Super Fitness Health BlogTreating Legionnairesa Disease
The Legionellaceae family contains over 40 acknowledged species, but less than half these cause disease in humans. The absolute most generally pathogenic species is Legionella pneumophila, of which there are 14 serogroups. L. pneumophilaaccounts for 90% (and serogroups 1- 6 for 85%) of most infections. Other crucial species incorporate Legionella micdadei, Legionella bozemanii, Legionella dumoffii and Legionella longbeachae.The major clinical condition is pneumonia (Legionnairesa disease), though M. pneumophila in addition has been implicated in cases of endocarditis and myocarditis, and in haemodialysis infections.
Treatment strategies for Legionnairesa disease are generally centered on clinical experience of the first known outbreak in Philadelphia in 1976; in a evaluation, patients treated with erythromycin or tetracycline had a 50% lower death rate compared with patients treated with I-lactams.1 Subsequently, erythromycin became the treatment ofchoice. Now, a number of new antimicrobial agents have appeared, but formally determining their comparative efficacy in treatment has proved difficult. No prospective controlled trials of therapy have now been performed.
Examination of the possible and effectiveness application of antimicrobials against Legionellaspp. Is dependant on four strategies. First, in-vitro susceptibility testing can be carried out to screen for active agents. Legionella spp. may be developed in both buffered yeast extract (BYE) broth or buffered charcoal- yeast extract (BCYE) agar, equally supplemented with I -ketoglutarate. The MICs of an antibiotic can vary between these growth media. Several antimicrobials, including I-lactams, are extremely effective in vitro. However I -lactams don’t enter the intracellular compartment and as legionellae are intracellular pathogens in vitro, extracellular vulnerability does not always correspond to in-vivo activity.
Next, L. pneumophila has been grown in vitroin a number of cell lines so that you can measure the intracellular activity of antimicrobials. The cells used have involved guinea pig alveolar macrophages, human monocytes or macrophages, HeLa and HL-60 cells. A good correlation is generally given by results obtained with this method with animal studies. One exception is gentamicin, that will be active against microorganisms grown in cell lines but inactive in human disease and animal models. A disadvantage of this technique is that it is time intensive and expensive, even though better methods are now being produced. 2
Next, guinea pigs produce severe pneumonia when L. pneumophilais introduced into their lower respiratory system by aerosol and so they really can be utilized being an animal model to examine antimicrobials. Intraperitoneal infection has been also used by some studies in guinea pigs. Clinical efficacy in humans has corresponded to efficacy in the respiratory tract model.
Finally, clinical studies have been attempted but these have generally been case series and retrospective analyses. They suffer with being little reports, usually centering on extreme hospitalized cases and often not controlling for severity of disease. This helps it be difficult to evaluate the results with regard to moderate, community-acquired cases. It’s been calculated that around 900 circumstances will be needed in each treatment arm of a trial on community-acquired pneumonia to demonstrate a 50% reduction in mortality by usage of an antimicrobial agent. 3 But, Legionnairesa condition is not common, with c. 200 established cases each year in England and Wales, 4 and there is often a delay for making the diagnosis until after scientific treatment is finished. Hence a large, prospective controlled trial has not been done and is unlikely to take place.
On the basis of studies using these four methods the efficiency of main classes of antimicrobials is examined below. Many respected reports have focused on M. pneumophila, but there’s evidence that other Legionella spp. are equally susceptible.
Between the macrolides most experience has been acquired with erythromycin. However, by in-vitro extracellular, assessment it’s less active than clarithromycin, azithromycin and roxithromycin, while more active than dirithromycin and josamycin (Dining table). In certain comparative studies clarithromycin has been more active than azithromycin 5,,6 but generally azithromycin has been shown to be the more active. Within HL-60 cells azithromycin achieves the maximum inhibition of growth of L. pneumophila, used so as of activity by clarithromycin, roxithromycin, dirithromycin and erythromycin. 7 Within guinea pig alveolar macrophages azithromycin prevents growth of M. pneumophila better than erythromycin. 8 Azithromycin also exerts a effect in these alveolar macrophages: after azithromycin in high concentrations (5 mg/L) is washed out, regrowth of L. pneumophila is restricted for a further 5 days. In this model azithromycin is also bactericidal, while erythromycin is just bacteriostatic.
In the guinea pig model of pneumonia mg/L is reached 13.4 by azithromycin concentrations in infected lung. 9 After 48 h of therapy the concentration of azithromycin within alveolar macrophages is 582 times the extracellular concentration and that is fivefold more than the concentration of erythromycin. In M. pneumophila-infected guinea pigs the usage of azithromycin, 3.6 mg/kg, leads to 100% success although none survive with the exact same dose of clarithromycin, a dosage of 28.8 mg/kg being necessary for clarithromycin to reach 100% survival.10
Usually erythromycin, 2a’4 g/day, has been used to treat patients with Legionnairesa pneumonia. With these doses, gastrointestinal negative effects are typical and ototoxicity is observed at the bigger amount in in regards to a quarter of people. 11 Macrolides apart from erythromycin aren’t associated with the same frequency of negative effects. Short courses of erythromycin have been associated with relapse and, thus, 10a’14 days of treatment is advised. Clinical studies evaluating erythromycin with other macrolides are several. Just one case report of someone with severe Legionnairesa condition described failed treatment with erythromycin plus rifampicin and healing only after intravenous azithromycin. 12 When azithromycin can be used from the start in managing community-acquired legionellosis cure has been observed with a total dose of 1.5 g given more than 3 or 5 days. 13 Other macrolides have proved clinically effective. 3
On the basis of the available information, azithromycin appears to be to function as most readily useful macrolide, with good intracellular penetration, bactericidal action, established clinical efficacy, short times of treatment and a good safety profile. More over, the 15-membered lactone ring of azithromycin doesn’t connect to cytochrome P450 3A isoenzymes, unlike another, 14-membered macrolides. This reduces the prospect of drug interactions. Up to now, antimicrobial resistance to azithroymcin, or indeed any macrolide, has not been a challenge in clinical isolates of L. pneumophila.
On the foundation of the above information, when managing Legionnairesa disease, the option is first between macrolides and quinolones, and then between available, registered examples in each group. In the foreseeable future other antimicrobials, such as streptogramins and ketolides, may be worth consideration.
Quinolones and macrolides have been compared in vitro and in vivo. Ciprofloxacin was more active than azithromycin, clarithromycin and erythromycin in a few studies comparing extracellular vulnerability 5,,6,8 in yet another was less active than clarithromycin, while being more active than erythromycin and azithromycin. 29 In other studies levofloxacin and moxifloxacin were more effective than erythromycin and roxithromycin, 32 and grepafloxacin and ofloxacin were much like clarithromycin. 31 Trovafloxacin 17 and levofloxacin 19 lower bacterial counts of L. pneumophila within guinea pig alveolar macrophages better than erythromycin. In HL-60 cells erythromycin was less capable of suppressing L. pneumophila development than levofloxacin, ciprofloxacin and ofloxacin. 20
In a retrospective overview of coordinated, extreme cases of Legionnairesa disease, demanding admission to intensive care, none of seven patients treated with pefloxacin alone died, although seven of 20 patients treated with erythromycin alone did. 25 Other clinical evaluations of macrolides and quinolones are based on group of community-acquired pneumonia, within which some cases became because of Legionella spp. The amounts of patients with legionella disease have now been little, and drawing conclusions on relative effectiveness is difficult.
The overall picture to emerge from the above mentioned studies is that quinolones are far more active than macrolides. However, if one specifically discusses azithromycin, the very best of the available macrolides, and newer quinolones (ciprofloxacin, grepafloxacin, levofloxacin and ofloxacin are licensed in the UK) there are no direct comparative studies.
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