Pharmacokinetics and effects on bowel and throat microflora of oral levofloxacin as antibacterial prophylaxis in neutropenic patients with haematological malignancies

Abstract

Summary:Gram-positive breakthrough infections pose a major drawback to the use of quinolones for antibacterial prophylaxis in neutropenic patients. Levofloxacin offers the advantage of an augmented Gram-positive spectrum and may potentially overcome this problem. In an openlabel, clinical pilot study, we investigated the effects on throat and bowel microflora and pharmacokinetics of a once-daily oral dose of 500 mg levofloxacin, during neutropenia in 20 patients with haematological malignancies. Gram-negative bowel flora and Staphylococcus aureus were successfully eradicated. No Gram-negative infections occurred. Minimal inhibitory concentration values for viridans group (VG) streptococci tended to increase, in four patients over 8 mg/l, indicating resistance to levofloxacin. Four patients developed blood-stream infections with levofloxacin-resistant Gram-positive cocci. No significant changes in numbers of anaerobic microorganisms were observed. Pharmacokinetic parameters of levofloxacin, including the maximum serum concentration (C max ), time to C max (T max ), area under the concentrationtime curve (AUC), volume of distribution at steady state (V ss /F) and clearance (CL/F) were not statistically different at first dose and during neutropenia. In conclusion, levofloxacin eradicates Gram-negative microorganisms and S. aureus and spares the anaerobic flora. Its pharmacokinetic profile is unaltered during neutropenia. However, prolonged administration of levofloxacin as antibacterial prophylaxis may be hampered by the emergence of levofloxacin-resistant VG streptococci. Quinolones are widely used for the prevention of bacterial infections during neutropenia in patients with haematooncological diseases. The quinolones are attractive for this purpose because they are active against a broad range of bacteria and are well tolerated. Moreover, quinolones have been shown to reduce the incidence of Gram-negative infections and fever in neutropenic patients significantly, although a reduction of mortality does not seem to occur. 1 Of concern is the increased incidence of Gram-positive infections, which has been noted even in the first reports on the use of quinolones for the prevention of Gram-negative bacteraemia. 2,3 Especially, viridans group (VG) streptococci and coagulase-negative staphylococci have emerged as important pathogens in patients receiving quinolone prophylaxis. 2,4,5 To solve this problem, it has been attempted to augment the Gram-positive activity of the prophylactic regimen by the addition of a second antimicrobial agent, such as roxitromycin, rifampicin or penicillin. This approach indeed has been reported to result in significantly lower rates of gram-positive infections. [5][6][7][8][9][10] Recently, quinolone agents with enhanced Gram-positive activity have become available. A new fluoroquinolone, levofloxacin, shows excellent in vitro activity against many Gram-positive bacteria, including streptococci, enterococci and staphylococci, yet the drug retains the potent Gramnegative activity of earl...

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Impact of bloodstream infections on outcome and the influence of prophylactic oral antibiotic regimens in allogeneic hematopoietic SCT recipients

“…72,73 As mentioned earlier, fluoroquinolone is one of the most common agents linked to this collateral damage, that is, the emergence of various kinds of pathogens. [21][22][23][24][25][27][28][29][30][31][32][33][34][35][36][37][38]71 However, the patterns of emergence vary among studies; no single study has demonstrated the impact of fluoroquinolone use on all of the specific antibiotic-resistant patterns. Differences in the hospital environments, hospital infection control policies, local microbial epidemiology, patient population and treatments, technology, or even study designs may influence the conclusion.…”

“…11,13,19 Despite the advantage of antibiotic prophylaxis, 13 a major concern remains on the potential of antibiotic prophylaxis to increase antibacterial resistance, particularly the influence of fluoroquinolone exposure. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] For example, emergence of fluoroquinoloneresistant bacteria in neutropenic patients receiving fluoroquinolone prophylaxis has been well-documented. [21][22][23][24][25][26][27][28][29] Furthermore, the occurrence of cross-resistant or multiple-drug-resistant (MDR) pathogens, such as an increase in MDR Gram-negative bacteria (GNB), 30,[35][36][37][38] increase in nosocomial methicillin-resistant Staphylococcus aureus infections 31,33,34,38,39 and an emergence of extended spectrum beta-lactamase producers, 32 have all been reported in literature.…”

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“…Studies on the effects of levofloxacin on bowel and throat microflora in neutropenic patients taking prophylactic levofloxacin showed a reduction in colonization with viridans streptococci, but over time minimum inhibitory concentrations (MIC) increased, indicating developing resistance within an individual [28]. Clinical studies have shown that in neutropenic patients receiving levofloxacin prophylaxis, bacteremia with viridans streptococcus occurred in 16% and all isolates showed diminished susceptibility to levofloxacin and cross-resistance to other quinolones, suggesting that levofloxacin prophylaxis may result in selection of quinolone-resistant viridans streptococci [29].…”