and William Townsend, O.D.
Improved mechanism of action sets these antibiotics far above their predecessors, and the result is a change in an age-old medical dynamic. By Arthur B. Epstein, O.D.
We all know how the antibiotic lifecycle works: A new and more effective antibiotic is introduced. To maintain maximum clinical effectiveness, clinicians limit its use to severe infections. The drugs clinical success makes it popular, leading to increased use and consequently increased resistance. Soon, the agent is not so clinically effective.
For any given antibiotic, this cycle takes about a decade to occur. In the past, the best we could hope for was to delay the process as long as possible. Hence the prevailing save the big gun philosophy that advocates holding off on using the most potent drugs for as long as possible, and only when absolutely positive of the diagnosis.
Though many people may find this difficult to believe, that paradigm need no longer exist. Fourth-generation fluoroquinolones have changed how we prescribe antibiotics in eye care today.
Consider: In the average second- or third-generation antibiotic, researchers have observed spontaneous resistance in about one bacterium in 10 million. Exposure to newer fourth-generation fluoroquinolones, however, is believed to produce a resistant organism in about one bacterium in 100 trillion. The kill ratio is so high with these new drugs that the bacteria simply do not have the opportunity to mutate and survive. This leads to a dramatic and prolonged increase in clinical effectivenessthe likes of which medical science has never witnessed.
Does this mean all drug resistance is a thing of the past? Of course not. However, the weight of clinical evidence is now so much in favor of these new fourth-generation agents that we would be doing our patients a disservice if we choose not to prescribe them for most ocular infections.
For example, resistance to third- and second-generation fluoroquinolones is growing. One study looked at levels of resistance in Haemophilus influenzae and Streptococcus pneumoniae, the primary causes of pediatric conjunctivitis, and found that resistance and susceptibility to previous generations is increasing.1
In some facilities the increase in resistance has been dramatic. Data collected at the University of Pittsburgh showed that 95% of methicillin-resistant Staphylococcus aureus (MRSA) keratitis isolates were resistant to traditional fluoroquinolones.2 In a New York facility 43% of endophthalmitis isolates were resistant to ciprofloxacin.3
Fourth-generation drugs yield much lower levels of in vitro minimum inhibitory concentrations, or MICs (the primary laboratory method used to determine antibiotic resistance). A 2002 study compared differences in the susceptibility patterns among second-, third- and fourth-generation fluoroquinolones. The fourth-generation drugs appeared to cover bacterial resistance to the second- and third-generation agents, and were more potent than the second- and third-generations for Gram-positive bacteria. They were equally potent for Gram-negative bacteria.4
Fighting atypical mycobacteria is another area in which second- and third-generation agents are lacking. Some 51% of post-LASIK keratitis cases are caused by atypical myco-bacteria, such as M. chelonei/abscessus, M. fortuitum, M. mucogenicum.5 Second-and third-generation fluoroquinolones have almost no activity against atypical mycobacteria and only limited effectiveness against Gram-positive organisms, both of which are primary causes of postoperative infections.6
But the most convincing argument for the use of the fourth-generation agents is their unique mechanism of action. All fluoroquinolones inhibit bacterial DNA synthesis by interfering with topoisomerases. DNA gyrase is the primary target in Gram-negative bacteria, and topoisomerase IV is the primary target in Gram-positive bacteria. Their major advantage is that fourth-generation fluoroquinolones appear to have a more balanced activity against both DNA gyrase and topo-isomerase IV. Older fluoroquinolones have greater effectiveness against DNA gyrase than topoisomerase IV, which makes them much less effective against Gram-positive bacteria. According to a 2000 review study on this topic, Resistance to fluoroquinolones occurs as a result of mutational amino acid substitutions in the subunits of the more sensitive (or primary target) enzyme within the cell. If, however, both enzymes are similarly susceptible to a fluoroquinolone, then the level of resistance caused by primary-target mutation may be low and may be limited by the sensitivity of the secondary target.7 In other words, resistance requires simultaneous independent mutations in two bacterial genes. This is how fourth-generation drugs achieve such low levels of resistance.
Continuing to use prior generations of fluoroquinolones not only decreases the likelihood of therapeutic success; it increases the likelihood of creating species of bacteria resistant to newer antibiotics, shortening the span of effectiveness of these new drugs. No matter how you look at it, this is a poor choice from a public health perspective.
Fourth-generation agents have numerous other advantages that I have not touched on here: better penetration into ocular tissues, less toxicity, etc. But their enhanced ability to reduce resistance makes these agents the colossal advance they are, and constitutes a vast paradigm shift in ophthalmic antibiotics.
Dr. Epstein is in private practice in Roslyn, N.Y., and is clinical adjunct assistant professor at Northeastern State University College of Optometry, Tahlequah, Okla.
and William Townsend, O.D.
1. Block SL, Hedrick J, Tyler R, et al. Increasing bacterial resistance in pediatric acute conjunctivitis (1997-1998). Antimicrob Agents Chemother 2000 June;44(6):1650-4.
2. Mah F. Unpublished data 2002.
3. Ritterband DC, et al. Annual Meeting of the Association for Research in Vision and Ophthalmology; May 6, 2002; Fort Lauderdale, Fla. Abstract.
4. Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 2002 Apr;133(4):463-6.
5. Dhaliwal D. Unpublished data and literature review. 2002.
6. Alcon Laboratories, Inc. Data on file.
7. Hooper DC. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis 2000 Aug;31 Suppl 2:S24-8.
The new antibiotics represent a huge step forward in fighting infection, but sometimes other drugs are still the better choice. By William Townsend, O.D.
Bacteria are arguably the most successful life form on the planet. There are more of them alive now than any other creature. Your body is home to more than 100 billion. With bacterial fossil records dating back 3.5 billion years, they are the oldest organisms known to man.
Part of their success results from bacterias ability to divide rapidly. They replicate every 12-20 minutes. Thus a single bacterium can produce up to 1 billion offspring in a single day. This speeds up the natural selection process, allowing these single-cell creatures to evolve beyond a threat before it wipes out the population.
Resistance has been the Achilles heel of antibiotic therapy since the first antibiotic was introduced. Less than 10 years after its introduction, penicillin was found ineffective against 59% of selected Staphy-lococcus strains. Given enough time and exposure, any antibiotic can produce resistant strains, so practitioners have traditionally sought to use newly introduced agents sparingly, reserving the most powerful for the most serious infections.
Now, we are told, all this has changed. The new fourth-generation fluoroquinolones are touted as the final word in antibiotic therapy. Were told that these agents are so lethal that they have rendered resistance obsolete. Because they exterminate everything, the guesswork of prescribing is a thing of the past.
I will not deny fourth-generation agents are cause for great excitement. They are a huge step forward in fighting infection and a wonderful treatment option. But are they the be-all, end-all for killing bacteria? That claim simply does not bear clinical scrutiny.
Fluoroquinolones and quinolones work by inhibiting bacterial enzymes that facilitate the replication of DNA. The two enzymes targeted by these drugs are DNA gyrase and topoisomerase IV. Although these enzymes each have a similar amino acid sequence, they play very different roles in bacterial cell division. DNA gyrase seals DNA during replication, and is needed for the uncoiling and recoiling of the double helix. Fluoro-quinolones inhibit relaxation of coiled DNA, and increase double-strand breaks in the DNA. Topoisomerase IV is a decatenating enzyme that segregates interlinked daughter chromosomes after DNA replication. This enzyme is the primary fluoroquinolone target in most Gram-positive bacteria.
The manufacturers of fourth-generation fluoroquinolones argue that second- and third-generation fluoroquinolones target DNA gyrase solely, and have little effect on topoisomerase IV. They say that fourth-generation drugs target both DNA gyrase and topoisomerase IV and are therefore more lethal. They also argue that, because resistance to second- and third-generation agents is increasing, practitioners should rely solely on fourth-generations.
Although their case has a lot of truth in it, we should keep several significant exceptions in mind. Second- and third-generation fluoroquinolones can act on both DNA gyrase and topoisomerase IV,1 and in some cases second- and third-generation agents can be more efficacious at treating Gram-negative bacteria. In a 2000 study measuring effectiveness against Pseudomonas aeruginosa, ciprofloxacin was lethal in 90% of the strains. Some 72% of P. aeruginosa strains were susceptible to ofloxacin, compared to only 28% susceptible to moxifloxacin.2
Sometimes, bacteria that are resistant to third-generation agents show resistance to fourth-generations, too. In a 2003 study, 68 levofloxacin-resistant isolates of Streptococcus pneumoniae were analyzed for susceptibility to other agents. All the isolates were found to be resistant to ciprofloxacin and non-susceptible to gatifloxacin, and 62 isolates were non-susceptible to moxifloxacin.3
Also, some in vitro models showed that resistance to fourth-generation fluoroquinolones appears to depend on species. Researchers studied the emergence of resistance to moxifloxacin by using three strains of Strepto-coccus pneumoniae and two strains of Pseudomonas aeruginosa. The trial concluded that resistance occurred with P. aeruginosa but not significantly with S. pneumoniae. The resistance to P. aeruginosa was dependent on drug exposure and time of exposure.4
Another in vitro study said fourth-generation agents are not always the most potent. Investigators compared the antibacterial qualities of gatifloxacin with those of ciprofloxacin and ofloxacin. Gatifloxacin was two to four times more potent than the other two agents against staphylococci, streptococci, pneumococci and enterococci. However, gatifloxacin was two times less potent than ciprofloxacin, and the same as, or two-fold more potent than ofloxacin, against Enterobacteriaceae. Gatifloxacin and ofloxacin had similar potency against Pseudomonas aeruginosa, Pseudomonas fluorescens and Pseudomonas stutzeri, while ciprofloxacin showed two to eight times more potency against these species.5
There are many cases in which fourth-generation agents should be your first line. But we should not blindly adhere to the blanket statement that fourth generation is best for every bacterial infection. We must base our choice of antibiotic on judicious evaluation of the likely etiology. Based on this, we should ask ourselves if we really need a fourth-generation agent, or if a different drug would be adequate or perhaps better. Prescribing antibiotics still involves intelligence, judgment and knowledge. In other words, it requires the services of a doctor, not a robot.
Dr. Townsend is in private practice in Canyon and Hereford, Texas. He is an adjunct professor at the University of Houston College of Optometry.
1. Pan XS, Ambler J, Mehtar S, Fisher LM. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in S pneumoniae. Jl Antimicrob Chemother 1996 Oct;40(10):2321-6.
2. Fung-Tomc JC, Minassian B, Kolek B, et al. Antibacterial spectrum of a novel des-fluoro(6) quinolone, BMS-284756. Journal Antimicrob Agents Chemother 2000 December;44(12):3351-6.
3. Davies TA, Goldschmidt R, Pfleger S, et al. Cross-resistance, relatedness and allele analysis of fluoroquinolone-resistant US clinical isolates of Streptococcus pneumoniae (1998-2000). J Antimicrob Chemother 2003 Aug;52(2):168-75.
4. MacGowan AP, Rogers CA, Holt HA, Bowker KE.Activities of moxifloxacin against, and emergence of resistance in, Streptococcus pneumoniae and Pseudomonas aeruginosa in an in vitro pharmacokinetic model. J Antimicrob Chemother 2003 March;47(3):1088-95.
5. Fung-Tomc J, Minassian B, Kolek B, et al. In vitro antibacterial spectrum of a new broad-spectrum 8-methoxy fluoroquinolone, gatifloxacin. J Antimicrob Chemother 2000 April;45(4):437-46.