In recent analyses, Kollef and Ward [ 78 ] and Ibrahim et al. Many of the failures in these series reflected infection by P. Risk factors for isolation of these pathogens and so for poor outcomes included previous use of antibacterials and previous hospitalization. Such factors, as well as the likely pathogens and their likely local resistance patterns, should always be taken into account when designing empirical regimens for hospital units.
It should be added that the science of pharmacodynamics is allowing more precise modeling of the probability of cure of a given pathogen in a given infection, underscoring the fact that for many infection types, there is a strong relationship between in vitro susceptibility and outcome. These aspects are addressed elsewhere in this supplement by Drusano [ 80 ]. Complications among patients with peritonitis, in relation to whether initial empirical treatment was appropriate group 1, white ; was changed from inappropriate to appropriate after isolation of resistant bacteria group 2, gray ; or was not changed despite the isolation of resistant bacteria group 3, black.
Data are replotted from Mosdell et al. Differences in wound infection rates do not achieve statistical significance. Average lengths of stay were Reproduced with permission from Ibrahim et al. Increased morbidity and mortality are the most dramatic consequence of resistance. Other effects are more insidious. Physicians and surgeons are forced to use previously reserved agents as first-line therapy.
These may be inherently less potent or more toxic that classical regimens: vancomycin is increasingly used as a first-line antistaphylococcal and for prophylaxis but is less convenient to administer safely and less bactericidal than the semisynthetic antistaphylococcal penicillins, which themselves are fold less active than benzylpenicillin against fully susceptible staphylococci.
Previously reserved agents—now used earlier—may be undermined by resistance. The accumulation of cephalosporin-resistant bacteria is driving the earlier clinical use of carbapenems and is a reasonable justification for the development of oral and long half-life carbapenems. Nevertheless, the selection pressure that mass use of these will cause is disturbing, coming precisely when the number of reported carbapenemases is growing sharply [ 81 ].
Finally, resistance adds cost: treatment failures extend the length of hospital stay or demand repeated physician visits; hospital beds are blocked to new patients, and productive time is lost. If new or hitherto reserved antibacterials are needed as therapy, these are usually more expensive than previous regimens.
These costs seem unlikely to decline in the future, especially with the growing demand of regulators and the new costs of genomics-based drug discovery. Concern about resistance increased in the late s. Since then, many governmental and agency reports have been published, adding to those of professional societies [ 82—84 ]. These reports vary in emphasis, especially as regards the agricultural use of antibacterials, but all advise 1 less use of antibacterials, 2 more appropriate choices of antibacterials and regimens, 3 prevention of cross-infection, and 4 development of new antibacterials.
Measuring the effect of these charges demands better surveillance of resistance prevalence and of prescribing. Optimists hold that it may be possible to reverse resistance trends, and pessimists hold that it may only be possible to slow the accumulation of resistance sufficiently to keep one step ahead of bacterial evolution. In a few cases, reductions in prescribing at a national level have been followed by a reduced prevalence of resistance. In one example of success, the prevalence of penicillin-resistant pneumococci in Iceland was reduced from By , however, macrolide use had increased to 2.
In both these cases, the resistances displaced were associated with clonal strains—two widely disseminated S. Displacement seems more difficult when resistances are multiple and linked and when they have disseminated among different strains. Resistance to streptomycin and chloramphenicol remains frequent in gram-negative bacteria, although these drugs have fallen into virtual disuse in humans, and are compromised by mechanisms that do not directly affect any antibacterial that remains in extensive human use [ 88 ].
The continued prevalence of resistance in disused antibacterials begs the question, Why? Potential contributory factors include continued agricultural use and—as was shown with the sulfonamide resistance in E. More generally, evolution acts to favor those determinants that exert the least fitness cost on their host bacteria and those strain variants in which this cost is minimized.
Thus, once antibacterials have been used heavily for long periods, evolution seems likely to have honed the resistant strains. Laboratory experiments illustrate how this process may arise. Similarly, the growth rate of a streptomycin-resistant E. Such well-adapted strains are unlikely to be swiftly displaced.
Some plasmids have specific binding sites to the chromosome, favoring segregation with each daughter cell. So long as the plasmid is present, antitoxin is manufactured and the cell survives, but residual toxin kills any daughter cell that fails to inherit a plasmid copy [ 91 ]. Such factors maintain plasmid carriage within populations, increasing the pressure to minimize the fitness cost.
It remains plausible but unproven that a generalized reduction in prescribing may lead to a reduction in resistance prevalence. An answer may be forthcoming. Since an annual peak in — the British financial year runs from April to March , antibacterial prescriptions in the community have decreased by Although there are few examples of reducing resistance on any large scale, there are many examples of altered rather than reduced prescribing being followed by changes in the local epidemiology of resistance.
A formulary switch to amikacin was followed, over several years, by declining gentamicin resistance among opportunistic gram-negative bacteria [ 92 , 93 ]. More recently, Bradley et al. A return to empirical ceftazidime was followed by a reemergence of vancomycin-resistant enterococci, despite continued emphasis on infection control.
Other examples of apparent success include reductions in the prevalence of AmpC-derepressed Enterobacter spp. Incidence of colonization and infection with vancomycin-resistant enterococci in a London hematology unit in relation to preferred empirical therapy.
These examples highlight positive consequence, but caveats should be noted. First, changes that achieve positive consequences are perhaps more likely to be reported than those that fail to do so. Second, others who followed these strategies were not always so successful.
Formulary switches from gentamicin to amikacin have been associated with increasing amikacin resistance [ 99 ]. Third, authors often concentrate on one pathogen and demote other effects; thus, deaths owing to multidrug-resistant gram-negative bacteria occurred in both the ceftazidime and piperacillin-tazobactam arms of the study outlined in table 5 [ 94 ], and a formulary switch from cephalosporins to imipenem was followed by the emergence of imipenem-resistant Acinetobacter and P.
Among opportunistic infections in the seriously ill, the cynic can argue that resistance is like a balloon: squeeze it on one side, and it bulges on the other. It is salutary to emphasize how much remains unknown. Does drug cycling have positive effects, or does it lead to the accumulation of multidrug-resistant strains [ ]? At what prevalence of resistance should empirical therapy be changed in different types of infection? To what extent does combination therapy militate against resistance except in the case of tuberculosis, where its value is beyond dispute?
What are the relative selectivities of different antibacterials, allowing that a recent Finnish study found a correlation between macrolide use and resistance in S. Is it in any way desirable to encourage all community physicians to use the same therapies in the same indications, or is it wiser to make the selection pressure more diffuse [ ]? What is the ideal duration of therapy, allowing that underdosing may fail to eliminate the least susceptible members of the original population and that excessive duration may exacerbate disruption of the normal flora?
Are drugs with unlinked resistances e. The new respiratory quinolones exemplify a further conundrum. As a result of greater antipneumococcal activity, they are less likely to than ciprofloxacin to select first-step quinolone-resistant mutants of S. The scientific answers to these questions on antibacterial use are uncertain, and to complicate matters, the whole problem of resistance is intertwined with moral, social, political, and commercial issues.
Concern about resistance is used as ammunition for other agendas, most obviously including marketing by the pharmaceutical industry and cost containment within managed or socialized health care. To some extent, the individual patient gains when powerful antibacterials are used early, but the resistance risks for society are raised.
In reality, matters are complex. Hungary, before , had a restricted list of antibacterials for community prescription, yet achieved one of the world's highest prevalence rates for penicillin-resistant pneumococci [ ]. Moreover, the argument assumes a vacuum in which no new drugs are developed. This assumption, made in many reports on resistance, is already untrue for gram-positive pathogens [ ]. Concerns about resistance have led to the banning of most agricultural growth promoters in Europe.
Such concerns are also used to support wider objections to intensive farming and to the genetic modification of crop plants where unexpressed resistance genes remain within the cloning vectors. Less is said on the other aspects of modern life that potentially exacerbate resistance: large hospitals; the concentration of the very young and very old in socialized care; and increasing travel.
Action on these would be socially and politically impossible, even if they are more pertinent to the sum total of resistance than the use recently banned in the European Union of zinc bacitracin as a agricultural growth promoter! Both concerns are ethical, humane, and honorable—but counterpoised. Antibacterial resistance is complex and dynamic. Although the major genetic and biochemical mechanisms have long been recognized, new factors continue to be discovered, including integrons, multidrug efflux, hypermutability, and plasmid addiction.
Within many individual isolates, the complexity of resistance is increasing, with multiple determinants carried, and with genes being gained, amplified, and lost. Many international resistance problems reflect the spread of a few multidrug-resistant strains, but the reasons underlying the success of particular lineages remain almost universally obscure. Resistance is a significant cause of excess morbidity, mortality, and cost.
Numerous reports have emphasized the need for less and better use of antibacterials, improved infection control, and the development of new agents. However, reductions in antibacterial use do not always lead to reduced resistance, perhaps because bacteria are now well adapted to the carriage of resistance.
Download data: Drug-resistant C. Also known as: C. Download data: C. About : CRE are a major concern for patients in healthcare facilities. Some Enterobacterales are resistant to nearly all antibiotics, leaving more toxic or less effective treatment options. About : N. Download data: Drug-resistant N.
About: Campylobacter usually causes diarrhea often bloody , fever, and abdominal cramps, and can spread from animals to people through contaminated food, especially raw or undercooked chicken. About: Dozens of Candida species—a group of fungi—cause infections, ranging from mild oral and vaginal yeast infections to severe invasive infections. Many are resistant to the antifungals used to treat them. They can spread rapidly and cause or complicate infections in healthy people.
Estimated cases in hospitalized patients in : , About: Enterococci can cause serious infections for patients in healthcare settings, including bloodstream, surgical site, and urinary tract infections. About: P. Download data: Multidrug-resistant P. About: Nontyphoidal Salmonella can spread from animals to people through food, and usually causes diarrhea, fever, and abdominal cramps. Some infections spread to the blood and can have life-threatening complications.
About: Salmonella Typhi causes a serious disease called typhoid fever, which can be life-threatening. Most people in the U. About: Shigella spreads in feces through direct contact or through contaminated surfaces, food, or water. Most people with Shigella infections develop diarrhea, fever, and stomach cramps. About : S. MRSA can cause difficult-to-treat staph infections because of resistance to some antibiotics.
Abstract The ongoing explosion of antibiotic-resistant infections continues to plague global and US health care. Open in new tab Download slide. Antimicrobial resistance: a growing threat to public health.
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Issue Section:. Download all slides. Comments 0. Add comment Close comment form modal. I agree to the terms and conditions. You must accept the terms and conditions. Add comment Cancel. Submit a comment. As with addressing climate change, protecting biodiversity, or COVID, global cooperation is needed to reduce the evolution and spread of resistance.
The two experts concluded that once better hygiene and sanitary conditions exist on a global scale, our dependence on antibiotics will be reduced as a result of greater access to clean water. The World Health Organisation WHO has recently published new recommendations for tackling the spread of antimicrobial resistance.
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