<p>Bacteria are responsible for up to 70% of all ocular infections including conjunctivitis, keratitis and endophthalmitis. If left untreated, a reduction of visual acuity, and in severe cases, sight loss, is possible. Treatment usually consists of a topically applied antibacterial preparation for patients with superficial infections. With intraocular infections, topical administration is augmented with systemic treatment or local instillation. While several types of drugs are available for ocular therapy, the fluoroquinolone class of antimicrobials is especially effective. This is due in part to their broad-spectrum of activity and low toxicity. However, as with any globally prescribed antimicrobial agent, bacterial resistance is an issue. Over the past 10 years there has been a decline in the effectiveness of older fluoroquinolones (ciprofloxacin and ofloxacin) in treating Gram-positive and, to a lesser extent, certain Gram-negative infections. In response to the declining activity of ciprofloxacin and ofloxacin, newer fluoroquinolones have been developed such as levofloxacin (L-isomer of ofloxacin), and more recently, gatifloxacin and moxifloxacin.
In order to ensure the most potent drugs are being used to treat the most serious types of infection, studies need to be done to assess the activity of the current antimicrobial arsenal against pertinent infecting organisms. Three different types of experiments can be done to achieve this. In vitro potency can be tested two ways. The first is minimum inhibitory concentration (MIC). This test defines the concentration of antimicrobial drug that prevents growth of bacteria when tested against an inoculum of approximately 105 colony forming units (CFU)/ml. The second is the mutant prevention concentration (MPC), which is the amount of drug needed to inhibit a first step resistant mutant. This is a relatively new approach to measuring fluoroquinolone potency; like MIC it is not a measure of kill. A separate set of experiments are needed to assess in vitro killing. Kill curves measure the ability of an antimicrobial agent to reduce/kill a bacterial population over a period of 24 hours.</p><p>Because bacterial loads can vary greatly in in vivo infections, kill curves were conducted on a series of four inoculum sizes ranging from 106 to 109 cfu/ml. Some of the most common ocular pathogens are <i>Streptococcus pneumoniae</i>, <i>Staphylococcus aureus</i>, <i>Haemophilus influenzae</i> and <i>Pseudomonas aeruginosa</i>. <i>Mycobacterium fortuitum</i> and <i>Mycobacterium chelonae</i>, while much less commonly associated with ocular disease, are capable of causing vision-threatening infections. As a result, the above six organisms were used to test the in vitro potency of ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin and gatifloxacin.</p><p>Both MIC and MPC testing found both gatifloxacin and moxifloxacin to be 4-8-fold more potent <i>in vitro</i> against the Gram-positive organisms than the older fluoroquinolones with an average potency rank order of moxifloxacin = gatifloxacin > levofloxacin > ofloxacin = ciprofloxacin. The Gram-negative results, however, revealed that the older fluoroquinolones are still the most potent of the fluoroquinolones tested with an average potency rank order of ciprofloxacin > ofloxacin = levofloxacin > gatifloxacin = moxifloxacin.
Kill curve results showed a significant difference in the rate of killing between the MIC and MPC drug concentrations. At the MIC drug concentration there was generally only a noticeable reduction in viable cells following 24 hours of drug exposure and in many cases this was followed by a period of bacterial re-growth. At the MPC drug concentration, a significant bacterial count reduction was often observed as early as 4 to 6 hours for both S. pneumoniae and H. influenzae. Surprisingly, there was little difference between the five fluoroquinolones in their rates of and amount of bacterial reduction.</p><p>Because of high in vitro resistance rates in drugs like penicillin, the fluoroquinolones are an important broad-spectrum alternative. Consequently, it is imperative that measures are taken to maintain the efficacy of this class. One approach is to ensure that the most potent drug is being used to eradicate possible resistant sub-populations present in in vivo infections. The data from these experiments suggest that the new fluoroquinolones gatifloxacin and moxifloxacin are much more potent (<i>in vitro</i>) than older fluoroquinolones against Gram-positive bacteria. With Gram-negative pathogens, however, ciprofloxacin remains the most potent agent <i>in vitro</i>.</p>
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-09062005-121116 |
| Date | 13 September 2005 |
| Creators | Hedlin, Peter David Skarsgard |
| Contributors | Sanche, Steve, Qualtiere, Louis, Deneer, Harry, Chirino-Trejo, Manuel, Blondeau, Joseph |
| Publisher | University of Saskatchewan |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-09062005-121116/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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