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New Intervention Strategies for Reducing Antibiotic Resistance^*

^* From Tyler Hospital, Tyler, TX.

	Abstract

TOP Abstract Introduction ß-Lactam Resistance in... Recovery of Antibiotic... Management of Antimicrobial... Appendix 1 References

 
Rising antibiotic resistance rates among bacterial pathogens have resulted in increased morbidity and mortality from nosocomial infections. Widespread use of certain antibiotics, particularly third-generation cephalosporins, has been shown to foster development of generalized ß-lactam resistance in previously susceptible bacterial populations. Reduction in the use of these agents (as well as imipenem and vancomycin) and concomitant increases in the use of extended-spectrum penicillins and combination therapy with aminoglycosides have been shown to restore bacterial susceptibility. Studies have shown that education-based methods, as opposed to coercive measures, are effective in changing the prescribing habits of physicians. Cooperative interaction among infectious-disease physicians, clinical pharmacists, microbiology-laboratory personnel, and infection-control specialists is essential to provide useful suggestions regarding antibiotic choice and dosing to the prescribing physician in real time. Several hospitals have implemented antimicrobial resistance management programs based on these findings. The results of these programs validate the use of a multidisciplinary, education-based, antibiotic-resistance management approach.

Key Words: antibiotic resistance • antibiotic susceptibility • extended-spectrum penicillins • nosocomial infections

	Introduction

TOP Abstract Introduction ß-Lactam Resistance in... Recovery of Antibiotic... Management of Antimicrobial... Appendix 1 References

 
Mortality and morbidity resulting from infectious disease have increased in recent years despite the introduction of powerful new antibiotics. Overall infectious disease mortality increased by 58% from 1980 to 1992, and age-adjusted mortality increased by 39%.¹ Respiratory tract infections increased by 20% and sepsis increased by 83% over the same time period. After decades of decline, the danger from infectious disease is now on the rise.

Much of this increase can be traced to the spread of antibiotic resistance among pathogenic bacteria. Antibiotic resistance is particularly pronounced in nosocomial infections.² Inappropriate use of antibiotics contributes to increased bacterial resistance both by selecting for the more resistant members of a population and by eliminating the patient’s indigenous flora, which might otherwise compete with the pathogen. Use of antibiotics at suboptimal levels, or for too little time, encourages the development of resistance.

Antibiotics represent a significant portion of overall health-care costs—from 20 to 50% of total hospital drug expenditures.³ Over half of all hospitalized patients are treated with antibiotics,³ and it has been estimated that 50% of all antibiotics prescribed are either the wrong drug, the wrong dose, or are taken for the wrong duration.⁴ In addition to its potential to increase mortality, antibiotic resistance increases costs by increasing the length of stay in the hospital.^{5 ,6} Slowing the spread of resistance requires changes in the pattern of antibiotic use.

	ß-Lactam Resistance in Bacterial Pathogens

TOP Abstract Introduction ß-Lactam Resistance in... Recovery of Antibiotic... Management of Antimicrobial... Appendix 1 References

 
Troublesome bacterial pathogens include Gram-negative rods, such as Pseudomonas aeruginosa, Enterobacter sp, Citrobacter sp, Acinetobacter sp, Serratia sp, and certain Gram-positive organisms, such as Enterococcus sp and methicillin-resistant Staphylococcus aureus. Resistance to ß-lactams in Gram-negative bacteria most often involves their production of a ß-lactamase.⁷ Plasmids may carry either a standard ß-lactamase or a broad-spectrum ß-lactamase of the SHV or TEM family. These latter enzymes were first observed in Klebsiella sp but have since spread to Escherichia coli and other Gram-negative rods.^{7 ,8} Bacteria harboring an inducible chromosomal amp-C ß-lactamase may remain sensitive to ß-lactam agents that are weak inducers of the enzyme’s production. Mutation, however, can result in constitutive high-level production of ß-lactamase sufficient to confer resistance to a wide range of ß-lactams, as has been observed in some species of Enterobacter, Citrobacter, Serratia, and Pseudomonas.⁷ Metallo-enzyme carbapenemases are found in Stenotrophomonas (formerly Pseudomonas, Xanthomonas) maltophilia, Bacillus sp, and Bacteroides fragilis.⁷

Generation of ß-lactam resistance has been extensively studied in Enterobacter. Use of cefoxitin and third-generation cephalosporins is particularly likely to cause ß-lactam resistance. These mutants are usually resistant to both third-generation cephalosporins and penicillins. Cephalosporin therapy is thus prone to failure owing to the selection of highly resistant mutants during the course of treatment, even when the pathogen was initially sensitive to cephalosporins.

	Recovery of Antibiotic Susceptibility by Changes in Antibiotic Use

TOP Abstract Introduction ß-Lactam Resistance in... Recovery of Antibiotic... Management of Antimicrobial... Appendix 1 References

 
Widespread use of third-generation cephalosporins has been correlated with increased incidence of ß-lactam resistance in Gram-negative bacteria.⁹ Several studies have shown, however, that although overuse of antibiotics can foster the rise of resistance, appropriate changes in antibiotic use can lead to recovery of susceptibility. Ballow and Schentag¹⁰ observed that increased use of ceftazidime at the Millard Fillmore Hospital in Buffalo, NY, resulted in an increase in cephalosporin resistance among Enterobacter cloacae isolates from 17 to 46% between 1988 and 1990. Substitution of piperacillin plus an aminoglycoside for ceftazidime resulted in a reversal of the previous trend, reducing ceftazidime resistance to 25% within 2 years and causing a similar recovery of penicillin susceptibility. A similar result was obtained at the University of Iowa Hospitals and Clinics where increased ceftazidime use correlated with an increase in Gram-negative resistance not only to cephalosporins, but also to piperacillin.⁵ Despite an antibiotic restriction program that required prior approval of all third-generation cephalosporins, an outbreak of extended-spectrum ß-lactamase-producing Klebsiella occurred at a community hospital in Queens, NY. In addition, all cephalosporin/cephamycin derivatives became ineffective against a growing proportion of Klebsiella isolates. A study was designed to test whether cephalosporin resistance could be reversed by withdrawing the selective pressure incurred by use of these agents. The hospital-wide cephalosporin class restriction resulted in a 44% reduction in ceftazadine-resistant Klebsiella infection and colonization. However, as a result of the restriction, imipenem use rose by over 140%. The incidence of imipenem-resistant P aeruginosa increased by 68.7%.¹¹ This increased resistance was then partially reversed by a 50% decrease in ceftazidime use.⁵ An outbreak of ceftazidime-resistant Klebsiella pneumoniae at a veterans’ hospital in Cleveland, OH, increased ceftazidime resistance from 6 to 28% in 1 year, but the resistance rate was reduced to 10% < 1 year after implementation of a policy that decreased ceftazidime use 50% and significantly increased the use of piperacillin/tazobactam.¹² No change in resistance to piperacillin/tazobactam was observed despite the sharp increase in its use. Taken together, the above studies suggest that when antipseudomonal penicillin (piperacillin), with or without an aminoglycoside, replaced ceftazidime, high-level antibiotic resistance in Gram-negative organisms could be reduced. In addition, the substitution of piperacillin for ceftazidime has been found to improve patient outcome. A 25-center study has shown that piperacillin is more effective than ceftazidime (when each is used in combination with tobramycin) for treatment of nosocomial lower respiratory tract infections.¹³

Vancomycin-resistant Enterococcus (VRE) is another major cause for concern. VRE risk factors include broad-spectrum antibiotic use, cephalosporin or vancomycin use, immunosuppression, and lapses in infection-control measures. In response to an outbreak of VRE, Noskin et al implemented strict guidelines that reduced third-generation cephalosporin use by 81%, with concomitant increases in the use of ampicillin/sulbactam (73%) and piperacillin (20%). Even though vancomycin use was unchanged, VRE isolates decreased significantly.

A similar approach was used to deal with outbreaks of both VRE and Clostridium difficile colitis at a veterans’ hospital in Brooklyn, NY.¹⁴ Use of third-generation cephalosporins, vancomycin, and clindamycin was curtailed, and use of ampicillin/sulbactam and piperacillin/tazobactam was increased. The choice of penicillin/ß-lactamase inhibitors was particularly appropriate in this case since they provided coverage of C difficile, which had been lacking with the previous cephalosporin regimen. Fecal colonization with VRE decreased from 47 to 15%, and the incidence of C difficile dropped over 50% within 1 year of the shift in antibiotic use. An outbreak of clindamycin-resistant C difficile diarrhea at a Veteran’s Affairs Medical Center in Virginia was not controlled by implementation of barrier precautions and patient isolation.¹⁵ However, limiting clindamycin use and substituting other drugs with antianaerobic activity such as a penicillin/ß-lactamase inhibitor combination controlled the outbreak. C-difficile-associated diarrhea decreased more than threefold, and clindamycin susceptibility rose from 9 to 61% after the restriction.

	Management of Antimicrobial Resistance

TOP Abstract Introduction ß-Lactam Resistance in... Recovery of Antibiotic... Management of Antimicrobial... Appendix 1 References

 
Programs for the management of antimicrobial resistance usually include modifications of antibiotic use, especially in the decreased use of third-generation cephalosporins (particularly ceftriaxone), imipenem, and vancomycin and increased use of extended-spectrum penicillins and combination therapy with aminoglycosides.^{5 ,10 ,12 ,14} Such programs also require strict adherence to infection control procedures and timely dissemination of bacterial susceptibility data.¹⁶ Methods to alter antibiotic use patterns include implementation of a restricted antibiotic formulary, the requirement of prescription approval by an infectious disease (ID) specialist, use of antibiotic stop orders or antibiotic order forms,^{17 ,18} and education-based intervention.¹⁹ A restricted formulary can limit the use of broad-spectrum and expensive agents but can also lead to overuse of a small subset of approved drugs. Antibiotic stop orders and order forms increase paperwork and may or may not improve therapeutic outcomes. Mandatory ID approval and restrictive formularies can also lead to conflict among the medical staff members.

Physician education is an important part of an antibiotic resistance-management program. Such education should emphasize outcomes rather than cost to foster physicians’ acceptance of antibiotic-use recommendations.¹⁹ Education-based intervention is most effective when the prescribing physician perceives it as assistance rather than as a restriction. The best approach is to provide real-time feedback and educated suggestions and then to allow the physician to make the final decision based on this information. Advantages of the educational approach include reduced red tape, less conflict, a greater diversity in antibiotics prescribed, and the direct involvement of infection control specialists and microbiologists. In addition, recruiting physicians (especially those on the staff of ICUs, where antibiotic resistance is most severe) as participants in the implementation of improved antibiotic utilization procedures results in increased compliance.¹⁹

The overall goals of any antibiotic resistance control program should be to improve antibiotic utilization, reduce antibiotic resistance, improve patient outcomes, and reduce antibiotic expenditures. Such a program requires the cooperation of hospital personnel at all levels, including clinical pharmacists, microbiologists, infection-control specialists, ID specialists, and prescribing physicians.^{18 ,20}

Education can be accomplished by a variety of means. An antibiotic review subcommittee to the pharmacy and therapeutics committee can be created to engage in discussions at section meetings, circulate newsletters, and speak at grand rounds. Updated antibiograms should be provided to clinicians at least once a year to ensure that the data are current and thus useful.¹⁸ Separate unit-specific antibiograms are also useful to inform ICU physicians of the pathogen and resistance data within their own unit. In addition, a properly trained clinical pharmacist can provide daily patient-specific intervention data, recommend IV-to-oral switches, or streamline antimicrobial therapy when appropriate.²¹

Computerized data tracking, as implemented at LDS Hospital in Salt Lake City, UT,³ and at Millard Fillmore Hospital in Buffalo, NY,²¹ increases the speed and decreases the workload associated with antibiotic use management.

A program to curb antimicrobial resistance was implemented at our institution in 1994 (Fig 1 ). From 1994 to 1997, use of third-generation cephalosporins and imipenem has decreased significantly, while piperacillin/tazobactam use has increased dramatically. During the same period, Gram-negative resistance to ß-lactam antibiotics has decreased significantly, and overall antibiotic expenditures have fallen significantly.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Structure of an antibiotic resistance control program.

	Appendix 1

TOP Abstract Introduction ß-Lactam Resistance in... Recovery of Antibiotic... Management of Antimicrobial... Appendix 1 References

 
Dr. Bowton: Piperacillin/tazobactam is our preferred nosocomial pneumonia and ICU drug, plus or minus vancomycin because we have lots of methicillin-resistant S aureus. We encourage the use of piperacillin/tazobactam rather than ceftazidime because of the resistance that ceftazidime generates when it is used.

Dr. Campbell: Why would cephalosporins in general tend to be more active in inducing resistance than penicillins?

Dr. Yates: Cephalosporins probably just induce overgrowth of Enterococcus.

Dr. File: So you are saying that it is just a numbers game? That the more Enterococcus there is, the more likely there is to be resistance?

Dr. Yates: Yes. At another hospital in Indianapolis, IN, the primary risk factor for resistant Enterococcus was ceftriaxone. If ceftriaxone gets in at high concentrations, it wipes out all the other flora. Enterococcus would flourish in that situation.

Dr. File: Several clinicians indicate that cephalosporins should not be used empirically because of their tremendous selection pressure, not only for Enterococcus, but also for these other resistance patterns we are seeing.

Dr. Yates: When we asked our different sections not to use cephalosporins, we did not raise cost issues, we raised the issue of VRE. Everyone was very concerned about VRE and wanted to know how to prevent it. That is why I think we got pretty good compliance with our push toward penicillins and away from cephalosporins and oral vancomycin.

Dr. Campbell: With a 1,000-bed hospital, and, say, 350 people receiving antibiotics, a clinical pharmacist would have to work on your program as his only job. We would really have to convince administration that it saves money, because this is a huge commitment.

Dr. Yates: Yes, it is. It must have cost about $100,000 per year, so it took a lot of work to convince the hospital administration to go along with it.

Dr. File: I congratulate you on developing this model. This is something we can all benefit from. This kind of work is very helpful in convincing administrators.

Dr. Yates: It is fine to come out with intelligent, well-thought-out guidelines, but if in practice those guidelines are not being followed, they are worthless. What this model does is help disseminate pharmacodynamic knowledge, how to dose antibiotics, clinical knowledge, and use of guidelines. And it gets that information to physicians in a more forceful and complete manner. The pharmacist has to be a pleasant person and have a pretty thick skin in a program like this. And it is important that it be known that the recommendations of the pharmacist are supported by the ID physician. You cannot come across as the antibiotic cost police.

Dr. Segreti: We have had a similar program in place for the last 10 years, but ours has been driven more by cost rather than susceptibility. We now have a 95% compliance rate. (But in a pilot study, we did not see any difference in outcomes between those patients for whom we recommended antibiotic changes and those we did not.)

	Footnotes

 
Correspondence to: Richard R. Yates, MD, 619 S Fleishel, Suite 200, Tyler, TX 75701; e-mail: yatesr@trimofran.org

Abbreviations: ID = infectious disease; VRE = vancomycin-resistant Enterococcus

	References

TOP Abstract Introduction ß-Lactam Resistance in... Recovery of Antibiotic... Management of Antimicrobial... Appendix 1 References

 

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