July 7, 2009 | In: GENERAL TOPICS
ANTIBIOTICS
11. Are antibiotics the classic wonder drugs?
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Only because you wonder if they are going to work, if they are going to cause more harm than good, and if the next generation will be unaffordable or toxic.
Skepticism is healthy with regard to any procedure or agent in heath care but especially with regard to antibiotics, which are embraced almost universally as agents that both prevent and cure infections. The primacy of the host defense in this vital process and the potential interference by the very drugs given credit for infection control are overlooked. We must look critically at the limited role that antibiotics should play in health care and restrain their overuse, which generates even more harm than unnecessary expense.
12. What is meant by generations of antibiotics, as in third-generation cephalosporins?
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The earliest antibiotics were bacteriostatic, largely through interference in protein synthesis, so that they might keep a microorganism from reproducing even if they did not kill it. The difference between infestation (presence of living microbes in the host) and infection (replication and spread of microorganisms in the host) may be useful in understanding how earlier drugs possibly controlled infection but were less capable of eliminating organisms in any brief period of therapy.
Penicillin changed all that. It may be the first antibiotic with a legitimate claim to the title “wonder drug” because it has the microbicidal capability of eradicating sensitive organisms. Penicillin was the first generation of the beta-lactam antibiotics, joined by the congener first-generation cephalosporins (e.g., cefazolin). They shared beta-lactam structure and had good gram-positive coverage with less range in any effect over gram-negative microbes.
The second-generation beta-lactam antibiotics (e.g., cefoxitin) covered new classes of microbes beyond gram-positive aerobes, such as many of the Bacteroides species, but had little effect on gram-negative aerobic microbes. Because the third-generation cephalosporins covered some of the latter microbes, they were touted as single-agent therapy for all principal-risk flora.
As with penicillin, the original wonder drug, the wonderment waned with failures of the new agents because of rapidly induced antimicrobial resistance. The most easily measured and calculated difference in the generations is cost: wholesale values are about $2.00/g for the first generation, $5.00/g for the second, and $30.00/g for the third. Despite this bracket creep in cost, the higher generations lose some of their potency against the original gram-positive organisms for which the first-generation agents were truly wonderful. Therefore, it takes 2 g of moxalactam to be half as good as 1 g of cefazolin for gram-positive coverage. It does not take a pharmacoeconomist to ask, “What have I got in return for this 60-fold surcharge?”
13. What is the role of third-generation cephalosporins in surgical prophylaxis?
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None (no more wondering here!). If the principal-risk flora are gram-positive, the first generation is better; if the anaerobic risk is sizable, the second generation is better. And either class is cheaper by far and seems to have generated less resistance than the third-generation cephalosporins, which are unconscionably expensive for use in prophylaxis and rarely as effective as other single-agent therapy for established surgical infection. Specific indications, such as pediatric meningitis, hospital-acquired pneumonia, or other specific infections outside the indications of surgical predominance, might use or exclude these agents.
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14. How do enzyme inhibitors combined with antibiotics enhance their antimicrobial spectrum?
Microorganisms have defense mechanisms of their own, and the strains that have the capacity to make antibiotic-degrading enzymes achieve an unnatural selection advantage with the widespread use of antibiotics. This is what happened to penicillin: penicillinases emerged. But clever pharmaceutical manufacturers closed that loophole for bacterial ingenuity in degrading penicillin by strategic placement of a methyl group to ruin the survival fitness of penicillinase producers. Methicillin was the result, but the persistence of the microbes means that we now have a plague of methicillin-resistant Staphylococcus aureus (MRSA). Besides, microbes outnumber pharmaceutical manufacturers and have a shorter turnaround time than the approval process of the Food and Drug Administration (FDA). Microbes will always be ahead of us in ingenuity if only because of their numbers.
Newer strategies by the bacteria included the production of beta-lactamases. The response of the pharmaceutical industry was a group of inhibitors of beta-lactamase, such as clavulanic acid or sulbactam. The combination of a beta-lactamase inhibitor with a modified penicillin such as ampicillin should have enhanced activity against bacteria that produce beta-lactamase, provided that they were ampicillin-sensitive in the first place. Higher doses of the original agent for a shorter time may accomplish the same effect, often at lower cost, because the combined drugs were developed much more recently and are under patent protection.
15. What are the most expensive kinds of antibiotic therapy?
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* Drugs that are given when they are not needed.
* Drugs that are badly needed but do not work.
* Drugs that cause more harm than good because of host toxicity, whatever their antibiotic potential.
16. Can oral antibiotics be given in place of intravenous antibiotics in seriously ill surgical patients?
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Yes, if only they could take them! These patients almost invariably can take nothing by mouth (NPO), are often unconscious, and are as likely as not to be on a ventilator. In addition, the gut has been put out of commission by nasogastric suction tubes, laparotomy, and ileus, and primary intraabdominal problems often associated with the need for the antibiotics, such as intraabdominal sepsis and pancreatitis. Usually such patients are on complete gut rest and are likely to be on parenteral nutrition as well.
The attempt to use some form of gut-delivered antibiotic is based on the favorable pharmacokinetics and spectrum of quinolones, which can be started intravenously and switched as soon as possible to the oral form when feeding has resumed. Nearly all such patients begin on some form of intravenous (IV) antibiotic program and the start-up of the antibiotic regimen is more important than the form to which patients are tapered before treatment is discontinued.