The first true antimicrobial drugs were introduced in 1935 (sulphonamides) and 1942 (penicillin). Since then, hundreds of new antimicrobials have been launched into the market.
Some ¾ of the antibacterial drugs used in outpatient care are prescribed for the treatment of respiratory tract infections, e.g otitis media and sinusitis. The next most common indications for antimicrobial drug therapy are infections of the urinary tract and skin. In hospitals, the most frequent indication is surgical prophylaxis.
Development of resistance
Bacteria have been present on the earth for 3.8 billion years. Depending on the manner of calculation, the human species is a few hundred thousand years old. Bacteria are able to multiply every 20 minutes in optimal circumstances, and they have an excellent capacity of adaptation to changes in their environment. Some bacteria are known to withstand temperatures of several hundred degrees or survive the hydrostatic pressure at thousands of meters below the sea surface. Thanks to their DNA repair mechanism, some bacteria are even resistant to radioactive radiation.
During the past 80 years, there has been an unparalleled selection pressure on the bacteria of humans and of humans' immediate surroundings. The use of antimicrobial drugs favours bacteria with a natural resistance to drugs. Susceptible bacteria die and the most resistant ones survive, whereby, most probably, the species composition or relative frequencies of species in human microbial flora has already been significantly altered. As research on the composition of human normal microbial flora has become possible only in the recent years, it is impossible to fully appraise the consequences of the changes. Preliminary information exists to indicate that use of antimicrobial drugs may favour dysbiosis. In dysbiosis, damage to the intestinal endothelium together with certain intestinal bacteria, their metabolic products and the remaining intestinal content causes a non-physiological inflammatory reaction. This inflammatory reaction has been associated with several diseases, such as chronic gastrointestinal conditions, with obesity, as well as with type 1 and 2 diabetes.
Hundreds of different resistance genes have been discovered in bacteria. They have been surmised to originate from human and natural bacterial populations, but bacteria are also able to compile new resistance genes. The pneumococcal penicillin resistance genes, for instance, are a compilation from other bacteria of the oral flora.
The most worrying feature of bacteria is multiple resistance, i.e. the ability to withstand several antimicrobial drugs at the same time. Many resistant bacteria of clinical relevance possess multiple resistance. Bacteria are able to collect resistance-coding genes into gene cassettes that are transferred from one bacterium to another. On the other hand, resistance may also be encoded by mutations in chromosomal genes and is thus mainly transferred through the multiplication of the bacterial genome.
The most worrying phenomenon in the 2010's has been the spread of Gram-negative bacilli, e.g. E. coli and Klebsiella, that are resistant to all modern antimicrobial drugs Multidrug-Resistant Bacteria in Hospitals. In the treatment of infections caused by these bacteria that are also resistant to carbapenems, one has been forced to rely on colistin, a toxic and ineffective drug originating from the 1950's. Strains of bacteria resistant even to that drug have rapidly spread in some parts of the world. According to recent reports, carbapenem-resistant Klebsiella bacteria with increased virulence have been found in Europe. Increasing virulence of resistant bacteria is a particularly alarming phenomenon.
Control of resistance
Bacterial resistance is among the most serious societal threats. According to a report by the United Kingdom government, in year 2050 bacteria resistant to antimicrobial drugs are predicted to cause worldwide over 10 million deaths annually, which is more than the estimate regarding cancer mortality. The worldwide cumulative costs caused by the resistance are estimated to be more than USD 100 billion within the next 35 years.
Resistance poses problems for everyday clinical work within primary care and especially in hospitals. As the use of antimicrobial drugs is a necessity, bacterial resistance will remain a permanent problem. The resistance problem is still clearly smaller in the Nordic countries than in e.g. southern Europe.
In the last couple of decades, one has been able to develop only a few new antimicrobial drugs, and they have not yet been of any extensive help in solving the resistance problem. The development of a new drug is estimated to take 10 years. Thus, there is no quick aid to be expected from the drug development.
Bacterial resistance can be controlled by reducing the use of antimicrobials and by preventing bacteria from spreading. Different methods are combined, such as hygiene measures and vaccines.
Carry out a thorough clinical examination.
Use laboratory tests and radiological investigations according to recommendations.
Always try to reach a precise microbiological diagnosis, if possible.
Use antimicrobial drugs when needed. Do not deviate from the therapeutic recommendations for the various indications, unless you have a valid reason for doing so.
If you decide not to start antimicrobial drug therapy, ensure careful follow-up of the patient.
Adhere to stringent hand hygiene. Use hand rubs between every patient contact. Alcohol-based hand rubs reduce hand contamination and are better tolerated than regular soap cleansing Handrubbing with an Alcohol Based Solution Vs. Conventional Handwashing with Antiseptic Soap. Alcohol-based hand rubs are not effective against certain microbes, Clostridium difficile being the most important example Clostridioides Difficile Diarrhoea. Therefore, hand washing with water and soap is still a necessary alternative in hospitals and other care facilities.
The importance of normal bacterial flora increases
It is in the patient's interest that antimicrobial drugs be used only when clearly necessary. Several studies have found that antimicrobial treatment increases the patient's risk of being colonised by new resistant bacteria. Animal experiments have shown that 1 000 to 100 000 times less bacteria are needed for colonisation during antimicrobial treatment than without such treatment.
Antimicrobial drugs destroy bacteria of the normal flora, and the resultant vacuum is easily occupied by foreign resistant bacteria that now have room to proliferate. The patient then starts shedding these resistant bacteria, thereby facilitating their spreading.
In young women, antimicrobial treatment of any infection involves a two- to fivefold risk of urinary infection. This is probably due to the suppression of normal bacterial flora, which favours colonisation by pathogenic bacteria two to four weeks after the treatment.
Preliminary studies suggest that correction of the disturbance in bacterial flora by means of oral and oropharyngeal alpha-haemolytic streptococci after antimicrobial treatment affords a statistically significant protection against the recurrence of otitis media and pharyngitis. However, except for faecal transplantation used in the treatment of recurrent antibiotic-associated diarrhoea caused by Clostridium difficile, bacterial therapy has so far not been sufficiently researched in order to be used in the treatment of patients. Dozens of studies are, however, currently underway regarding the effects of faecal transplantation in different diseases or conditions.
In addition, bacterial flora appears to have importance in the aetiology and control of many diseases. Furthermore, it produces health-promoting compounds, such as building materials for cells and short-chain fatty acids that are used as energy sources.
Diarrhoea caused by antibiotics
Suppression of the normal intestinal flora allows Clostridium difficile to grow in the intestine. C. difficile produces diarrhoeagenic toxins. Its significance has increased, especially with the increased use of cephalosporins and fluoroquinolones. Wide-spectrum antibiotics together with repeated treatments are important risk factors for antibiotic-associated diarrhoea. A strain of C. difficile associated with significant mortality has spread in different parts of the worldClostridioides Difficile Diarrhoea. Metronidazole has been widely used in the treatment of C. difficile, but the new strain is less sensitive to it than was earlier the case.
Prevention of antibiotic-associated diarrhoea
Avoid unnecessary use of antimicrobial drugs.
Isolate patients with antibiotic-associated diarrhoea in hospitals.
Adhere to good hand hygiene. Alcohol hand rub does not kill the spores of C. difficile. Therefore, wash your hands meticulously with soap and water and then dry them carefully.
In children, the administration of Lactobacillus GG or Saccharomyces boulardii products prevents antibiotic-associated diarrhoea Probiotics for Children Receiving Antibiotics, particularly in children less than 2 years of age in whom antibiotic-associated diarrhoea is common. The dosage indicated in the package should be followed. A liquid product can be used, or the contents of capsules can be mixed with food or drink.
If a patient has recurrent episodes of antibiotic-associated diarrhoea, Saccharomyces boulardii yeast may help preventing them. Faecal transplantation has successfully been used in several Finnish hospitals for the treatment of recurrent diarrhoeal episodes.
Specific recommendations regarding the diagnostics and treatment of the most common infections encountered in primary care exist in EBM Guidelines and often also within local guidelines.
There is room for improvement in the use of antimicrobials even in developed countries.
Use of antimicrobial drugs other than those included in recommendations should be separately justified.
Within primary care, new broad-spectrum antimicrobials are indicated only in special cases.
References
Mattila E, Uusitalo-Seppälä R, Wuorela M et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology 2012;142(3):490-6. [PubMed]