cell–cell signaling [5]. These interactions lead to the formation of complex matrices of polysaccharide/extracellular DNA and biofilm development, especially in the ICU setting where many devices are used. The biofilm promotes cellular resistance due to a high mutation rate (up to 100 times higher than planktonic cells) leading to faster development of antibiotic-resistant mutants while the various pathogens within biofilm facilitate horizontal gene transfer and acquisition and spread of resistance determinants [6]. From all the above it appears that bacteria are involved in a continuous effort to “find” new pathways and to develop newer and newer mechanisms of resistance in order to overcome antibiotics usage.

We still use antibiotics and will do so for the foreseeable future so antibiotic resistance will continue to emerge to existing as well as to new agents, and it will probably escalate over time. Even when antibiotic restriction practices are applied to sizable urban communities like Shanghai, large-scale consumption of antibiotics continues to occur [7]. The consumption patterns of antibiotics seem to favor the use of parenteral agents and specifically cephalosporins, macrolides, and quinolones, classes of antibiotics already having some of the highest rates of resistance. Moreover, the demographic characteristics of both developing and developed countries favor increasing utilization rates of antibiotics. For example, of the 7.7 million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents [8]. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905,059 deaths) and diarrheal diseases among older children (38,325 deaths) [8]. These patterns of disease would suggest that pressures on antibiotic utilization will continue to occur unless the causes of disease and death are altered on a global scale. It is very likely that the newly available antibiotics will see increased utilization over time, as they have been specifically developed to treat existing antibiotic-resistant microorganisms. Ceftazidime-avibactam is the first antimicrobial approved by the US Food and Drug Administration (FDA) for the treatment of carbapenem-resistant Enterobacteriaceae. A recent report has already described a KPC-producing Klebsiella pneumoniae isolate resistant to ceftazidime-avibactam (MIC, 32/4 μg/ml) from a patient with no prior treatment with ceftazidime-avibactam [9]. Similarly, the addition of relebactam, a novel beta-lactamase inhibitor, did not improve the activity of imipenem against Acinetobacter baumannii [10]. MICs were unchanged for isolates with overexpression of ampC and/or blaOXA-51, suggesting a lack of relebactam activity against these enzymes. The importance of this observation is that relebactam is a new agent that has not yet been released for clinical use. Additionally, as global health care becomes more sophisticated, and long-term care facilities increase in number, the prevalence of antibiotic-resistant strains will continue to increase, putting increasing resistance pressures on all antibiotic classes [11].

Unsurprisingly, the looming crisis of resistance and the paucity of new antibiotic classes have prompted much consideration of alternative, non-antibiotic approaches. There is certainly no shortage of ideas [12]. Among the most familiar are vaccines to prevent infection, antimicrobial peptides or phage therapy, designed to kill bacteria using targets that will not be susceptible to genetic evolution, and antibodies or probiotics that can be broadly thought of as anti-virulence strategies. Czaplewski et al. recently provided a very comprehensive review of alternative strategies at various stages of development [13]. There are other things that we can do that will also help: better antibiotic stewardship and improved diagnostics are good examples. But how likely is it that these strategies will stop, or at least delay, the emergence of yet further resistance? The O’Neill committee, a highly authoritative group commissioned by the Wellcome Trust and the UK government to consider both the scope and the possible responses to the threat of antimicrobial resistance, recently published the latest chapter of their review [14]. This deals specifically with alternatives to antibiotics, and they identified a number of significant problems. These include

  • Limited spectrum of activity. Unlike conventional “broad-spectrum” antibiotics, most of the novel strategies have a restricted target. This creates problems with both the clinical use of such agents and the economics since their relatively limited use makes them commercially unattractive.

  • Novel science. This relates both to the preclinical development (e.g., agents that depend on or target host immunity may require hugely expensive primate studies) and also regulatory challenges, particularly if the novel drug is designed to be used in combination with an antibiotic.

  • Low knowledge base. This is an area in which there has been very little investment, either in academia or in industry. There is a paucity of expertise and lack of enthusiasm from industry because of the perceived commercial risks.

A detailed review of the current portfolio of novel agents in all stages of development led Czaplewski et al. to conclude that, at least in respect of some of the most common and problematic Gram-negative bacteria, it was “unlikely that alternatives to antibiotics… will be developed in the next 10 years” [13]. At the present time, it would seem to be unwise to assume that non-antibiotic strategies will provide a global solution to the problem of antimicrobial resistance (Table 1).

Table 1 Strategies to PREVENT RESISTANCE in the intensive care unit [15]
Full size table