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Bacteriostatic Versus Bactericidal

admin — Tue, 02 Sep 2008 10:22:25 +0000

At the MIC the antibiotic is inhibiting growth, but it may or may not actually be killing the organism. Antibiotics that inhibit growth of the organism without killing it are termed bacteriostatic. If antibiotics are taken away, the organisms can begin growing again. However, bacteriostatic antibiotics usually are successful in treating infections because they allow the patient’s immune system to catch up and kill off the organisms. Other antibiotics are considered bactericidal; their action kills the organisms without any help from the immune system. For most infections, outcomes using appro-priate bacteriostatic versus bactericidal drugs are similar; however, for certain infections bactericidal drugs are preferred. These infections include endocarditis, meningitis, osteomyelitis, and infections in neutropenic patients. For these infections, there is reduced contribution from the immune system because of the anatomic location or the immuno-suppression of the patient. Bactericidal activity is determined by taking a sample of the broth at the MIC and below and spreading the broth on agar plates (Figure 3-1). The number of bacterial colonies on the plates are counted and the concentration corresponding to a 99.9% reduction in the original bacterial inoculum is considered to be the minimum bactericidal concentration (MBC). When the MBC is 4 times or less the MIC, the drug is considered to be bactericidal; if the MBC/MIC ratio is greater than 4, it is considered bacteriostatic. Table 3-2 lists drugs according to whether they are generally considered bacteriostatic or bactericidal; however, it should be noted that this activity can vary based on the pathogen being treated, the achievable dose, and the growth phase of the organism.
Besides differing in whether they kill bacteria or merely inhibit their growth, antibiotics also differ in how they manifest their effects over time. Careful studies have revealed that for certain antibiotics, activity against bacteria correlates with the duration of time that the concentration of the drug remains above the MIC (time-dependent activity). For other antibiotics, antibacterial activity correlates not with the time above the MIC but with the ratio of the peak concentration of the drug to the MIC (concentration-dependent or time-independent activity). For some antibiotics, the best predictor of activity is the ratio of the area under the concentration-time curve to the MIC.

Antibiotics Pharmacodynamics

admin — Tue, 02 Sep 2008 10:21:10 +0000

The term antibiotic pharmacodynamics refers to the manner in which antibiotics interact with their target organisms to exert their effects: Does the antibiotic kill the organism or just slow its growth? Is it better to give a high dose of antibiotics all at once or to achieve low concentrations for a long time? Clinicians increasingly recognize such considera-tions as important in maximizing the success of therapy, especially for difficult-to-treat infections or in immunocompromised patients.
Susceptibility Testing
Typically, one judges the susceptibility of a particular organism to an antibiotic based on the minimum inhibitory concentration (MIC) for the organism-antibiotic combination. The clinician determines the MIC by mixing a standard concentration of the organism that the patient has grown with increasing concentrations of the antibiotic in a broth solution. Classically this was done in test tubes (see Figure 3-1), but today it is done more commonly on microdilution plates. The mixture is incubated for about a day, and the clinician examines the tubes or plates (with the naked eye or with a computer) for signs of cloudiness, indicating growth of the organism. The mixture with the lowest concentration of antibiotic where there is no visible growth is deemed to be the MIC. For each organism-antibiotic pair there is a particular cutoff
MIC that is considered susceptible. This particular MIC is called the breakpoint. Table 3-1 provides examples of breakpoints for different organism/ pathogen combinations. Note that just because an antibiotic has the lowest MIC for a pathogen, that does not mean it is the best choice—different antibiotics achieve different concentrations in the body. Thus, antibiotic MICs for a single organism generally should not be compared across different drugs in selecting therapy. Finally, be aware that other methods of susceptibility testing exist, including disk diffusion and E-tests, but that broth dilution methods are generally considered the gold standard.

Case Study

admin — Tue, 02 Sep 2008 10:17:56 +0000

Here is an example of treating a patient with an infection by the above pathway:
TR is a 63-year-old man with a past medical history of diabetes, hypertension, and coronary artery disease who comes to the hospital complaining of pain, redness and swelling around a wound on his foot. Close inspection reveals that he has an infected diabetic foot ulcer. He is admitted to the hospital (Day 1). The clinician performs surgical debridement that evening and sends cultures from the wound during surgery as well as blood cultures. The clinician initiates empiric therapy with vancomycin and piperacillin/ tazobactam.
On Day 2, Gram stain results from the wound are available. There are many white blood cells with many Gram-positive cocci but no Gram-negative rods, so the clinician discontinues piperacillin/ tazobactam. Blood cultures do not grow any organisms.
The following day (Day 3), culture results from the wound reveal many Staphylococcus aureus. Because vancomycin is usually effective against this organism, its use is continued.
On Day 4, susceptibility results from the wound culture return. The S. aureus is found to be susceptible to methicillin, oxacillin, cefazolin, piperacillin/tazobactam, clindamycin, trimethoprim/ sulfamethoxazole, and vancomycin. It is resistant to penicillin, ampicillin, tetracycline, and levoflox-acin. As the isolate from TR’s wound is methicillin-susceptible Staphylococcus aureus (MSSA), the clinician discontinues vancomycin and initiates definitive therapy with oxacillin.
Note how in TR’s case we began empiric therapy with a broad-spectrum regimen of vancomycin and piperacillin/tazobactam to cover the Gram-positive and Gram-negative aerobes and anaerobes that tend to cause diabetic foot infections but narrowed that therapy gradually as Gram stain and culture data returned. Eventually we were able to choose a highly effective, narrow-spectrum, inexpensive, and safe choice of definitive therapy that was driven by microbiology results. Both vancomycin and piperacillin/ tazobactam were active against TR’s Staphylococcus aureus as well, but both are broader in spectrum than oxacillin and represent less-ideal choices of therapy.

Definitive Therapy

admin — Tue, 02 Sep 2008 10:16:14 +0000

After culture and sensitivity results are known, the definitive therapy phase of treatment can begin. Unlike empiric therapy, with definitive therapy we know on what organisms to base our treatment and which drugs should work against them. At this phase it is prudent to choose antimicrobial agents that are safe, effective, narrow in spectrum, and cost effective. This helps us avoid unneeded toxicity, treatment failures, and the possible emergence of antimicrobial resistance and it also helps manage costs. In general, moving from empiric to definitive therapy involves decreasing coverage, because we do not need to target organisms that are not causing infection in our patient. In fact, giving overly broad-spectrum antibiotics can lead to the development of superinfections, infections caused by organisms resistant to the antibiotics in use that occur during therapy.
The clinician who is treating an infected patient should strive to make the transition to definitive therapy. Although it seems obvious, this does not always occur. If the patient improves on the first antibiotic, clinicians may be reluctant to transition to more narrow-spectrum therapy. Also, some infections may resolve with empiric therapy before culture results would even be available, such as uncomplicated urinary tract infections. In other cases, cultures may not be obtained or may be negative in spite of strong signs that the patient has an infection (e.g., clinical symptoms, fever, increased WBC count). In most situations it is important that clinicians continuously consider the need to transition to definitive therapy. Overly broad-spectrum therapy has consequences and the next infection is likely to be harder to treat.

General Approach to Infectious Diseases

admin — Tue, 02 Sep 2008 10:15:03 +0000

The pharmacotherapy of infectious diseases confuses many clinicians, but the approach to the patient with an infection is relatively simple and consistent. Understanding this approach is the first step in developing a useful expertise in infectious diseases and antibiotic use.
Prophylactic Therapy
The use of antimicrobial chemotherapy—that is, the treatment of microorganisms with chemical agents—falls into one of three general categories: prophylaxis, empiric use, and definitive therapy. Prophylaxis is treatment given to prevent an infection that has not yet developed. Use of prophylactic therapy is limited to patients at high risk of complications from an infection, such as those on immunosuppressive therapy, those with cancer, or patients who are having surgery. These patients have weakened natural defenses that render them susceptible to infection. Because the likelihood of infection by some types of organisms in these patients is high and the consequences of infection are dire, we administer antimicrobial drugs to prevent infections from occurring. However, the world is not sterile and breakthrough infections do occur. The key to understanding antimicrobial prophylaxis is to remember that patients who receive it do not have an infection, but are at risk for one.
Empiric Therapy
Unlike prophylactic therapy, empiric therapy is given to patients who have a proven or suspected infection, but the responsible organism(s) has or have not yet been identified. It is the type of therapy most often initiated in both outpatient and inpatient settings. After the clinician assesses the likelihood of an infection based on physical exam, laboratory findings, and other signs and symptoms, s/he usually will collect samples for culture and Gram staining. For most types of cultures, the Gram stain is performed relatively quickly. In the Gram stain, details about the site of infection are revealed, such as the presence of organisms and white blood cells (WBCs), morphology of the organisms present (e.g., Gram-positive cocci in clusters), and the nature of the sample itself, which in some cases describes if the sample is adequate. The process of culturing the sample begins around the time that the clinician performs the Gram stain. After a day or so, biochemical testing will reveal the identification of the organism, and eventually the organism will be tested for its susceptibility to various antibiotics.
However, this process takes several days, so empiric therapy is initiated before the clinician knows the exact identification and susceptibilities of the causative organism. Empiric therapy is our best guess of which antimicrobial agent or agents will be most active against the likely cause of infection. Sometimes we are right, and sometimes we are wrong. Keep in mind that empiric therapy should not be directed against every known organism in nature, just those most likely to cause the infection in question.