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Antibiotic Resistance: Its Impact on a Great Medical Center in the Last 30 Years
From: Columbia University
| By:
Harold C. Neu |
EDITOR'S INTRODUCTION |
Harold Neu served as chief of the division of infectious diseases at Columbia University's College of Physicians and Surgeons for almost 30 years. During his tenure, he witnessed the genesis of an enormous array of antibacterial chemicals, and he witnessed microbes remarkably outsmarting them. Neu reviews the major antibiotics that appeared during his service at Columbia, their mechanisms of action and the ways that bacteria have eluded them. |
 n the 30 years that I have been at the Columbia-Presbyterian Medical Center (CPMC) and Columbia University, many new antibiotics have been discovered in nature or synthesized. In 1960, there were only two penicillins (penicillin G and V), three oral tetracyclines, three sulfonamides, one aminoglycoside for parenteral use (streptomycin), chloramphenicol, and one macrolide (erythromycin). Today there are more than 50 penicillins, 75 cephalosporins, 12 tetracyclines, nine aminoglycosides, three carbapenems, one monobactam, nine macrolides, three dihydrofolate reductase inhibitors, and at least 20 fluoroquinolones. Given this huge array of antimicrobial agents, it would seem that an individual could not possibly die of an infection in a hospital such as the Milstein Hospital at CPMC. Unfortunately, that is not true, and indeed one could not only die in CPMC but also in New York Hospital, San Francisco General or the Massachusetts General Hospital. This is a result of the development of resistance by many of the bacteria that one encounters both in the hospital and more recently in the community setting.1 |
This article will address what particular effect resistance has had upon antimicrobial therapy at CPMC over the last 30 years. During this period of time our division has studied virtually every class of antimicrobial agent available throughout the world. In many cases we have been the first to study the human pharmacology of the drug and to perform the initial clinical trials which have been published in the American and European literature. |
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Antibiotics that effectively inhibit bacterial cell wall synthesis include the beta-lactams, penicillins, cephalosporins, monobactams, carbapenems, penems and drugs such as the glycopeptides, vancomycin and the soon to be available teicoplanin (Table 2) . Many drugs interfere with protein biosynthesis. These include 50S ribosome inhibitors such as clindamycin, chloramphenicol and the macrolides, three of which are now available in the United States. The 30S ribosome inhibitors include the tetracyclines and aminoglycosides. Within the last two decades, DNA directed RNA polymerase inhibitors such as rifampin for Mycobacterium tuberculosis and recently rifabutin, for the therapy of Mycobacterium avium infection, have become available. There are a large number of DNA gyrase inhibitors such as ciprofloxacin and ofloxacin. The brilliant work of George Hitching and Gertrude Elliot showed that a combination of trimethoprim with a sulfonamide (TMP/SMX) would synergistically inhibit bacterial folic acid metabolism. This provided an important antibiotic combination for bacterial infections, but now TMP/SMX is also a mainstay for treatment and prevention of Pneumocystis carinii in AIDS patients. |
Unfortunately, bacterial antibiotic resistance can develop as a result of a chromosomal mutation, inductive expression of a latent chromosomal gene, or by exchange of genetic material through transformation, transduction or conjugation by plasmids or transposons. Plasmid transfer of DNA is extremely common among the Enterobacteriaceae, Haemophilus, Neisseria gonorrhoeae and Pseudomonas species which cause infections both within the hospital and within the community. |
Most recently it has been shown that organisms such as Enterococcus have the ability to transfer genetic material to other gram-positive species, thereby providing resistance to hemolytic streptococci, pneumococci and recently to Staphylococcus aureus.2 Over the last 30 years, organisms such as Streptococcus pneumoniae have acquired multiple genes controlling production of transpeptidases from oral streptococci, making it extremely difficult to inhibit some S. pneumoniae with beta-lactams. |
Antimicrobial agents are rendered inactive by three major mechanisms. The first is inactivation either by destruction, such as occurs with the beta-lactamases, or by a major modification of the compound so that it does not bind to its target, as is seen with the aminoglycosides and chloramphenicol. A second mechanism is prevention of access to the target. For example, in gram-negative organisms the outer membrane proteins may be altered such that antibiotics are unable to cross the cell wall. In some organisms, such as those which cause sexually transmitted disease, resistance to tetracycline is due to a protein which modifies the receptor on the 30S ribosome. The third mechanism of resistance which has become increasingly important is change in the target site. For example, in staphylococci a new transpeptidase which is generally referred to as a penicillin binding protein (PBP) is produced by the microorganism. This new PBP2a does not bind any beta-lactam compound, i.e., penicillin, cephalosporin, monobactam or carbapenem. This mechanism has also been utilized to change the target of drugs such as erythromycin and the new macrolides, clarithromycin and azithromycin. Methylation of adenine in a loop of the 16S component of the 23S rRNA allows protein synthesis to proceed normally. Organisms causing urinary tract infections and diarrhea such as Escherichia coli, Salmonella and Shigella have plasmids which produce a new dihydrofolate reductase that has a low affinity for trimethoprim and sulfonamides. |
In a 1992 article in Science, I reviewed the mechanisms of resistance to most antibiotics, described the organisms in which antibiotic resistance is currently a problem, and described the potential for crises in the future.9 In this article, I will specifically address the changes that have occurred in the Washington Heights area, where the outpatient department at CPMC handles 500,000 visits per year and the inpatient department includes a 1,500-bed hospital, a major heart transplant center and a medical intensive care unit. Tables 3 and 4 classify the organisms according to those which cause community acquired infections and those which cause nosocomial infections. |
Community acquired infections
Major changes have occurred in the resistance of at least seven organisms which cause a significant number of community acquired infections in the Washington Heights area. These include Haemophilus influenzae, Neisseria gonorrhoeae, Moraxella catarrhalis, Staphylococcus aureus and three organisms involved in the diarrheal disease, namely Salmonella and Shigella species and toxigenic E. coli. |
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In 1961, ampicillin became available at CPMC. It was utilized in the therapy of Haemophilus influenzae infections including meningitis in children, sinusitis, otitis media and acute bacterial exacerbations of chronic bronchitis. In Germany in 1974, it was reported that H. influenzae had developed resistance to ampicillin. The basis of this resistance was production of a beta-lactamase, an enzyme capable of hydrolyzing ampicillin. It has been postulated that E. coli, known since 1966 to produce a plasmid-mediated beta-lactamase, transferred the plasmid into H. parainfluenzae, an organism which is part of the normal oral flora. From H. parainfluenzae the plasmid moved into H. influenzae. Through the 1970s, less than 5 percent of the H. influenzae were ampicillin-resistant in this institution. By 1989, however, approximately 10 percent of H. influenzae respiratory isolates were resistant to ampicillin and related drugs. In 1993, 26 percent of isolates from the respiratory tract produce the TEM beta-lactamase. What this means clinically is that treatment of otitis media, sinusitis or exacerbations of bronchitis in this community using ampicillin or amoxicillin would be unwise. In one-fourth of such cases caused by H. influenzae, the patient would not be receiving an effective antimicrobial agent. This clearly has added to the cost of therapy of patients in the ambulatory setting, since newer drugs are invariably more expensive than the older compounds. |
In the 1960s, an organism today referred to as Moraxella (Branhamella) catarrhalis was called Neisseria catarrhalis. This organism was not considered a true pathogen in the 1960s and 1970s. Today we realize that a significant proportion of otitis media infections and lower respiratory infections in the elderly are due to this organism. In 1966, less than 1 percent of our Moraxella produced a beta-lactamase enzyme. In our most recent survey in 1992, however, 85 percent of respiratory and ear isolates produced a beta-lactamase capable of destroying ampicillin and cefaclor, a second-generation cephalosporin. Since this is one of the organisms that must be anticipated in patients with upper respiratory infection, prescribing practices have clearly had to be changed in a community such as ours. |
One of the most important social problems in Washington Heights is the high level of venereal disease. Until 1980, Neisseria gonorrhoeae were susceptible to penicillin G. In the 1980s we noted a major increase in beta-lactamase-producing isolates so that 44 percent of our N. gonorrhoeae are now resistant to penicillins by virtue of a plasmid-mediated beta-lactamase. We also have Haemophilus ducreyi causing chancroid in this area of New York, and these isolates are resistant to penicillins and tetracycline. |
In the 1940s, research was under way at CPMC with Drs. Dawson and Hobby in an attempt to isolate penicillin. In the 1940s, if penicillin had been lying on a counter in a room, the pneumococci within several feet would have died as a result of its lethal action. A concentration of 0.004 uh/ml inhibited Washington Heights S. pneumoniae. That is no longer true. Today there are S. pneumoniae, albeit infrequently encountered in the outpatient setting, which are relatively or totally resistant to penicillin. |
At one of our satellite hospitals, we have found penicillin-resistant isolates of serotype 23 S. pneumoniae, the same serotype found in Barcelona, Spain, where penicillin resistance is a major problem. These isolates have caused severe pneumonia and even death. At present approximately 4 percent of our S. pneumoniae are relatively resistant to penicillin, inhibited by <15g/ml but more than 0.125g/ml. This is less than the nationwide figure of 10.5 percent, but undoubtedly this figure will increase at CPMC, as was the case with the frequency of ampicillin-resistant H. influenzae. |
As a result of this concern about relative resistance of S. pneumoniae, penicillin is infrequently utilized today as initial therapy of suspect S. pneumoniae meningitis. Cefotaxime and ceftriaxone, drugs extensively studied at this institution, have become the initial therapy until one has ascertained that the pneumococcus is susceptible to penicillin. |
In a melting-pot area such as Washington Heights, there is exposure to a large number of enteric pathogens. Many of the individuals in this neighborhood have emigrated from parts of the world in which diarrheal disease remains a major problem. In the last decade, there have been significant changes in the susceptibility of Salmonella and Shigella species isolated from children with diarrheal disease. |
In 1970, it would have been appropriate to use ampicillin to treat diarrheal disease in children. This is no longer true, since more than 40 percent of Salmonella and Shigella stool isolates are now resistant to ampicillin, tetracycline and many other antimicrobial agents. We have encountered isolates of Salmonella typhi from CPMC employees and recent immigrants living in Washington Heights that are resistant to all antibiotics except newer fluoroquinolones such as ciprofloxacin and ofloxacin. Furthermore, with the epidemic of cholera on the West Coast of South America, we have suddenly encountered patients infected with Vibrio cholera strains that are resistant to trimethoprim/sulfamethoxazole (TMP/SMX), tetracycline, chloramphenicol and most beta-lactams. |
In recent years it has been increasingly apparent that Campylobacter intestinalis is a major cause of diarrhea both in children and adults. Although there is controversy over therapy of this infection, children are usually treated with erythromycin in order to prevent outbreaks in day-care centers and other school settings. Recently, adults have been treated with fluoroquinolones such as ciprofloxacin. Both here and abroad we have noticed the development of resistance to ciprofloxacin among the Campylobacters producing diarrhea. |
Escherichia coli remains the major cause of uncomplicated urinary tract infections. Until recently, most E. coli were susceptible to amoxicillin or oral cephalosporins of the first generation. Most isolates of E. coli were inhibited by low concentrations of TMP/SMX. Currently, among individuals seen in our employee health service or in the outpatient departments, as many as 30 percent of E. coli produce a beta-lactamase, and TMP/SMX resistance has been increasing as well. E. coli causing urinary tract infections, particularly those isolated from individuals from the Caribbean or South America, tend to be resistant to TMP/SMX because of its excessive use as an over-the-counter medication in these countries. |
Nosocomial infections
Resistance has not only been seen in the community. It is a much more difficult situation within the hospital itself. The reasons for this are multiple, but include the type of patients seen at this institution. These patients require tertiary care, and are often unable to return to a stable home setting and hence remain in the hospital for an extended period. Multi-resistant bacteria are the cause of significant numbers of nosocomial infections in an institution such as CPMC, even though there is a very active epidemiology service attempting to reduce nosocomial urinary, blood, respiratory and skin infections. |
Another factor which contributes to the extensive resistance seen at CPMC is the number of patients admitted to the hospital from extended-care facilities where antibiotics are prescribed excessively. Many elderly individuals living in chronic-care facilities develop urinary tract infections or decubitus ulcers and as a result are treated with oral cephalosporins and more recently the new fluoroquinolones. |
A major problem has been Staphylococcus aureus. In 1941, virtually all strains of S. aureus in the United States were susceptible to penicillin, but by 1944 S. aureus was shown to produce a beta-lactamase. More than 95 percent of S. aureus in outpatients and inpatients at CPMC are resistant to penicillin, ampicillin and the anti-pseudomonal penicillins such as ticarcillin and piperacillin. Semi-synthetic penicillins with methoxy groups, such as methicillin and oxacillin, were developed in 1960 at the same time as ampicillin. These compounds inhibited beta-lactamase producing S. aureus but had little activity against gram-negative organisms. |
Until the mid-1980s, there was little problem at CPMC with methicillin-resistant S. aureus (MRSA). MRSA are resistant to all beta-lactams because of a mecA gene that produces as new penicillin binding protein (PBP), PBP2a, that has a low affinity for beta-lactam antibiotics. In our neighborhood, many intravenous drug abusers enter the hospital with cutaneous or bloodstream infections or endocarditis due to MRSA. As a result, these patients cannot be treated with beta-lactams, and initial therapy has traditionally been with vancomycin. We will see how the extensive use of vancomycin has resulted in significant resistance in another microorganism, Enterococcus faecium. |
We recently completed a study of medical personnel in a dermatology unit that treats psoriasis patients with PUVA therapy. These patients frequently become colonized with MRSA; in turn, many of the personnel become colonized as well. As a result of transposition and site-specific integration of DNA, the chromosomal change mediates resistance not only to beta-lactams but also to drugs such as erythromycin, tetracyclines, aminoglycosides, sulfonamides and disinfectants such as silver and mercury. |
MRSA is an example of the rapid failure of a new antimicrobial agent with respect to one species. In our initial study of the fluoroquinolone antimicrobial agents, ciprofloxacin inhibited 100 percent of the MRSA at CPMC at <1 µg/ml. Indeed, fluoroquinolones were able to eradicate the nasal carrier state of MRSA and cured serious infections due to MRSA.³ Our initial in vitro laboratory studies demonstrated that Enterobacteriaceae and P. aeruginosa could rapidly develop resistance to fluoroquinolones if multiply transferred while exposed to the antibiotic. This, however, had been difficult to achieve in the laboratory with MRSA or susceptible S. aureus. |
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Nonetheless, since 1986, when we first performed the large-scale study of ciprofloxacin in the treatment of serious Pseudomonas infections, we have gone from 100 percent susceptibility to <20 percent of MRSA inhibited at a clinically achievable concentration. More than 50 percent of blood isolates of MRSA are resistant to ciprofloxacin, ofloxacin and all the commercially available drugs. We have recently tested several compounds which show activity against these organisms. However, we suspect that once these agents are in clinical use the MRSA will become resistant. Our isolates of S. aureus are resistant not only to beta-lactam antibiotics but the majority are also resistant to macrolides such as erythromycin, aminoglycosides such as gentamicin, and even TMP/SMX in recent years. Fortunately, all S. aureus in this institution presently remain susceptible to vancomycin and to a drug soon to be released by the FDA, teicoplanin. Nonetheless, over the last 15 years there has been a steady increase in the concentration required to kill MRSA, from 0.25 to as high as 7 mcg/ml. We anticipate, as has occurred in the United Kingdom, that ultimately there will be resistance of MRSA to vancomycin. |
Does this mean that the game is totally over with MRSA? No. We have recently looked back at a series of old compounds which the medicinal chemists have been able to modify to increase their activity against MRSA. These include Synercid, which is a mixture of two streptogramins produced by Rhone-Poulenc Rorer, and everniomicin, produced by Schering-Plough. Clinical trials are just beginning in our institution to determine the toxicity and clinical efficacy of these drugs. |
To date, at CPMC the majority of S. aureus including MRSA are susceptible to mupirocin, a pseudomonic acid derivative that interferes with isoleucine transfer RNA, thereby inhibiting protein synthesis. Studies done by our group have clearly demonstrated that application of mupirocin to the anterior nares results in the eradication of nasal carriage of S. aureus. We are embarking upon a further study of individuals who circulate within the hospital as carriers of MRSA and thereby cause infection in critically ill patients. |
MRSA is a costly problem for the hospital. It requires strict isolation of patients with the use of gowns, gloves and single rooms. Decontamination of the room after the patient has left is also a problem. Furthermore, most nursing facilities are unwilling to accept patients with MRSA, even though the facilities themselves often are the source of contamination in these patients. |
Thirty years ago, coagulase-negative staphylococci were referred to as Staphylococcus albus. Today there are 31 species of coagulase-negative staphylococci. The most common is S. epidermidis, followed by S. hemolyticus. S. epidermidis has become a major clinical problem in hospital settings because of its resistance to many antimicrobial agents. It contains the mecA gene, making it resistant to all beta-lactams; and simultaneously it has acquired resistance to aminoglycosides and other compounds as well. |
In an institution that engages in extensive cardiac surgery, there is a major risk of post-operative wound infection due to S. epidermidis. As a result, vancomycin is extensively used as a prophylactic agent by many of the cardiac surgeons. Over the past decade, the concentrations of vancomycin needed to inhibit most S. epidermidis have risen remarkably, from levels of 0.5 µg/ml to occasional strains requiring 8 µg/ml. These strains are difficult to eradicate and require administering vancomycin in an appropriate dose that also will not causing hearing loss or renal dysfunction. Although teicoplanin, a new glycopeptide antibiotic, has only been used in a small number of patients in investigational studies at CPMC, there are already rare teicoplanin-resistant strains of S. epidermidis. This has been a particular problem for us, since these strains, now resistant to virtually all commercially available antimicrobial agents, cause infections of indwelling long-term intravenous lines. |
Enterococcus faecium is an organism which did not have a name in the 1960s or 1970s but has emerged as a major threat in US hospitals. A recent discussion with William Martone, head of the Hospital Epidemiology Branch at the Centers for Disease Control, indicates that most large teaching hospitals in the US are having major problems with E. faecium. When I arrived at CPMC in 1960, a patient who had enterococcal aortic endocarditis died because the organism was resistant to the available agents at that time and ampicillin was not yet available. We recently have had a 60 percent death rate among patients who acquire infection with this E. faecium (Jacob & Neu, in preparation). The attributable mortality rate and extra length of hospital stay that can be ascribed to E. faecium is not yet established. Most of these patients have had major underlying illness, and many of them have been on the oncology or dialysis services. |
E. faecium has the ability to be resistant to the glycopeptides such as vancomycin and teicoplanin, which inhibit the late stages in bacterial cell wall peptidoglycan synthesis. There are three major phenotypes of vancomycin resistance. Most of our resistance at CPMC is due to the vanA genetic form of resistance. These bacteria make a new type of cell wall in which the D-alanine-D-alanine terminal linkage is replaced by a D-alanine-D-lactate linkage that fails to bind vancomycin. A number of different genes are involved in this process. Most frighteningly, this form of resistance is plasmid-mediated, and enterococci have the ability to transfer this resistance to oral streptococci, group A streptococci, Listeria monocytogenes, S. pneumoniae and, as recently shown in the United Kingdom, even to S. aureus. To date, we have not had vancomycin resistance in any of the aforementioned species. Nonetheless, I would anticipate that within the decade this will in fact occur. Enterococci have also acquired, probably from staphylococci, the ability to produce a beta-lactamase. About 30 percent of E. faecalis are resistant to high concentrations of aminoglycosides. This means that there is no synergy between ampicillin and gentamicin. We have had occasional patients with an enterococcus not inhibited by any known antimicrobial agent. As a result, when such a strain causes endocarditis, it is difficult to achieve cure without surgical removal of the valve. |
Why has this resistance in E. faecium appeared? It appears related to the extensive use of oral vancomycin to treat nosocomial diarrhea due to or thought to be due to Clostridium difficile. We have instituted a program (difficult to enforce) requiring initial therapy of C. difficile diarrhea by metronidazole, an imidazole, which does not select for antibiotic-resistant enterococci. |
Resistance of hospital acquired gram-negative bacteria
There are a number of very important gram-negative bacteria that cause hospital acquired and community acquired infections in an institution such as CPMC. Pseudomonas aeruginosa is a ubiquitous microorganism found in most water supplies. It is a major pathogen in patients with cystic fibrosis. The early studies defining cystic fibrosis were performed in the Department of Pediatrics, and CPMC continues to be a leader in the field. Carbenicillin was first used by our group in the 1960s. Subsequently we evaluated ticarcillin, piperacillin, azlocillin, ceftazidime, aztreonam, imipenem and most recently ciprofloxacin. 4-12 |
Unfortunately, over the years Pseudomonas organisms have become increasingly resistant to antibiotics. In the original publication in 1987 on the use of ciprofloxacin, we noted that adult cystic fibrosis patients who had received multiple courses of ciprofloxacin eventually developed resistant strains.1 Today a significant number of P. aeruginosa from cystic fibrosis patients followed at CPMC and at other centers across the United States are resistant to many of the available penicillins, cephalosporins, carbapenems, aminoglycosides and fluoroquinolones. To date, it has not been possible to construct a fluoroquinolone that will inhibit ciprofloxacin-resistant strains or a carbapenem that will inhibit imipenem-resistant isolates. |
P. aeruginosa has also become a major problem in intensive care units. It can become resistant to imipenem, a carbapenem that inhibits virtually all bacteria with only one or two exceptions. How does this occur? The microorganism loses an outer membrane protein which lines the channel through which imipenem traverses to reach its target, the PBP. We have noted with extensive use of imipenem, as is sometimes required, that one will suddenly have infections due to imipenem-resistant P. aeruginosa. Many of our hospital P. aeruginosa isolates are already resistant to investigational carbapenems. |
Extensive use of imipenem in ICU patients, which is often necessary, will also result in selection of an organism, Xanthomonas maltophilia, which is resistant to virtually all antibiotics with the exception of TMP/SMX.13 Most recently, some CPMC Xanthomonas isolates have been resistant to TMP/SMX and hence are not inhibited by any agent. |
The first study of the third-generation cephalosporins, cefotaxime, came from our group in the 1970s.4-18 At that time, virtually all Klebsiella pneumoniae were inhibited by low concentrations of cefotaxime and ceftriaxone. Many workers in the field of infectious diseases felt that these drugs had eliminated the problem of plasmid-mediated beta-lactamases. Unfortunately, by the mid-1980s K. pneumoniae in France and Germany were resistant to cefotaxime, ceftriaxone and ceftazidime, agents considered totally beta-lactamase stable.9 The cause of this resistance was the production of new plasmid-mediated beta-lactamases that had the ability to destroy these compounds. |
The original beta-lactamase referred to as TEM-1 underwent mutations in one to three amino acids, resulting in a structural alteration, allowing the beta-lactamase to fit appropriately about the beta-lactam compounds and destroy them. During this time, another group of beta-lactamases also changed in Klebsiella. These enzymes referred to as SHV (sulfohydrovariable inhibited) also had the ability to destroy the aforementioned compounds. |
In the latter part of the 1980s we began to see K. pneumoniae that were resistant to all beta-lactams except imipenem. Although in some countries there has been transfer of these plasmids from Klebsiella to other species, in our institution this has been exceedingly uncommon. Beta-lactamase inhibitors such as clavulanate, sulbactam and tazobactam inhibit these new enzymes, but the antibiotics with which these beta-lactamase inhibitors are combined, ampicillin or ticalcillin, are not effective against most of the new TEM and SHV beta-lactamase containing Klebsiella seen at CPMC. |
Through an effective epidemiology program, it is possible to rapidly recognize strains of Klebsiella that possess these enzymes and to institute measures to prevent their dissemination from the original infected patient. Nonetheless, there have been serious problems in several of the intensive care units due to this organism. |
Another major source of resistance seen at CPMC as well as in other institutions is the appearance of Enterobacter cloacae as a significant cause of nosocomial infections.1 Enterobacter species became an important organism with the introduction of cephalosporin antibiotics in the 1950s. These organisms unfortunately possess a cephalosporinase type of beta-lactamase that is of chromosomal origin and not normally expressed. Expression of high concentrations of the enzyme is triggered by exposure to many cephalosporins. However, most resistance in Enterobacter is the result of the selection of pre-existing mutant species that produce large amounts of beta-lactamase constitutively. One can anticipate that E. cloacae will remain a significant hospital problem for the coming decade. In spite of attempts to control the spread of the organism among patients, there has been dissemination of the organism in certain areas of the hospital, necessitating the utilization of drugs such as imipenem, which subsequently results in selection of resistant P. aeruginosa or X. maltophilia. |
One could continue with other species of organisms such as Serratia marcesens, Citrobacter freundii, Providencia species and Acinetobacter anitratus, but in many ways they have been less of a problem than the organisms so far detailed. |
Solutions to resistance
Are there any answers to this complicated problem of resistance? One major way to overcome bacterial resistance is to improve hygienic practices and stop the spread of bacteria in a hospital. This can be achieved by proper hand washing and attention to simple practices of sterility when dealing with patients who are infected. The antibiotic control program is an effective method to reduce the inappropriate use of antibiotics in a hospital. Such a program is in effect at CPMC, and as a result many of the more potent drugs are not utilized when a less potent agent is available. |
Unfortunately, such programs do not exist within the community, particularly in residence facilities for the elderly. Hence patients frequently bring multi-resistant bacteria into the hospital. |
The pharmaceutical industry will need to develop new agents to overcome the resistance mechanisms that have been discussed herein. Currently we are working on compounds that appear to inhibit MRSA, E. faecium, resistant Pseudomonas and E. cloacae. However, compounds highly successful in the laboratory setting and in animal protection tests may not prove usable in humans due to toxicity. There will always be a need for new antibiotics, since bacteria have the remarkable ability to overcome each new agent that is synthesized or found in nature. |
Appropriate use of antibiotics has been shown to delay and in many cases prevent the emergence of resistance discussed in this article. In order to reduce resistance, a physician must have an appreciation of the factors that promote resistance, such as situations in which large numbers of organisms are present and an antibiotic concentration adequate to reduce the number of organisms is unlikely to be achieved. |
Hopefully, a program of appropriate use of antibiotics combined with the development of new compounds will provide a way to prevent "superbugs" from overpowering us in the coming decade. There is no question that there will be continued progress in transplantation, chemotherapy of malignancy, and therapy of the severely traumatized patient. Such patients invariably will develop respiratory, urinary and/or wound infections within the hospital. Ideally, these infections will not be caused by organisms that cannot be treated. Antibiotic resistance has had a major impact on this great medical center over the last 30 years. Fortunately, we have not had some of the disastrous outbreaks that have occurred in other institutions around the country. Nonetheless, continued vigilance is necessary so that we do not encounter problems with enterococci, Pseudomonas, or Enterobacter that are resistant to all antibiotics. |
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