|Year : 2013 | Volume
| Issue : 1 | Page : 4-9
Rising bacterial resistance to beta-lactam antibiotics: Can there be solutions?
Gajanan S Gaude, Jyothi Hattiholli
Department of Pulmonary Medicine, J. N. Medical College, KLE University, Belgaum, India
|Date of Web Publication||13-Mar-2013|
Gajanan S Gaude
Department of Pulmonary Medicine, J. N. Medical College, KLE University, Belgaum - 590 010
Source of Support: None, Conflict of Interest: None
Antibiotic resistance is the ability of a microorganism to with stand the effects of an antibiotic. Antibiotic resistance evolves naturally via natural selection through random mutation, but, it could also be engineered by applying an evolutionary stress on a population. If a bacterium carries several resistance genes, it is called multi-resistant or informally, a superbug. Antibiotic resistance can also be introduced artificially into a microorganism through transformation protocols. This can be a useful way of implanting artificial genes into the microorganism. Antibiotic resistance is a consequence of evolution via natural selection. The antibiotic action is an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce and then they will pass this trait to their offspring, which will be a fully resistant generation. Several studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broad-spectrum antibiotics, such as second- and third-generation cephalosporin, greatly hastens the development of methicillin resistance. Treating a serious infection is a balancing act between timely appropriate empiric antibiotic therapy and avoiding unnecessary antibiotics. The rapidly increasing antibiotic resistance is one of the major clinical, epidemiological, and microbiological problems facing the medical fraternity. This problem needs to be tackled head on using a multi-pronged approach.
Keywords: Antibiotic resistance, beta-lactamases, prevention, strategy
|How to cite this article:|
Gaude GS, Hattiholli J. Rising bacterial resistance to beta-lactam antibiotics: Can there be solutions?. J NTR Univ Health Sci 2013;2:4-9
|How to cite this URL:|
Gaude GS, Hattiholli J. Rising bacterial resistance to beta-lactam antibiotics: Can there be solutions?. J NTR Univ Health Sci [serial online] 2013 [cited 2020 Apr 4];2:4-9. Available from: http://www.jdrntruhs.org/text.asp?2013/2/1/4/108504
| Introduction|| |
Antibiotics and similar drugs, together called antimicrobial agents, have been used for the last 70 years to treat patients who have infectious diseases. Since the 1940s, these drugs have greatly reduced illness and deaths from infectious diseases. Antibiotic use has been beneficial and when prescribed and taken correctly, their value in patient care is enormous. However, these drugs have been used so widely and for so long that the infectious organisms the antibiotics are designed to kill have adapted to them, and thus, making the drugs less effective. People infected with antimicrobial-resistant organisms are more likely to have longer, more expensive hospital stays, and may be more likely to die as a result of the infection. In the past 60 years, antibiotics have been critical in the fight against infectious disease caused by bacteria and other microbes. Antimicrobial chemotherapy has been a leading cause for the dramatic rise of average life expectancy in the twentieth century. However, disease-causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. One part of the problem is that bacteria and other microbes that cause infections are remarkably resilient and have developed several ways to resist antibiotics and other antimicrobial drugs. This happens mainly due to increasing usage, and misuse, of existing antibiotics in variety of medical illnesses even if it is not indicated.  Nowadays, about 70% of the bacteria that cause infections in hospitals are resistant to at least one of the drugs most commonly used for treatment. Some organisms are resistant to all approved antibiotics and can be treated only with experimental and potentially toxic drugs. An alarming increase in resistance of bacteria that cause community acquired infections has also been documented, especially, in the staphylococci and pneumococci (Streptococcus pneumonia), which are prevalent causes of disease and mortality. Antimicrobial resistance, a global problem, is particularly pressing in developing countries where the infectious disease burden is high and cost constrains the replacement of older antibiotics with newer, more expensive ones. Management of common and lethal bacterial infections has been critically compromised by the appearance and rapid spread of antibiotic-resistant bacteria. In a recent study,  25% of bacterial pneumonia cases were shown to be resistant to penicillin, and an additional 25% of cases were resistant to more than one antibiotic. Urinary tract infections (UTI) are amongst the most common infections encountered in the clinical practice. The most common pathogen involved in UTIs is the E. coli, being the principal pathogen both in the community as well as in the hospital. The bacterial resistance to various antibiotics for this pathogen is on the rise, with a recent study from Puducherry  reporting high prevalence of bacterial resistance to various pathogens such as E. coli, Pseudomonas, Proteus, Klebsiella, and Acinetobacter. Another important finding was that the resistance was high to various antibiotics including, some of the newer antibiotics, which is of concern to the treating clinicians. 
Evidence also began to accumulate that bacteria could pass genes for drug resistance between strains and even between species. For example, antibiotic-resistance genes of staphylococci are carried on plasmids that can be exchanged with bacillus, streptococcus, and enterococcus providing the means for acquiring additional genes and gene combinations. Some of the genes are carried on transposons, segments of DNA that can exist either in the chromosome or in plasmids. In any case, it is clear that genes for antibiotic resistance can be exchanged between strains and species of bacteria by means of the processes of horizontal gene transmission. Multiple drug resistant organisms are resistant to treatment with several, often unrelated, antimicrobial agents as described above in Shigella.  Some of the most important types of multiple drug resistant organisms that have been encountered include:
Methicillin/oxacillin-resistant Staphylococcus aureus (MRSA)Vancomycin-resistant enterococci (VRE)
Extended-spectrum beta-lactamases (ESBLs) (which are resistant to cephalosporins and monobactams)
Penicillin-resistant Streptococcus pneumonia (PRSP)
MRSA and VRE are the most commonly encountered multiple drug resistant organisms in patients residing in non-hospital health-care facilities, such as nursing homes and other long- term care facilities. PRSP are more common in patients seeking care in out-patient settings such as physician's offices and clinics, especially, in pediatric settings. ESBLs are most often encountered in the hospital (intensive-care) setting, but MRSA and VRE also have significant nosocomial ecology. The ESBL enzymes are plasmid mediated enzymes capable of hydrolyzing and inactivating a wide variety of beta lactams, including, third generation cephalosporins, penicillins, and aztreonam. These enzymes are result of mutations of TEM-1 and TEM-2 (Temoniera enzymes) and SHV-1(Sulfhydryl variable enzymes). All these beta-lactamases enzymes are commonly found in the enterobacteriacea family. Normally, TEM-1, TEM-2, and SHV-1 enzymes confer high level resistance to first generation cephalosporins. Widespread use of cephalosporins and aztreoman is believed to be a major cause of mutations in these enzymes that has led to the emergence of the ESBLs. The first ESBL isolates were discovered in Western Europe in mid 1980s and subsequently in the US in the late 1980s. The resistant organisms are now a worldwide problem. There are various enterobacteriaceae species; however, majorities of ESBL producing strains are K. pneumonia, K. oxytoca, and E. coli. Other organisms reported to harbor ESBLs include Enterobacter spp., Salmonella spp., Morganella morganii, Proteus mirabilis, Serratia marcescens, and Pseudomonas aeruginosa. However, the frequency of ESBL production in these organisms is low.
Respiratory infections remain one of the important causes of morbidity and mortality in the world today and the need for effective antimicrobial agent is as pressing now as at any time. The safety and efficacy of beta-lactam antibiotics has established the importance of this class of antibacterial agents for the therapy of many bacterial infections. Thus, benzylpenicillin, or one of the first choice for the treatment of infections caused by Gram-positive cocci and a beta-lactam antibiotic is frequently preferred for the treatment of infections caused by Gram-negative bacteria. In recent years, the number of new cephalosporins and novel beta lactams such as cephamycins, oxacephams, and the carbapenems in clinical use has increased rapidly however, widespread usage has resulted in the selection of bacterial variants resistant to some or all of the beta lactam agents currently available. The success of the penicillanase-stable penicillins in the therapy of infections caused by penicillin-resistant staphylococci has been accompanied by the emergence of methicillin-resistant staphylococci as a major problem. These strains existed before the development of the semi-synthetic penicillins but the frequency of isolation has increased significantly, and in many hospitals epidemic of MRSA infections have become difficult to control. A recent concern has been spread from the large specialist hospitals to the smaller community care hospitals or residential nursing home facilities.  Many strains of MRSA are susceptible only to vancomycin and there is a vital need for the new drugs active against MRSA in light of the potential for the possible spread of vancomycin-resistance from enterococci to staphylococci. The report of experimental penicillin binding to the low-affinity penicillin binding protein-2 of MRSA and displaying antibacterial activity against these resistant staphylococci illustrates one potential fruitful line of research. Unless, antibiotic resistance problems are detected as they emerge, and actions are taken immediately to contain them, society could be faced with previously treatable diseases that have become again untreatable, as in the days before antibiotics were developed. Highly resistant pathogens are a major cause of excess mortality among patients with community- and hospital-acquired pneumonia. In the hospital setting, major risk-factors for infection with resistant pathogens include extended hospitalization, mechanical ventilation, and inadequate initial antibiotic therapy. 
Bacteria can become "resistant" to individual antibiotics by developing specific defense-mechanisms, which make the antibiotic ineffective. Generally, there are three mechanisms that are utilized by bacteria to develop resistance:  (i) preventing the antibiotic from binding with and entering the organism, (ii) producing an enzyme that inactivates the antibiotic, or (iii) changing the internal binding site of the antibiotic. One way in which bacteria have become resistant to beta-lactam antibiotics is by being able to express beta-lactamase enzymes - an example of the second type of resistance. There are actually dozens of enzymes, produced by many different bacteria, which are capable of degrading the beta-lactam structured antibiotics. In the development of resistance toward these drugs, scientists have witnessed one of the few cases of evolution occurring on a time scale of years. The TEM-1 enzyme, capable of degrading ampicillin emerged about 40 years ago. This enzyme has since evolved leading to roughly, 128 different TEM beta-lactamases; some with activity against almost all beta-lactams. Other important classes of beta-lactamases are SHV, PSE (Pseudomonas specific enzymes), and OXA (Oxacillnases enzymes) and a similar evolution can be observed in these classes. In addition, chromosomal Amp beta-lactamases have relocated into plasmids and emerged in different pathogenic species where they cause resistance to virtually all beta-lactams. Of even greater concern is the worldwide emergence of increasing number of isolates of Streptococcus pneumonia with reduced susceptibility to penicillins and cephalosporins. The pneumococcus is the most important cause of community acquired pneumonia and the beta-lactam antibiotics have long been the drugs of first choice. At present, the level of resistance to beta-lactam of many isolates is comparatively low and penicillins and cephalosporins can often be prescribed, possibly at higher dosage, however, the number of resistant isolates can be expected to increase.  Furthermore, the transfer of antibiotic resistance genes between staphylococci, enterococci, and streptococci leading to acquisition of staphylococcal beta-lactamase by enterococcci raised the possibility of the spread the enzyme to other streptococci, including the pneumococcus.
The discovery that beta-lactamase mediated resistance to penicillins and cephalosporins could be transmitted among enteric bacterial population as whole, one that has largely fulfilled by the dissemination of plasmid-mediated beta-lactamase amongst many Gram-negative bacteria. The third generation cephalosporins excited the attention of the infectious disease community and the pharmaceutical industry alike because of the high level and range of antibacterial activity of this group against beta-lactamase producing Gram-negative bacteria.  To some extent, these advantages have proved illusory in that the selective pressure engendered by the extensive usage of the third generation cepahlosporins has resulted in the emergence in-hospital of resistant strains of Gram-negative bacteria possessing beta-lactamase capable of hydrolyzing the antibiotics in question. Bacteria possessing plasmid-mediated extended spectrum beta-lactamase are comparatively uncommon but the development of oral derivatives and widespread usage in both community and hospital could well see the spread of these novel enzymes. The other area in which the usage of second and third generation cepharosporins has created significant therapeutic problems is the selection of the highly resistant strains of important nososcomial pathogens, such as Enterobacter, Pseudomonas, and Serratia species. 
Inappropriate use of antibiotics in the medical environment
One problem is the casual use of antibiotics in medical situations where they are of no value. This is the fault of both health-care workers and patients. Prescribers sometimes thoughtlessly prescribe "informed" - demanding patients with antibiotics. This leads to use of antibiotics in circumstances where they are of not needed, e.g., viral upper respiratory infections such as cold and flu, except when there is serious threat of secondary bacterial infection. Another problem is patient failure to adhere to regimens for prescribed antibiotics. Patients and doctors need to realize their responsibility when they begin an antibiotic regimen to combat an infectious disease.  There are several measures that should be considered: Patients should not take antibiotics for which there is no medical value (corollary: Doctors should not prescribe antibiotics for which there is no medical value); patients should adhere to appropriate prescribing guidelines and take antibiotics until they have finished; patients should be give combinations of antibiotics, when necessary, to minimize the development of resistance to a single antibiotic; patients need to be given another antibiotic or combination of antibiotics if the first is not working.
| Combating Antibiotic Resistance|| |
Use the right antibiotic in an infectious situation as determined by antibiotic sensitivity testing, when possible. One should stop unnecessary antibiotic prescriptions. Unnecessary antibiotic prescriptions have been identified as causes for an enhanced rate of antibiotics resistance development. Unnecessary prescriptions of antibiotics are made when antibiotics are prescribed for viral infections (antibiotics have no effect on viruses). This gives the opportunity for indigenous bacteria (normal flora) to acquire resistance that can be passed on to pathogens. One should finish antibiotic prescriptions for the full period. Unfinished antibiotic prescriptions may leave some bacteria alive or may expose them to sub-inhibitory concentrations of antibiotics for a prolonged period of time.
Appropriate antibiotic selection by physicians can be aided by the adoption of rapid diagnostic methods, which will become increasingly available and should encourage a more rational choice of narrow spectrum antibiotics.  Much nosocomial infection in the hospital is due to the extensive use of indwelling lines and catheters required by the technological advances in medicine, better hygienic practice, and the use of specific topical antibacterial agents and the introduction of material resistant to bacterial adhesion in the incidence of bacteraemic episodes due to antibiotic resistant bacteria. Avoidance of unnecessary prolonged antibiotic use can help prevent the development of resistance. Early initiation of treatment with an appropriate empiric antibiotic, followed by an antibiotic that specifically targets pathogens identified following gram stain and culture results with a defined course of therapy plays a major part in improving outcomes and reducing the risk of resistance. Clinicians who manage patients with both community-acquired and hospital-acquired pneumonia need to be aware of the predominant pathogens in their institutions and the level of local in vitro antibiotic susceptibility. Institutions with endemic ESBL-producing organisms need to determine whether there is a high-rate of cephalosporins usage, especially, third generation cephalosporins. Several studies have shown that by limiting the use of these agents alone or in combination with infection control measures, the frequency of ESBL isolates can be reduced substantially. Educational programs for medical staff to increase awareness also should be developed.  The development of specific vaccines, rendered more effectively by advances in genetic engineering, provides another approach.  In a review by Kollef et al.  focusing on antibiotic resistance in the ICU, the antimicrobial strategies deemed effective at limiting the emergence of resistance included: the establishment of protocols and guidelines to avoid unnecessary use of antibiotics, hospital formulary restrictions, use of narrower-spectrum antibiotics, use of quantitative bacterial cultures in instances such as ventilator-associated pneumonia, combination antibiotic therapy, routine input by infectious disease specialists, antibiotic cycling, area-specific modification of antibiotic usage, and prudent use of newer antimicrobial agents. However, the authors advocate use of selective digestive decontamination only in high-risk patients in an outbreak situation in conjunction with infection-control practices.  The authors also advocate the following non-antimicrobial strategies for the prevention of resistance: reducing the duration of mechanical ventilation; minimizing use of central venous catheters with strict hygiene precautions during insertion; vaccination against Haemophilus influenzae, Streptococcus pneumoniae, and influenza virus; hand washing; reducing nursing and house-staff workloads in the ICU; and use of gloves and gowns.
The Center for Disease Control (CDC),  in a campaign to prevent antimicrobial resistance in health-care settings, has elucidated the following 12 steps: Vaccination; get the catheters out; target the pathogen; access the experts; practice antimicrobial control; use local data; treat infection, not contamination; treat infection, not colonization; know when to say no to vancomycin; stop antimicrobial treatment; isolate the pathogen; and break the chain of contagion.
The national guidelines should be formulated and implemented for the correct and effective use of the antibiotics in clinical practice to combat the bacterial resistance. Every hospital should have the antibiotics committee that should formulate the antibiotic guidelines by taking into consideration the local antibiotics resistance patterns. So a close cooperation should exist between the microbiologist and the clinicians. The guidelines should be based on the systematic review of the scientific data. The committee should identify evidence that is lacking and areas for further research. The guidelines should be reviewed by respected peers who are not members of guideline panel, however, who are experts in the relevant field. Guidelines should not be static. They should be reviewed at periodic intervals that should be specified, and updated to take account of advances in medical knowledge, changes in clinical practice and local circumstances, and outcome of guideline evaluations. 
The development of novel antibiotics would in itself lead, sooner or later, to the selection of yet further resistant bacteria but the current unavailability of drugs to treat the drug-resistant strains of tuberculosis in many parts of the world is a salutary reminder of the ever continuing need for research and development of new anti-bacterial agents.  In the case of beta-lactams, advances in our understanding at the molecular level of the nature of resistance offers real hope for the design of novel agents active against resistant bacteria. Thus, the rational design of novel structures to combat bacterial resistance is almost within the grasp of the research scientist.
Antimicrobial stewardship is the ongoing effort by a health-care institution to optimize antimicrobial use among hospitalized patients to improve patient outcomes, ensure cost effective therapy and reduce emergence of antibiotic resistance. Educating clinicians is of paramount importance as they need to understand that prescribing an antibiotic to a patient does not only affect the patient but has an impact on the bacterial flora of the hospital. Formulary restriction is a method of restricting the use of high-end antibiotics, such that they can only be prescribed post- authorization by an infectious diseases specialist. The program needs to be spear headed by the antimicrobial management team, which is a multi-disciplinary team consisting of a microbiologist, infectious diseases specialist and antibiotic pharmacist.  This group should audit the use of antibiotics, perform surveillance of resistance data and provide a timely feedback to clinical teams. Dose optimization, de-escalation changing the route of administration from intravenous to oral in a timely manner and implementing care pathways form part of the scope of activities of this team.
Two complementary types of surveillance are recommended:  surveillance for antibiotic resistance and surveillance for antibiotic use. This supports a recommendation made in the national policy document. By itself, surveillance of any type will not change antibiotic use or the spread of resistant organisms, however, knowing resistance levels and tracking them over time is a powerful tool to support real changes. Once the link between resistance and antibiotic use is accepted, tracking antibiotic use can be used as a surrogate for changes in resistance patterns. To some extent, these patterns can produce evidence for whether interventions are working, and can help identify problem areas, as is the case for antibiotic resistance surveillance. Surveillance results/data can also be fed into standard treatment guidelines and essential drug lists.
Antibiotic resistance in a variety of common respiratory pathogens continues to be a problem. Vigilance for patients at risk for developing resistance is key, along with fastidious infection control measures and appropriate use of antibiotics. Antimicrobial resistance is here to stay. In a telling commentary by Livermore,  the author reports that it may be naive to anticipate reaching a grand control over resistance. The hope perhaps lies in slowing down development of newer resistance while continuing to develop new agents at a rate sufficient to keep ahead of bacteria.
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