The antimicrobial activity of ciprofloxacin against <i>Legionella</i> species and the treatment of experimental <i>Legionella</i> pneumonia in guinea pigs

The activity of the quinolone temafloxacin against respiratory pathogens was compared with those of ciprofloxacin and ofloxacin. MICs for 90% of strains tested indicated that temafloxacin was at least two-to fourfold more potent than the other two quinolones against Staphylococcus aureus, Streptococcus pneumoniae, and Legionella pneumophila. Temafloxacin had potency equal to that of ciprofloxacin and was twofold more active than ofloxacin against Streptococcus pyogenes, Moraxella catarrhalis, and Bordetella pertussis. Against Haemophilus influenzae and Klebsiella pneumoniae, temafloxacin was four-and twofold less potent than ciprofloxacin, respectively. When administered orally in mouse protection tests against S. aureus, S. pneumoniae, and S. pyogenes, temafloxacin was at least eight times more potent than ciprofloxacin and was two to four times more active than ofloxacin. Against H. influenzae, temafloxacin was as active as ofloxacin and was two times less active than ciprofloxacin following oral administration in mice. In treating L. pneumophila in guinea pigs and H. influenzae otitis media in gerbils, temafloxacin and ofloxacin were more effective than ciprofloxacin. Against S. pneumoniae otitis media in gerbils, temafloxacin and ciprofloxacin were more active than ofloxacin. Following subcutaneous administration in mice, temafloxacin achieved higher lung levels than ciprofloxacin or ofloxacin did.Temafloxacin is a new fluoroquinolone with broad-spectrum potency and favorable pharmacokinetics. Previously, it has been reported that temafloxacin is active against a wide range of bacteria and that it is effective in treating both gram-positive and gram-negative infections in mice (2,4,8,13,18,19). Temafloxacin also is well absorbed in humans, with a mean peak level in serum of 3.3 ,ug/ml and a serum elimination half-life of 6.8 h following a single oral dose of 400 mg (17).Like most of the new fluoroquinolones, temafloxacin has substantial activity against many of the classic respiratory pathogens, including Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus aureus, and Legionella pneumophila. Current clinical data indicate that the new quinolones can be successfully used to treat acute exacerbations of chronic bronchitis and other lower respiratory tract infections caused by these bacteria. In treating these conditions, the rates of cure or improvement for ciprofloxacin, ofloxacin, enoxacin, and pefloxacin range from 70 to 100% (23)(24)(25). However, the use of these new quinolones in treating bronchopulmonary infections appears to be limited by their reduced in vitro activity against Streptococcus pneumoniae, one of the most frequently isolated bacteria from community-acquired respiratory tract infections. Clinical and bacteriological relapses in S. pneumoniae-infected patients receiving quinolones have been reported; and in one study the rate of persistence, recurrence, or reinfection because of pneumococcus in quinolonetreated patients was 67% (5, 24). Temafloxacin is repor...

Section: Discussionsupporting

confidence: 89%

Activity of temafloxacin against respiratory pathogens

Swanson

Hardy

Chu

et al. 1991

“…This discrepancy may be linked to poor intracellular penetration, the activities of some antibiotics, or both (37). To overcome these problems, several investigators have developed animal (6,11,18,19,22,26,29,35,36) and cell (17,23,25,27,36,37,40) models of Legionella infections. We have previously used the macrophage model to assess the activity of antibiotics against L. pneumophila that was multiplying intracellularly (37).…”

Section: Resultsmentioning

confidence: 99%

“…Three new fluoroquinolones, pefloxacin (6,37), ciprofloxacin (17)(18)(19), and ofloxacin (35,36), have been shown to be more active than erythromycin (6,37) and josamycin (36) against Legionella pneumophila in cellular and experimental animal infection models. Other new difluorinated and trifluorinated quinolone agents have also been found to be active against L. pneumophila (7,13,16,26,31).…”

mentioning

confidence: 99%

Comparative postantibacterial activities of pefloxacin, ciprofloxacin, and ofloxacin against intracellular multiplication of Legionella pneumophila serogroup 1

Rajagopalan-Levasseur

Dournon

Dameron

et al. 1990

The inhibitory and postantibacterial activities of pefloxacin, ciprofloxacin, and ofloxacin against virulent Legionella pneumophila serogroup 1 were evaluated in cell-free and cellular models. In the absence of macrophages (with the tissue culture medium alone), bacterial numbers remained unchanged at 24 h in the presence of 0.1 ,ug of pefioxacin, ciprofloxacin, or ofloxacin per ml and 1.0 ,ug of pefloxacin per ml, whereas they were reduced in the presence of 1.0 ,ug of ciprofloxacin or ofioxacin per ml. Experiments to evaluate the postantibacterial effects of these drugs were therefore performed with concentrations of 0.1 ,ug/ml. In the cell-free model, brief exposure (1 h) of bacteria to each antimicrobial agent resulted in a transient decrease in numbers followed by logarithmic growth. In the cellular model, all three drugs (at 0.1 and 1.0 ,ug/ml) inhibited the intracellular multiplication of L. pneumophila. The intracellular postantibacterial effects of 0.1 ,ug of pefloxacin, ciprofloxacin, and ofloxacin per ml, which were left in contact with L. pneumophila-infected human macrophages for 24 h, were evaluated at various times after removal of the drugs. Pefloxacin was found to exhibit a significant inhibitory effect at 72 h, whereas following the removal of ciprofloxacin and ofloxacin, rapid bacterial multiplication occurred, leading to the destruction of the macrophage monolayer within 48 h.Thus, while pefloxacin, ciprofloxacin, and ofloxacin all inhibited the multiplication of L. pneumophila in human monocyte-derived macrophages, only pefloxacin exhibited a prolonged postantibacterial effect.Three new fluoroquinolones, pefloxacin (6, 37), ciprofloxacin (17-19), and ofloxacin (35, 36), have been shown to be more active than erythromycin (6, 37) and josamycin (36) against Legionella pneumophila in cellular and experimental animal infection models. Other new difluorinated and trifluorinated quinolone agents have also been found to be active against L. pneumophila (7, 13, 16, 26, 31). We have previously demonstrated that pefloxacin shows a potent postantibacterial effect (PAE) against virulent L. pneumophila serogroup 1 in guinea pig infection and human monocyte-derived macrophage models (6, 37). Recently, Edelstein and Edelstein (12) have shown that contrary to ciprofloxacin, WIN 57273, a new quinolone antimicrobial agent, inhibits the growth of L. pneumophila grown in guinea pig alveolar macrophages in an irreversible manner.The objective of this study was to evaluate and compare the intracellular PAEs of three quinolones, pefloxacin, ciprofloxacin, and ofloxacin, against L. pneumophila. The drug concentration that would inhibit but not kill the Legionella strain that was used, thus allowing the determination of intracellular PAE, was assessed first in a macrophage-free model. We then compared the intracellular inhibitory activities and PAEs of the three antimicrobial agents in a macrophage model. MATERIALS AND METHODSBacteria. L. pneumophila serogroup 1 (strain Paris CB 81-13) was used in all experiments. T...

“…Antimicrobial treatment of an animal model of Legionnaires disease has demonstrated good correlation with clinical observations, but is too expensive for screening purposes (3,7,10,(18)(19)(20). To address this, several investigators have validated the use of monocyte or macrophage growth inhibition tests to predict the effectiveness of antimicrobial agents in animal models (1,9,11,(20)(21)(22).…”

mentioning

confidence: 99%

WIN 57273 is bactericidal for Legionella pneumophila grown in alveolar macrophages

Edelstein

1989

The in vitro antimicrobial activity of WIN 57273, a new quinolone antimicrobial agent, was determined for 21 LegioneUa strains, using broth macrodilution and agar dilution testing methods; ciprofloxacin and erythromycin were tested as well. Three different buffered yeast extract media were used for the agar dilution studies, two of which were made with starch rather than charcoal. Broth macrodilution susceptibility testing was performed with buffered yeast extract broth and two Legionella pneumophila strains. Antimicrobial inhibition of L. pneumophila growth in guinea pig alveolar macrophages was also studied, using a method able to detect bacterial killing. The MICs for 90% of the 21 strains of Legionella spp. grown on buffered charcoal yeast extract medium were 0.125 ,g/ml for WIN 57273, 0.25 ,Ig/ml for ciprofloxacin, and 1.0 ,ug/ml for erythromycin. These MICs were falsely high, because of inhibition of drug activity by the medium used. Use of less drug-antagonistic, starch-containing media did not support good growth of the test strains. The broth macrodilution MICs for two strains of L. pneumophila serogroup 1 were s0.03 ,ug/ml for WIN 57273 and ciprofloxacin and 0.125 ,ug/mI for erythromycin. WIN 57273, ciprofloxacin, and erythromycin all inhibited growth of L. pneumophila in guinea pig alveolar macrophages at concentrations of 1 ,ug/ml, but only WIN 57273 prevented regrowth or killed L. pneumophila after removal of extracellular antimicrobial agent.Erythromycin is considered the treatment of choice for Legionnaires disease on the basis of retrospective studies. However, a major limitation of erythromycin therapy is that a long treatment course is required to prevent disease relapse (14). The search for alternatives to erythromycin therapy is compromised by the poor correlation of results of classical in vitro antimicrobial susceptibility testing with clinical experience (7,11,14). This discrepancy is likely due to antimicrobial antagonism by components of the media and to the protected intracellular site in which legioneilae exist.Some investigators have claimed the superiority of one medium over another for the purposes of susceptibility testing, mainly in terms of limited inhibition of antimicrobial agents, but few comparative studies have been performed (2,8,13,20).Antimicrobial treatment of an animal model of Legionnaires disease has demonstrated good correlation with clinical observations, but is too expensive for screening purposes (3, 7, 10, 18-20). To address this, several investigators have validated the use of monocyte or macrophage growth inhibition tests to predict the effectiveness of antimicrobial agents in animal models (1,9,11,(20)(21)(22). However, reversible inhibition of bacterial growth has been detected in these cellular systems (12, 21).We performed susceptibility testing of legionellae with erythromycin, ciprofloxacin, and WIN 57273, a new quinolone antimicrobial agent, to determine whether use of different media influenced susceptibility results and inhibition of antimicrobial agen...