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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Association of Medical Microbiology and Infectious Disease (AMMI) Canada/ Canadian Association for Clinical Microbiology and Infectious Diseases (CACMID) Annual Conference

Edmonton, Alberta / May 6-8, 2010

When selecting an antimicrobial therapy to treat a complex infection, one of the factors often considered is whether the drug is bactericidal or bacteriostatic. However, Dr. Edward A. Dominguez, Methodist Transplant Physicians, Dallas, Texas, questioned the clinical utility of this distinction.

As he explained to the audience here at AMMI-CACMID, there are two ways in which this property of a drug may be determined. The first is the ratio of minimum bactericidal concentration (MBC) to minimum inhibitory concentration (MIC). A drug with an MBC:MIC ratio of =16 is considered to be bacteriostatic, while a ratio =4 indicates a bactericidal drug. More commonly, the time-kill curve is used. A bactericidal drug is one which causes a >3-log reduction in colony-forming units (CFU)/mL after 24 hours’ incubation in liquid media using a standard inoculum of 5 X 105 CFU/mL in a volume of 0.01 mL.

These standardized criteria, however, may not correspond with clinical reality. Dr. Dominguez pointed out a number of important ways in which the clinical behaviour of the drug may differ from in vitro testing. In the patient, the antibiotic is subject to serum protein binding and differences in pH. Testing is done in log-phase growth, whereas bacteria in infection sites are often in stationary phase, and may be present in concentrations as high as 1010 CFU/g of tissue. Some bactericidal antibiotics have been shown to be ineffective at these concentrations, he noted.

Some antibiotics may show different properties according to the treated organism. Macrolides, for example, while classified as bacteriostatic, have shown in vitro bactericidal activity against Streptococcus pneumoniae and S. pyogenes; similarly, the bacteriostatic agent linezolid is bactericidal against S. pneumoniae when used in high doses to treat pneumonia and bacteremia, indicated Dr. Ethan Rubinstein, Head, Section of Adult Infectious Diseases, University of Manitoba, Winnipeg.

Bactericidal antibiotics have been shown to have bacteriostatic activity on some organisms. Furthermore, Dr. Dominguez noted that use of bactericidal antibiotics can cause an endotoxin surge in some types of infection, such as enterohemorrhagic Escherichia coli and infant botulism, due to rapid lysis of the bacteria. In pneumococcal meningitis, cerebral edema may be increased. Conversely, the use of bacteriostatic antibiotics might reduce toxin release, as with clindamycin, which inhibits toxic shock syndrome toxin 1 (TSST-1) production in Staphyloccus aureus.

Clinical comparisons between bactericidal and bacteriostatic agents have shown comparable efficacy in some indications. Dr. Dominguez cited comparisons between tigecycline (bacteriostatic) and levofloxacin (bactericidal) in community-acquired pneumonia (CAP) (cure rates 89.7% and 86.3%, respectively) and linezolid vs. the bactericidal vancomycin (53% vs. 52%) in nosocomial pneumonia. Similarities in efficacy between drugs allow other considerations to help determine drug choice, such as route of administration, risk of resistance and adverse effect profile.

Pharmacokinetics and Pharmacodynamics

Dr. Lynora Saxinger, Associate Professor, Division of Infectious Diseases, University of Alberta, Edmonton, explained the ways in which the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug can have a substantial effect on its efficacy in specific therapeutic settings. Exposure of bacteria to the drug depends not only on the dose used, but also on the function of the clearing organ and the effect site penetration. Drugs do not disperse evenly through body tissues and fluids, explained Dr. Saxinger, but are distributed heterogeneously. Drug concentrations in the epithelial lining fluid (ELF) are important for the treatment of pulmonary infections. Compared to serum levels, beta-lactams tend to have lower concentrations in the ELF, while macrolides tend to be higher in the ELF than in the serum. Quinolones all achieve higher ELF concentrations. As specific examples, azithromycin and linezolid levels are 13 and 2 times higher in the ELF than in serum, respectively, while those of ceftazidime are only 0.2 of serum concentrations, Dr. Saxinger noted. Tigecycline was also low, with ELF levels 0.18 or lower compared to serum levels over 12 hours. “The second half of the PK/PD equation is the MIC,” emphasized Dr. Saxinger.

As well as variations between organisms, MIC can vary in different patient populations. For example, the MIC for tigecycline was higher in patients with ventilator-acquired pneumonia (VAP) than in patients with CAP (Rubino CM. ICAAC 2009). Thus, knowledge of the MIC of a drug for a particular organism in a specific patient population can be valuable in determining the treatment regimen. In the case of vancomycin, the target 24-hour AUC:MIC is 400. Del Mar (Intensive Care Med 2007;33:279-85) showed that this is achievable for most patients with an MIC of 1 or less. However, in patients with glycopeptide intermediate-resistant S. aureus (GISA) infections, the probability of attaining the target value is much lower. Furthermore, another study (Lodise et al. Antimicrob Agents Chemother 2008; 52(4):1330-6) indicated an increasing risk of nephrotoxicity in patients who required 4 g/day or more of vancomycin to achieve therapeutic levels (34.6% of patients with nephrotoxicity compared to 6.7% in a control group treated with linezolid).

CANWARD Results

Antibiotic-resistant nosocomial bacterial strains are widespread problem, leading to greater morbidity and mortality, as well as increasing need for laboratory testing, infection control measures, the use of more expensive antimicrobials, and longer hospital stays. Researcher Melanie DeCorby, Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, presented 2009 data from CANWARD (Canadian Ward Surveillance Study), an ongoing program to monitor the prevalence and progression of resistant pathogens in Canadian hospitals. Since 2007, CANWARD has published annual data on the status of these organisms. Among the gram-positive organisms, MRSA accounted for 21.1% of S. aureus infections across Canada; however, there was considerable regional variation, from 22.8% in Ontario to 10% in the Maritimes. Analysis of the relative proportion of community-acquired MRSA (CA-MRSA) to hospital-acquired organisms (HA-MRSA) showed even greater variation, from 56.9% CA-MRSA in the West to just 5.1% in Quebec, with a national average of 31% CA-MRSA.

“MRSA has levelled off in many areas,” reported Dr. Stephen Shafran, Professor, Division of Infectious Diseases, University of Alberta, “although we are seeing more and more clindamycin resistance in the community isolates. We’re seeing more blending between community- and hospital-acquired isolates, and we may one day stop saying ‘community-acquired’ vs. ‘hospital-acquired’ because the community is the hospital; patients go back and forth, and the distinction is increasingly less.” Clindamycin resistance now stands at 46.6%, while resistance to ceftriaxone, ciprofloxacin and clarithromycin is very high. On the other hand, CANWARD reported no MRSA resistance to daptomycin, linezolid, tigecyline or vancomycin in 2009.

Considerable regional variation in the distribution of a number of gram-positive organisms was seen. As a result, DeCorby emphasized, “It’s important to know what’s happening in your hospital and to be familiar with your local antibiograms.”