Beginning and possibly the end of the antibiotic era
- Declaration of conflict of interest: SA has received research grant support from: MedImmune, Wyeth, Berna, Pfizer, GSK, MSD, Sanofi-Aventis, Teva, Viropharma; speaker honoraria from MSD, GSK; and advisory fee from GSK.
Correspondence: Professor Shai Ashkenazi, Department of Paediatrics A, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petach Tikva 49202, Israel. Fax: +972 3 7608634; E-mail: email@example.com or firstname.lastname@example.org
Although substances with some antimicrobial activity were used for many years in the pre-antibiotic era, their activity was very limited and their use empirical. For example, before the antibiotic era, mortality rates from pneumococcal pneumonia and acute pyelonephritis were 30–35% and ∼20%, respectively. ‘Therapy’ of infectious diseases was mostly based on patient isolation.
In 1941, Howard Florey – one of the greatest Australian scientists – successfully treated, together with his colleagues, the first patient with penicillin. This led to large-scale production of penicillin and to actual entrance to the antibiotic era, and very justifiably awarded Howard Florey, Alexander Fleming and Ernst Boris Chain the Nobel Prize in physiology in 1945. In the following years, many additional antibiotic agents, belonging to new classes, were discovered and introduced into daily clinical practice.
The advent of antibiotics resulted in a major decline in bacterial infection-related mortality and morbidity. Mortality from pneumococcal pneumonia or pyelonephritis has become rare in developed countries.[1, 2] Moreover, the availability of effective antibiotics has undoubtedly had a great impact on the whole practice of medicine, enabling the performance of complicated operations with a minimal risk of uncontrolled infections, invasive procedures, the establishment of paediatric intensive care units and the conduct of organ transplantations. Physicians of all specialties have relied on the effectiveness of antibiotics. The availability of antibiotic agents has also changed the public perception of infectious diseases; antibiotics have often been perceived as ‘magic bullets’, and requested for every febrile episode. Paediatricians have therefore had to explain to the parents of sick children that antibiotics are not antipyretics.
Bacteria have devised a plethora of mechanisms that cause resistance to antibiotics.[1, 3] The main ones include the production of enzymes that degrade or modify antibiotics, changes in the cell wall that decrease the penetration of antibiotics, creation of efflux pumps that transfer antibiotics outside the cell, modification of the target site of antibiotics and creation of alternative metabolic pathways to those interfered by antibiotics.[1, 4, 5] Resistance is spread among bacteria by varied and efficient means for transfer of resistance-encoding genes, using processes such as genetic recombination and transfer of mobile genetic elements, including plasmids, integrons and transposons.[3, 6]
The evidence is compelling that antibiotic resistance genes existed long before the use of antibiotics. For example, bacteria resistant to antibiotics were isolated from glaciers in Canada estimated as 2000 years old. Nevertheless, the escalation in antibiotic resistance is undoubtedly driven mostly by human activities, especially the widespread use of antibiotics in the last seven decades. This has created a selective pressure, which enables resistant strains or resistant mutants to thrive and spread relatively easily.
Consistent with this trend, antibiotic resistance of bacteria causing paediatric infections have increased dramatically over recent years. While in the past, antibiotic resistance, particularly regarding multiply-resistant bacteria, was confined to hospital settings, especially to intensive care units and to children with serious underlying health problems, it is currently common also in community-acquired infections. Streptococcus pneumoniae, obviously the most common cause of paediatric community-acquired infections – such as pneumonia, bacteremia and meningitis – shows partial or complete resistance to penicillin that reaches 50% in certain locations.[3, 7] Another illustrative example is methicillin-resistant Staphylococcus aureus. While these resistant bacteria were once restricted to hospital-associated infections, they have rapidly spread to community-acquired infections. For example, they currently account for 70% of all community-acquired staphylococcal infections and 74% of all S. aureus pneumonia in Texas Children's Hospital, United States. Alternative antimicrobial agents, such as clindamycin, had to be evaluated for the treatment of community-acquired staphylococcal infections in children. Resistant Gram-positive bacteria are usually treated with vancomycin; reduced susceptibility and resistance to this antibiotic agent have been reported, with significant clinical implications.[3, 10]
Resistance to carbapenems
Carbapenems – imipenem, meropenem, ertapenem and doripenem – are usually the last option for the treatment of multi-drug resistant Gram-negative bacteria. Resistance to these agents, caused by impermeability due to porin channel loss in the outer membrane, alterations in penicillin-binding proteins or carbapenemase-mediated hydrolysis, have been reported.[11-13] Outbreaks of carbapenemase-producing bacteria have been reported in the United States, South America, Greece, Israel, India and China.[5, 12]
Most alarming is the recent rapid dissemination of the New Delhi metallo-β-lactamase 1 (NDM-1).[14, 15] The blaNDM-1-encoded gene was first detected in Sweden in 2008 from a strain of Klebsiella pneumoniae that was isolated from a patient who was hospitalized in New Delhi, India in 2007. The resistant gene is carried on readily transferred plasmids of varying sizes, which indeed spread rapidly, initially in 2009 to the United Kingdom and Pakistan, and subsequently, during 2010 and 2011, to all continents and to the community.[14, 16] The blaNDM-1-encoded mobile gene disseminated into diverse bacterial species, causing septicaemia, pneumonia, urinary tract infections, skin and soft tissue infections and diarrhoea, with many fatal cases.[15, 16] Some of these bacteria were resistant to all currently available antimicrobial agents,[13, 15, 17] raising the question as to whether we are facing the end of the golden age of antibiotics.
Why is the end of the antibiotic era possible?
As shown previously, because of the rampant increase in multiply-resistance bacteria, many of the previously most effective antimicrobial agents have become ineffective. Even antibiotic agents that were once considered a safe last option for resistant bacteria, such as vancomycin for Gram-positive bacteria and carbapenems for Gram-negative bacteria, are currently unreliable for multi-drug resistant strains.[10, 12, 14, 18] Thus, in particular and currently very limited settings, we have actually reverted to the pre-antibiotic era, in which no antibiotic agent is available for the effective treatment of specific resistant microorganisms. The obvious examples are carbapenem-resistant Enterobacteriaceae and pan-resistant Acinetobacter baumani.[11, 12]
Regarding these recent developments in antibiotic resistance, the relevant current question is not if, but why the end of the antibiotic era is a real possibility, even for the near future. There are several reasons.
- Since 1941 there have been about two human generations, but regarding the bacteria – which multiply about every 20 min – these 70 years encompass more than 46 000 generations. This is a significant period in terms of microbial evolution, long enough to render many bacteria as not susceptible to current antibiotics.
- A huge amount of antibiotics has been used – probably in many settings overused – continuously over the last 70 years. An average child in the United States, and probably other developed countries, receives 10 to 20 courses of antibiotics before the age of 18 years. It has been estimated that each year in the United States, 160 million prescriptions for antibiotics are given, for about 25 000 tons of antibiotics. Approximately 50% of this amount is for use by humans; the other half is for non-human applications, such as animal farms, agriculture and aquaculture. Animal-derived antibiotic-resistant strains present an increasing problem and a relatively common cause of human disease.
- Antibiotics taken by humans who may be suffering from bacterial infections do not affect only the culprit pathogens. There are 1013 to 1014 commensal bacteria in the human body as the normal flora; actually our bodies contain 10 times more bacterial cells than human cells and 100 times more bacterial genes than human genes. When an antibiotic agent is taken, it kills susceptible organisms of the normal bacterial flora, thus enhancing the survival of the resistant strains, due to the selective pressure that is introduced. These surviving resistant bacteria can later cause hard-to-treat infections in the same person, or spread and infect other innocent people. Moreover, the normal human bacterial flora, now called human microbiome, has been shown to be crucial to the maintenance of good health. Changes in the microbiome, caused mainly by antibiotic use, have been implicated in the considerable increase in non-infectious conditions such as obesity, inflammatory bowel disease, diabetes, allergic conditions and asthma.[19, 20]
- Worldwide, there are about 7 × 109 human beings but an estimated 1034 human bacteria. The release of tons of antibiotics into the biosphere – many antibiotic agents are excreted to the environment in an active form and affect many bacteria, especially those in soil – has led to profound deleterious consequences for microbial populations in nature. Even very low concentrations of antibiotics have been shown to exert a selective pressure on environmental bacteria.[1, 6]
- These processes have resulted in escalating rates of multi-drug resistant and pan-resistant bacteria, in an era in which there are very few antibiotic agents in the pipeline, and when the options for new targets for the activity of antimicrobial agents seem very limited.[18, 21]
What should be done?
There are several steps that need to be taken to stop the accelerated increase in antibiotic resistance and to enable the efficacy of antibiotics in the future.
- Judicious antibiotic use –This can be defined as using the right antibiotic agent, at the right time, with the right dose and for the right duration. Reaching this goal is obviously not simple. A multidisciplinary approach is needed to improve the quality of antibiotic prescribing, with education and implementation of practice guidelines as key interventions. The European Center for Disease Control set the control of antibiotic resistance as a high priority, and adopted a large-scale approach to promote antibiotic stewardship and to exert prudent control over antibiotic use. They introduced the European Antibiotic Awareness Day, scheduled for November 18 every year.
- Surveillance and infection control –Preventing the spread of resistant bacteria, especially in health-care institutions, is a key element in controlling antibiotic resistance. Surveillance is needed mainly for patients transferred from locations with high resistance rates and for multi-drug resistant bacteria, with strict adherence to infection control guidelines.
- Rapid diagnostic methods –In diverse clinical settings, antibiotics are initiated in sick children when a bacterial infection cannot be ruled out, leading to antibiotic overuse. Common examples are pneumonia, neonatal fever, febrile neutropenia and immunocompetent children with upper respiratory tract infections that are most often viral; while only a minority of the patients suffering from these medical conditions is affected by bacterial infections, antibiotics are generally administered indiscriminately, as there is no reliable means of diagnosing those with bacterial infections. Rapid, highly sensitive and specific diagnostic tests that will accurately identify the causative pathogens or distinguish between bacterial and viral infections will reduce antibiotic overuse.
- New vaccines –As learned from past experience, preventing infectious diseases by vaccines is the preferred way to control infections – an ounce of prevention is worth a pound of cure. Efficacious vaccines against infectious diseases can significantly reduce the prevalence of illnesses caused by a given pathogen, acting somewhat as ‘anti-resistance vaccines’. For example, the conjugate vaccine against Haemophillus influenzae type b – once a very common pathogen in infants and young children – nearly eliminated paediatric infections caused by this organism and reduced its colonization rates, thus rendering its antibiotic resistance as nearly irrelevant.
- New antibiotics –Because of the complex and diverse mechanisms of antibiotic resistance, and because the traditional bacterial targets for the action of antibiotics have already been exploited, very few new antibiotics are currently in the pipeline. Creative approaches are needed to discover new classes of antibiotics, with novel targets and mechanisms. The genomic sequences of many bacterial pathogens have recently been determined. Hopefully, sophisticated bioinformatic analyses will lead to antibiotics with new bacterial targets and novel mechanisms of activity, which will not be vulnerable to resistant mechanisms currently present in bacterial pathogens.
- Non-antibiotic antimicrobial therapy –Considerable effort has been invested in developing additional antimicrobial products that are safe and effective, such as bacteriophages, agents that will inhibit toxin production by bacteria, biofilm formation, bacterial adherence to mucosal surfaces, translation interference, monoclonal antibodies and novel immunomodulators. An example of unconventional antimicrobial strategy uses synthetic biology, which consists of genetically engineered modifications of biologic systems to perform novel functions that do not exist in nature. By means of this approach, engineered bacteria that sense and eradicate virulent Pseudomonas aeruginosa were recently constructed. It is hoped that this and other innovative approaches will make the transition from the research laboratory to the clinical arena.
After seven decades of antibiotic use, it seems that we have reached a critical point, in which bacteria resistant to antibiotics have become ubiquitous. Some strains are resistant to all currently available antibiotic agents.[11, 18] Our ability to effectively treat bacterial infections in adults and in children is indeed threatened. The golden ages of antibiotics may come to an end.
Hopefully, we have learned from the experience, and the measures mentioned previously will be implemented both in routine paediatric practice and in advanced research. A recent study demonstrated the success of a nationally implemented broad infection control programme in containing a nationwide outbreak of carbapenem-resistant K. pneumoniae. A multidisciplinary approach, based predominantly on education, adherence to infection control measures, active surveillance and cohorting, resulted in a 79% decrease in the monthly numbers of new cases of resistant strains. The success of these interventional programmes in controlling antibiotic resistance should encourage us to take immediate action to ensure the continued effectiveness of antibiotics.