Arnold Louie

Treatment of Invasive Aspergillosis with Posaconazole in Patients Who Are Refractory to or Intolerant of Conventional Therapy: An Externally Controlled Trial

BACKGROUNDnInvasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species.nnnMETHODSnWe investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group.nnnRESULTSnCases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses.nnnCONCLUSIONSnAlthough the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

Quinolone Efflux Pumps Play a Central Role in Emergence of Fluoroquinolone Resistance in Streptococcus pneumoniae

ABSTRACT The preferential use of older antimicrobial agents is, in general, sound public health policy and is meant to maintain susceptibility to newer agents. In the case of fluoroquinolones, however, this strategy is flawed and may actually hasten the spread of Streptococcus pneumoniae strains resistant to newer members of the class. In a mouse thigh infection model, we were unable to isolate clones of pneumococci resistant to the newer fluoroquinolone levofloxacin at 2 × or 4 × the baseline MIC. An initial exposure in vivo to the older agent, ciprofloxacin, allowed straightforward selection of clones resistant to levofloxacin in a subsequent experiment. The original ciprofloxacin exposure generated clones without changes in the parC/E and gyrA/B quinolone target sites almost exclusively but did allow overexpression of a reserpine-responsive pump. While this caused only minimal change in the levofloxacin MIC (0.6 mg/liter to 0.8 mg/liter), it allowed a major change in the mutational frequency to resistance for levofloxacin (<1/108.5 to approximately 1/104.5), which allowed levofloxacin-resistant clones to be isolated in a subsequent in vivo experiment. The reason underlying ciprofloxacins propensity to select for pump-overexpressed clones is likely related to its hydrophilicity. To preserve the susceptibility of Streptococcus pneumoniae to newer members of the class of quinolones, use of ciprofloxacin for community-acquired respiratory infections should be minimized.

Comparison of in vitro Inhibitory and Bactericidal Activities of Daptomycin (LY 146032) and Four Reference Antibiotics, Singly and in Combination, against Gentamicin-Susceptible and High-Level-Gentamicin-Resistant Enterococci

The in vitro inhibitory and bactericidal activities of daptomycin and reference antibiotics were determined by serial macrobroth dilution for 23 gentamicin-susceptible (MIC: < 2,000 mg/l) and 21 high-level-gentamicin-resistant (HLGR) Enterococcus faecalis, Enterococcus faecium, and Enterococcus avium isolates. The activities of daptomycin, vancomycin, and teicoplanin were independent of the gentamicin susceptibility profile and species tested. For all the isolates, the inhibitory activity of daptomycin (MIC90: 2 mg/l) was comparable to vancomycin (MIC90: 2 mg/l), but less than that of teicoplanin (MIC90: 0.5 mg/l). Daptomycin demonstrated excellent bactericidal activity against all enterococci tested (MBC90: 8 mg/l). In contrast, all microorganisms were tolerant to vancomycin and teicoplanin. Ampicillin and ciprofloxacin MICs and MBCs were dependent on enterococcal gentamicin resistance profile and species, with MICs and MBCs that ranged between 1 and > 64 mg/l. By time-kill curves, the combination of daptomycin plus ampicillin demonstrated synergistic bactericidal activity against gentamicin-susceptible and HLGR E. faecalis. Daptomycin, singly and in combination, may be useful in treating enterococcal infections, including those caused by HLGR microorganisms.

In vitro activity of sparfloxacin and six reference antibiotics against gram-positive bacteria.

The in vitro activity of sparfloxacin, a new fluoroquinolone, was assessed against 234 gram-positive bacterial isolates by agar dilution (10(4) CFU/spot). Sparfloxacin activity was compared with that of ciprofloxacin and five other antibiotics. Sparfloxacin was the most active drug tested against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MIC90, 0.125-0.25 mg/l). Sparfloxacin was also the most active drug tested against Enterococcus faecalis (MIC90, 1 mg/l) and showed equal activity against gentamicin-susceptible and gentamicin-resistant (MIC greater than 2,000 mg/l) enterococci. Sparfloxacin was the most active quinolone tested against Streptococcus pneumoniae and S. pyogenes (MIC90, 1 mg/l). Most Corynebacterium jeikeium showed exquisite susceptibility to sparfloxacin (MIC, 0.06-0.25 mg/l). For MRSA, time-kill curves showed sparfloxacin to be rapidly bactericidal at the MIC of the organism. Sparfloxacin showed greater and more sustained bactericidal activity than ciprofloxacin and vancomycin at 1x and 2x the MIC. Reduction in the activity of sparfloxacin occurred with decreased agar pH (from 7.0 to 6.0) and increased bacterial inoculum. Sparfloxacin showed superior activity compared to reference drugs against most gram-positive bacteria.