*DOI: http://dx.doi.org/10.5772/intechopen.83691 A New Era without Antibiotics*

*Technology, Science and Culture - A Global Vision*

defined as broad-spectrum antibiotics.

**2. Brief overview of Viruses**

on the machinery of the host.

decrease are discussed below.

**3. Antibiotics**

rarely viruses can infect different species.

Not all of the bacteria are classified in these groups. For instance, mycobacteria species do not respond to Gram staining as the result of a lipidic cell wall resistant to the stains. However, the Ziehl-Neelsen stain or acid-fast staining was developed *and these species are visualized as a bright red color.* The classification of bacteria in the Gram-positive and Gram-negative group is important to understand the activity of antibiotics, which will be described later on. In this regard, antibiotics can be specific to treat either Gram-positive, Gram-negative, or both of them and then

Viruses are ubiquitous infective materials composed of a genetic material generally protected by a proteinaceous coat. Only an electron microscope can visualize them. Viruses are obligatory parasites, which require a live cell to multiply. They cannot proliferate outside of the cell because they need the cell machinery to multiply their genetic material and to produce their own proteins always depending

Generally, viruses infect by introducing their genetic material into the host cell. Then, the viral genetic material hijacks the host systems and the host starts to produce the viral proteins as well as the genetic material. At the end of the process, the viruses opt for staying inside the host cell or to rupture it and disseminate. In order to use the host machinery, the genetic material of the virus codes for a few specific proteins able to interact with the host proteins. Although a small number of viral proteins are produced by the host, they have a high affinity for the host proteins. This is the reason why viruses are very specific to their host and very

Antibiotics are molecules able to inhibit the growth of bacteria. In nature, antibiotics are produced as secondary metabolites by specific groups of bacteria and fungi. The definition of secondary metabolites means that they are not involved in essential metabolic reactions in the cell. Then, if the genes responsible for their production are deleted from the bacterial DNA, they still can proliferate. Instead, it looks that antibiotics are produced in order to compete for nutritional sources by

Penicillin was the first antibiotic discovered in 1928 by Alexander Fleming and started to be used to combat infections in 1942. Since then, new antibiotics were approved with a concomitant decrease over the last decades. The reasons for this

When discussing the development of new antibiotic targets, it should be taken into consideration the bacterial target. Many metabolic pathways and enzymes in bacteria are highly conserved across living organisms. Therefore, these pathways and enzymes are not useful as targets because it will inflict similar damage(s) to human cells. Thus, the antibiotic targets should be directed to any bacterial target (e.g., protein, biosynthetic pathway, etc.) that does not have any similarity in human. Examples of antibiot-

Bacteria multiply by binary fission, which means that the parental cell divides into two daughters. Each daughter is considered a clone or genetically identical

inhibiting or stopping the development of other bacterial competitors.

ics targeting bacteria and mechanism of resistance are depicted in **Figure 2**.

**3.1 Bacterial variation and development of resistance**

**2**

offspring generated by vegetative multiplication. As mentioned before, bacteria multiply exponentially very fast with a generation time between 20 and 60 min, depending on the species. Thus, in a bacterial culture, although originated from a single cell, a prolonged growth may generate a residual change as a result of an adaptive process, resulting in spontaneous mutations. If we calculate the number of mutations (at a rate of 10<sup>−</sup>10 mutations per nucleotide base) in the genome of the bacteria *Staphylococcus aureus*, which contains 2.8 million nucleotide base pairs in its genome, an astonishing number of 300 mutations will be

#### **Figure 2.**

*Mechanisms of bacterial resistance to selected antibiotics. (A) Antibiotic mechanisms. (B) Mechanisms of bacterial resistance [2].*

produced in that population within a period of 10 h [3]. On the other hand, the human genome will accumulate approximately 60 mutations within a period of 20–25 years [4].

The term drug resistance refers to acquired changes in the bacterial genome against an antibiotic. These genomic changes will continue to exist even when the drug is removed from the environment and they will be inherited to the descendants of this bacterial clone. This type of changes can be driven either by a change in the sequence of a protein (target of the antibiotic) or by the infection of the bacteria with a foreign piece of DNA that brings new genetic material to it.

Treating bacteria with antibiotics produces a selection pressure on the bacterial cells. Based on the information provided above, it is reasonable to think that spontaneous mutations will appear, which will confer to that specific cell an advantage over the rest of the population. This new resistant strain can multiply in presence of the antibiotic because it has developed an adaptive mechanism to cope with the killing activity of the antibiotic.

This problem is aggravated when bacteria develop resistance to different antibiotics. In fact, different terms are used depending on the resistance. For example, multidrug-resistant (MDR) bacteria are resistant to at least one antibiotic in three or more antimicrobial categories; extensively drug-resistant (XDR) bacteria resistant to at least one antibiotic in all but two or fewer antimicrobial categories; and pandrug-resistant (PDR) bacteria, which are resistant to all antimicrobial categories [5].

To acquire resistance to an antibiotic, bacteria should develop a mechanism to neutralize it. Bacteria have developed different mechanisms to cope with the presence of antibiotics, which can be generalized as follows: (1) destruction of the antibiotic (enzymatic alteration of the antibiotic molecule by phosphorylation, adenylation, or acetylation), (2) changes in the antibiotic target (mutational alterations in the sequence of the protein targeted by the antibiotic), and (3) reduction in the permeability of the antibiotic (efflux pumps that pump out the internalized antibiotic) [6].

Once a single bacterial cell generates a mutation, which provides advantages to survive in the presence of the antibiotic, the genetic material conferring this resistance can be transferred to other bacterial cells by small autonomous pieces of DNA, termed plasmids, that are not integrated into the bacterial genome and exist as independent entities. This autonomous pieces are multiplied by the bacteria and transferred to the progeny (vertical transfer) or can be transferred to other species (horizontal transfer) during a process called conjugation [7]. Moreover, bacteria can continually exchange plasmids, and these pieces of DNA may contain resistance genes that will be passed to new bacteria. Interestingly, plasmids can move to new bacteria even in the absence of an antibiotic, suggesting that resistance can be disseminated in the bacterial population without the presence of an antibiotic agent.

#### **3.2 Multidrug-resistant bacteria**

The number of deaths related to infections is alarming in both Gram-positive and Gram-negative groups. For example, the toll death related to the Grampositive *Staphylococcus aureus* and *Enterococcus* species is of great threat [8]. According to published studies, *Staphylococcus aureus–*resistant strains, such as MRSA, kill more Americans than HIV infections together with Parkinson's disease and homicides combined [9]. On the other hand, the Gram-negative group with serious infections includes *Klebsiella pneumoniae*, *Pseudomonas aeruginosa,* and *Acinetobacter* species [8].

**5**

restrictions [15].

*DOI: http://dx.doi.org/10.5772/intechopen.83691*

hospital days, depending on the type of infection [11].

**3.3 The role of pharmaceutical companies**

the profitability of the company.

with an increase in the life expectancy to 78 years.

Health-care systems cope with antibiotic-resistant infections with a high economic burden. The main problems occur in hospitals as a result of vulnerable patient crowding. This issue is aggravated because the invasive procedures performed in these facilities with an excessive use of antibiotics to safeguard the lives of critical patients. For instance, a study published in the U.S. in 2002 revealed that approximately 2 million people developed hospital-acquired infection per year, causing 99,000 deaths as the result of antibacterial-resistant pathogens [10]. The appearance of infections caused in hospitals by antibacterial-resistant pathogens extends the hospitalization of the patients with a subsequent increase in the cost of

The role of pharmaceutical companies is to develop drugs to prevent or cure illness. Positive outcomes are based on a continuous introduction of new medicines

The drug discovery process is complex and involves investments of billions of dollars with a high risk. Therefore, pharmaceutical companies should assess carefully the profitability of their products before deciding in what drug to invest. The process of introducing a new drug in the market comprises mainly four phase: (1) drug discovery (3–4 years), (2) drug development (clinical phases, 5–6 years), (3) FDA filing and review (2–3 years), and (4) manufacturing and marketing. Thus, pharmaceutical companies need to evaluate a long drug discovery process associated with a patent that will expire at some point and a potential drug recall or withdrawal from the market. In conclusion, all the process involved from drug discovery until marketing may last for over a period of 12–15 years. In the case of the introduction of new antibiotics, the process is aggravated because of the appearance of bacterial resistance that will reduce the profitability of the antibiotics in the short term. Moreover, when new antibiotics are released into the market, they are often used as last resort because clinicians prefer to reserve them to treat complex infections. This situation prolongs the shelf live of the antibiotic reducing

When the pharmaceutical company chooses a specific drug, the transition between the phases is of high risk because regulatory agencies will monitor that each stage is safe for human consumption even before the drug is entering into clinical trials. For example, the selection of a candidate involves the screening of thousands of compounds, which as a result of its toxicity, efficacy, or safety may not proceed to the next step. This cost of the investment will be recovered only if the candidate drug successfully passes all the phases. As an illustration, 38% of the drugs failed in phase I (safety/blood levels), 60% of the remaining failed in phase II (basic efficacy), 40% of the remaining candidates failed in phase III (big, expensive efficacy), and 23% failed to be approved by the FDA [12]. Taking together, the number of medicines approved for new treatments has consistently dropped from

Based on all these explanations, it is reasonable to deduce that pharmaceutical companies have more interest to develop new medicines for the treatment of chronic diseases rather than antibiotics. Patients treated for these chronic diseases will consume the drugs for a long period of time (years) even for life, whereas antibiotics will be prescribed for a period of few days and then stopped. Taking all these concerns together, only three pharmaceutical companies in the world continue to develop new antibiotics [14]. Other contributors to the development of new antibiotics, such as the academy, have been affected by funding

approximately 35 to 20 new drugs/year in the last decade [13].

*A New Era without Antibiotics*

### *DOI: http://dx.doi.org/10.5772/intechopen.83691 A New Era without Antibiotics*

*Technology, Science and Culture - A Global Vision*

20–25 years [4].

categories [5].

antibiotic) [6].

killing activity of the antibiotic.

produced in that population within a period of 10 h [3]. On the other hand, the human genome will accumulate approximately 60 mutations within a period of

The term drug resistance refers to acquired changes in the bacterial genome against an antibiotic. These genomic changes will continue to exist even when the drug is removed from the environment and they will be inherited to the descendants of this bacterial clone. This type of changes can be driven either by a change in the sequence of a protein (target of the antibiotic) or by the infection of the bacteria with a foreign piece of DNA that brings new genetic material to it.

Treating bacteria with antibiotics produces a selection pressure on the bacterial cells. Based on the information provided above, it is reasonable to think that spontaneous mutations will appear, which will confer to that specific cell an advantage over the rest of the population. This new resistant strain can multiply in presence of the antibiotic because it has developed an adaptive mechanism to cope with the

This problem is aggravated when bacteria develop resistance to different antibiotics. In fact, different terms are used depending on the resistance. For example, multidrug-resistant (MDR) bacteria are resistant to at least one antibiotic in three or more antimicrobial categories; extensively drug-resistant (XDR) bacteria resistant to at least one antibiotic in all but two or fewer antimicrobial categories; and pandrug-resistant (PDR) bacteria, which are resistant to all antimicrobial

To acquire resistance to an antibiotic, bacteria should develop a mechanism to neutralize it. Bacteria have developed different mechanisms to cope with the presence of antibiotics, which can be generalized as follows: (1) destruction of the antibiotic (enzymatic alteration of the antibiotic molecule by phosphorylation, adenylation, or acetylation), (2) changes in the antibiotic target (mutational alterations in the sequence of the protein targeted by the antibiotic), and (3) reduction in the permeability of the antibiotic (efflux pumps that pump out the internalized

Once a single bacterial cell generates a mutation, which provides advantages to survive in the presence of the antibiotic, the genetic material conferring this resistance can be transferred to other bacterial cells by small autonomous pieces of DNA, termed plasmids, that are not integrated into the bacterial genome and exist as independent entities. This autonomous pieces are multiplied by the bacteria and transferred to the progeny (vertical transfer) or can be transferred to other species (horizontal transfer) during a process called conjugation [7]. Moreover, bacteria can continually exchange plasmids, and these pieces of DNA may contain resistance genes that will be passed to new bacteria. Interestingly, plasmids can move to new bacteria even in the absence of an antibiotic, suggesting that resistance can be disseminated in the bacterial population without the presence of an antibiotic

The number of deaths related to infections is alarming in both Gram-positive

and Gram-negative groups. For example, the toll death related to the Grampositive *Staphylococcus aureus* and *Enterococcus* species is of great threat [8]. According to published studies, *Staphylococcus aureus–*resistant strains, such as MRSA, kill more Americans than HIV infections together with Parkinson's disease and homicides combined [9]. On the other hand, the Gram-negative group with serious infections includes *Klebsiella pneumoniae*, *Pseudomonas aeruginosa,* and

**4**

agent.

**3.2 Multidrug-resistant bacteria**

*Acinetobacter* species [8].

Health-care systems cope with antibiotic-resistant infections with a high economic burden. The main problems occur in hospitals as a result of vulnerable patient crowding. This issue is aggravated because the invasive procedures performed in these facilities with an excessive use of antibiotics to safeguard the lives of critical patients. For instance, a study published in the U.S. in 2002 revealed that approximately 2 million people developed hospital-acquired infection per year, causing 99,000 deaths as the result of antibacterial-resistant pathogens [10]. The appearance of infections caused in hospitals by antibacterial-resistant pathogens extends the hospitalization of the patients with a subsequent increase in the cost of hospital days, depending on the type of infection [11].

### **3.3 The role of pharmaceutical companies**

The role of pharmaceutical companies is to develop drugs to prevent or cure illness. Positive outcomes are based on a continuous introduction of new medicines with an increase in the life expectancy to 78 years.

The drug discovery process is complex and involves investments of billions of dollars with a high risk. Therefore, pharmaceutical companies should assess carefully the profitability of their products before deciding in what drug to invest.

The process of introducing a new drug in the market comprises mainly four phase: (1) drug discovery (3–4 years), (2) drug development (clinical phases, 5–6 years), (3) FDA filing and review (2–3 years), and (4) manufacturing and marketing. Thus, pharmaceutical companies need to evaluate a long drug discovery process associated with a patent that will expire at some point and a potential drug recall or withdrawal from the market. In conclusion, all the process involved from drug discovery until marketing may last for over a period of 12–15 years. In the case of the introduction of new antibiotics, the process is aggravated because of the appearance of bacterial resistance that will reduce the profitability of the antibiotics in the short term. Moreover, when new antibiotics are released into the market, they are often used as last resort because clinicians prefer to reserve them to treat complex infections. This situation prolongs the shelf live of the antibiotic reducing the profitability of the company.

When the pharmaceutical company chooses a specific drug, the transition between the phases is of high risk because regulatory agencies will monitor that each stage is safe for human consumption even before the drug is entering into clinical trials. For example, the selection of a candidate involves the screening of thousands of compounds, which as a result of its toxicity, efficacy, or safety may not proceed to the next step. This cost of the investment will be recovered only if the candidate drug successfully passes all the phases. As an illustration, 38% of the drugs failed in phase I (safety/blood levels), 60% of the remaining failed in phase II (basic efficacy), 40% of the remaining candidates failed in phase III (big, expensive efficacy), and 23% failed to be approved by the FDA [12]. Taking together, the number of medicines approved for new treatments has consistently dropped from approximately 35 to 20 new drugs/year in the last decade [13].

Based on all these explanations, it is reasonable to deduce that pharmaceutical companies have more interest to develop new medicines for the treatment of chronic diseases rather than antibiotics. Patients treated for these chronic diseases will consume the drugs for a long period of time (years) even for life, whereas antibiotics will be prescribed for a period of few days and then stopped. Taking all these concerns together, only three pharmaceutical companies in the world continue to develop new antibiotics [14]. Other contributors to the development of new antibiotics, such as the academy, have been affected by funding restrictions [15].

Over the last two decades, regulatory agencies such as the FDA have changed the way antibiotic clinical trials are executed [16]. For example, the use of placebo in the clinical trials of antibiotics is now considered unethical, and instead, trials are addressing noninferiority of new antibiotics compared to existing drugs. These regulations increase the cost of the trials because larger populations are required with a concomitant reduction of the profitability [16]. Taking together, changes in the regulations should be pursued to accelerate the approval of new antibiotics [17]. These changes can, for example, be based on reducing the clinical trial to a smaller population, which will reduce the cost of the trial, as well as its acceleration for completion.

#### **3.4 Patent cliff**

Pharmaceutical companies face an additional problem and it is related to patent expiration. Taking into consideration that the patenting of a specific drug has been performed earlier and during the discovery phase, after the FDA approval and product launching to the market, companies have a period of approximately 10–12 years to recover the investment during the different phases. Once the patent expired, the company faces what is known as a "patent cliff" [18].

Patent cliff means that the company loses the exclusive marketing of a specific drug and it becomes "generic." A generic drug means that the product is sold at a considerably lower price compared to the original equivalent. Thus, sales and revenues for that specific drug plummet with a loss of price of up to 70% in a short period of time after the patent expiration.

#### **3.5 Misuse of antibiotics**

Antibiotics, without doubts, have had a positive impact on human health. In the past, deadly untreatable bacterial infections became treatable and stopped to be the main cause of death.

The history teaches us that penicillin resistance in *Staphylococcus aureus* appeared in 1945 only 3 years after the onset of its commercialization [19]. Today, *Staphylococcus aureus* has become completely resistant to penicillin and related derivatives [20]. Continuing with the same bacterial strain, a rapid increase (5–80%) in the antibiotic resistance to ciprofloxacin, thought to be effective because a novel mechanism unknown in nature, was observed within 1 year of antibiotic use [21].

Physicians routinely prescribe antibiotics to treat infections whose origin may have not been identified yet. For example, the treatment of viral infections with antibiotics has no benefits to the patient, but instead, increases the antibiotic resistance in other bacteria present in the patient microbiome. Thus, increasing the resistance to antibiotics in the normal flora of the patients will neutralize their activity in future infections. For example, after the examination of a patient with ear pain, the family doctor concluded that her/his ear has an infection. There is a 25 and 75% probability that this infection is caused by bacteria and viruses, respectively. Although it may be a discomfort for a few days, the infection will resolve without treatment in case that its origin is viral. To determine the origin of the infection, a culture test should be performed, which may take a couple of days with a higher cost than an antibiotic prescription. Thus, the patient prefers to purchase the antibiotics knowing that there is only a 25% probability. Under these facts, the patient will press her/his physician for an antibiotic prescription, making the patient happy. In conclusion, this event multiplied by thousands of doctor visits/year develops the resistance for untreatable bacteria in the future.

Overuse of antibiotics by physicians occurs when surgeons decide to administer antibiotics to the patients facing a surgery as a mean of prophylaxis to prevent infections during and after the procedure [22].

**7**

*DOI: http://dx.doi.org/10.5772/intechopen.83691*

Another aspect of antibiotic overuse is observed in the livestock industry, which uses large quantities of antibiotics not only to prevent infections [23, 24] but also to increase their growth [25]. These infections may take an enormous toll of death very fast and reduce considerably the number of animals, especially in intensive husbandry (e.g., turkey, chicken, and fish ponds). These antibiotics reach the environment where they create an ideal niche for the development of resistance in the microbiome. Thus, the misuse of antibiotics in these industries provides pressure on bacteria to acquire resistance. For example, it has been demonstrated the presence of resistant bacteria in meat consumers [26]. This phenomenon follows a sequence of events that starts in the antibiotic overuse in the farms. This overuse depletes susceptible bacteria and helps with the appearance of antibiotic-resistant bacteria, which are transmitted to humans through the food supply. Studies have demonstrated that approximately 90% of the antibiotics provided to animals are secreted in urine and stool, which subsequently are used as fertilizers altering the

Another growing problem is related to antibacterial products found in cleaning or hygienic purposes. For example, their effect on the environment affects the composition of indigenous bacterial populations having a direct effect on the

In order to tackle the antibiotic overuse, national or provincial programs should

1. educate not only health professionals but also the society to reduce this burden,

2.develop a fast test to evaluate whether an infection is caused by bacteria or

3. restrict or limit the excessive use of antibiotics by providing education pro-

An examination of the FDA approval during the period 1998–2003 revealed that the approval of new antibiotics has declined by 56% over the past 20 years [23]. Surprisingly, only 7 of a total of 225 new drugs approved in that period were antibiotics [9] and only 2 antibiotics had a new mechanism of action [27]. This low number is insufficient to meet with the growing needs of our society to cope with

The fact that the introduction of new antibiotics in the market decreased over the last decades together with the appearance of resistance fueled the investigation

The new research venues include bacteriocins, phages, and nanoparticles.

Bacteriocins are short or long sequences of amino acids with antibacterial activities produced by lactic bacteria. Their sequences are heterogeneous and classified according to their molecular weight [28]. For example, some of them consist of short peptide sequences (19–37 amino acids), but others can reach molecular

*A New Era without Antibiotics*

environmental microbiome [26].

be established to:

viruses;

infections.

**4.1 Bacteriocins**

weights of up to 90,000 Da.

grams to farmers.

**4. Alternatives to antibiotics**

of alternative sources of antimicrobial agents.

development of a proper immune system in humans.

including behavioral interventions;

## *DOI: http://dx.doi.org/10.5772/intechopen.83691 A New Era without Antibiotics*

*Technology, Science and Culture - A Global Vision*

period of time after the patent expiration.

**3.5 Misuse of antibiotics**

main cause of death.

**3.4 Patent cliff**

Over the last two decades, regulatory agencies such as the FDA have changed the way antibiotic clinical trials are executed [16]. For example, the use of placebo in the clinical trials of antibiotics is now considered unethical, and instead, trials are addressing noninferiority of new antibiotics compared to existing drugs. These regulations increase the cost of the trials because larger populations are required with a concomitant reduction of the profitability [16]. Taking together, changes in the regulations should be pursued to accelerate the approval of new antibiotics [17]. These changes can, for example, be based on reducing the clinical trial to a smaller population, which

Pharmaceutical companies face an additional problem and it is related to patent

Patent cliff means that the company loses the exclusive marketing of a specific drug and it becomes "generic." A generic drug means that the product is sold at a considerably lower price compared to the original equivalent. Thus, sales and revenues for that specific drug plummet with a loss of price of up to 70% in a short

Antibiotics, without doubts, have had a positive impact on human health. In the past, deadly untreatable bacterial infections became treatable and stopped to be the

Physicians routinely prescribe antibiotics to treat infections whose origin may have not been identified yet. For example, the treatment of viral infections with antibiotics has no benefits to the patient, but instead, increases the antibiotic resistance in other bacteria present in the patient microbiome. Thus, increasing the resistance to antibiotics in the normal flora of the patients will neutralize their activity in future infections. For example, after the examination of a patient with ear pain, the family doctor concluded that her/his ear has an infection. There is a 25 and 75% probability that this infection is caused by bacteria and viruses, respectively. Although it may be a discomfort for a few days, the infection will resolve without treatment in case that its origin is viral. To determine the origin of the infection, a culture test should be performed, which may take a couple of days with a higher cost than an antibiotic prescription. Thus, the patient prefers to purchase the antibiotics knowing that there is only a 25% probability. Under these facts, the patient will press her/his physician for an antibiotic prescription, making the patient happy. In conclusion, this event multiplied by thousands of doctor visits/year develops the resistance for untreatable bacteria in the future. Overuse of antibiotics by physicians occurs when surgeons decide to administer

The history teaches us that penicillin resistance in *Staphylococcus aureus* appeared in 1945 only 3 years after the onset of its commercialization [19]. Today, *Staphylococcus aureus* has become completely resistant to penicillin and related derivatives [20]. Continuing with the same bacterial strain, a rapid increase (5–80%) in the antibiotic resistance to ciprofloxacin, thought to be effective because a novel mecha-

nism unknown in nature, was observed within 1 year of antibiotic use [21].

antibiotics to the patients facing a surgery as a mean of prophylaxis to prevent

infections during and after the procedure [22].

expiration. Taking into consideration that the patenting of a specific drug has been performed earlier and during the discovery phase, after the FDA approval and product launching to the market, companies have a period of approximately 10–12 years to recover the investment during the different phases. Once the patent

will reduce the cost of the trial, as well as its acceleration for completion.

expired, the company faces what is known as a "patent cliff" [18].

**6**

Another aspect of antibiotic overuse is observed in the livestock industry, which uses large quantities of antibiotics not only to prevent infections [23, 24] but also to increase their growth [25]. These infections may take an enormous toll of death very fast and reduce considerably the number of animals, especially in intensive husbandry (e.g., turkey, chicken, and fish ponds). These antibiotics reach the environment where they create an ideal niche for the development of resistance in the microbiome. Thus, the misuse of antibiotics in these industries provides pressure on bacteria to acquire resistance. For example, it has been demonstrated the presence of resistant bacteria in meat consumers [26]. This phenomenon follows a sequence of events that starts in the antibiotic overuse in the farms. This overuse depletes susceptible bacteria and helps with the appearance of antibiotic-resistant bacteria, which are transmitted to humans through the food supply. Studies have demonstrated that approximately 90% of the antibiotics provided to animals are secreted in urine and stool, which subsequently are used as fertilizers altering the environmental microbiome [26].

Another growing problem is related to antibacterial products found in cleaning or hygienic purposes. For example, their effect on the environment affects the composition of indigenous bacterial populations having a direct effect on the development of a proper immune system in humans.

In order to tackle the antibiotic overuse, national or provincial programs should be established to:


An examination of the FDA approval during the period 1998–2003 revealed that the approval of new antibiotics has declined by 56% over the past 20 years [23]. Surprisingly, only 7 of a total of 225 new drugs approved in that period were antibiotics [9] and only 2 antibiotics had a new mechanism of action [27]. This low number is insufficient to meet with the growing needs of our society to cope with infections.
