The increasing emergence of antimicrobial-resistant organisms, especially methicillin-resistant Staphylococcus aureus (MRSA), has resulted in the increased use of rifampin combination therapy. The data supporting rifampin combination therapy in nonmycobacterial infections are limited by a lack of significantly controlled clinical studies. Therefore, its current use is based upon in vitro or in vivo data or retrospective case series, all with major limitations. A prominent observation from this review is that rifampin combination therapy appears to have improved treatment outcomes in cases in which there is a low organism burden, such as biofilm infections, but is less effective when effective surgery to obtain source control is not performed. The clinical data support rifampin combination therapy for the treatment of prosthetic joint infections due to methicillin-sensitive S. aureus (MSSA) after extensive debridement and for the treatment of prosthetic heart valve infections due to coagulase-negative staphylococci. Importantly, rifampin-vancomycin combination therapy has not shown any benefit over vancomycin monotherapy against MRSA infections either clinically or experimentally. Rifampin combination therapy with daptomycin, fusidic acid, and linezolid needs further exploration for these severe MRSA infections. Lastly, an assessment of the risk-benefits is needed before the addition of rifampin to other antimicrobials is considered to avoid drug interactions or other drug toxicities.

Rifampin Combination Therapy for Nonmycobacterial Infections

New agents for Gram-positive bacteria.

Staphylococcus aureus is a gram-positive facultative aerobe that can grow in the absence of oxygen by fermentation or by using an alternative electron acceptor. To investigate the mechanism by which S. aureus is able to adapt to changes in oxygen concentration, we analyzed the transcriptional regulation of genes that encode the aerobic class Ib and anaerobic class III ribonucleotide reductase (RNR) systems that are responsible for the synthesis of deoxyribonucleotides needed for DNA synthesis. The S. aureus class Ib RNR nrdIEF and class III RNR nrdDG genes and their regulatory regions were cloned and sequenced. Inactivation of the nrdDG genes showed that the class III RNR is essential for anaerobic growth. Inhibition of aerobic growth by hydroxyurea showed that the class Ib RNR is an oxygen-dependent enzyme. Northern blot analysis and primer extension analysis demonstrated that transcription of class III nrdDG genes is regulated by oxygen concentration and was at least 10-fold higher under anaerobic than under aerobic conditions. In contrast, no significant effect of oxygen concentration was found on the transcription of class Ib nrdIEF genes. Disruption or deletion of S. aureus nrdDG genes caused up to a fivefold increase in nrdDG and nrdIEF transcription under anaerobic conditions but not under aerobic conditions. Similarly, hydroxyurea, an inhibitor of the class I RNRs, resulted in increased transcription of class Ib and class III RNR genes under aerobic conditions. These findings establish that transcription of class Ib and class III RNR genes is upregulated under conditions that cause the depletion of deoxyribonucleotide. Promoter analysis of class Ib and class III RNR operons identified several inverted-repeat elements that may account for the transcriptional response of the nrdIEF and nrdDG genes to oxygen.

Analysis of Transcription of the Staphylococcus aureus Aerobic Class Ib and Anaerobic Class III Ribonucleotide Reductase Genes in Response to Oxygen

Moxifloxacin is an extended-spectrum fluoroquinolone which has improved coverage against Gram-positive cocci and atypical pathogens compared with older fluoroquinolone agents, while retaining good activity against Gram-negative bacteria. The antibacterial spectrum of moxifloxacin includes all major upper and lower respiratory tract pathogens; it is one of the most active fluoroquinolones against pneumococci, including penicillin- and macrolide-resistant strains. In in vitro studies, emergence of bacterial resistance was less common with moxifloxacin than with some other fluoroquinolones, but this requires confirmation in large-scale clinical studies. As with other fluoroquinolones, moxifloxacin achieves good penetration into respiratory tissues and fluids. It shows a low potential for drug interactions and dosage adjustment is not required for patients of advanced age or those with renal or mild hepatic impairment. The efficacy of oral moxifloxacin has been demonstrated in large, well-designed clinical trials in patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute sinusitis, Moxifloxacin 400mg once daily achieved bacteriological and clinical success rates of approximately 90% or higher. It was as effective as, or more effective than, comparators including clarithromycin, cefuroxime axetil and high dose amoxicillin in these trials. The most commonly reported adverse events in patients receiving moxifloxacin are gastrointestinal disturbances. Moxifloxacin is also associated with QTc prolongation in some patients; there are, as yet, no data concerning the possible clinical sequelae of this effect in high-risk patients. Moxifloxacin has a low propensity for causing phototoxic reactions relative to other fluoroquinolones, and animal data suggest that it has a low potential for causing excitatory CNS and hepatotoxic effects. Conclusions: As an extended-spectrum fluoroquinolone, moxifloxacin offers the benefits of excellent activity against pneumococci, once daily administration and a low propensity for drug interactions. Although studies are needed regarding its tolerability in at-risk patients with QT interval prolongation, available data suggest that moxifloxacin is likely to become a first-line therapy option for the treatment of community-acquired lower respiratory tract infections, particularly in areas where drug-resistant S. pneumoniae or H. influenzae are common. Moxifloxacin is an extended-spectrum fluoroquinolone which has an antibacterial spectrum that covers all of the major respiratory tract pathogens. It is one of the most active fluoroquinolones against Streptococcus pneumoniae (mean weighted MIC 90 <0.3 mg/L), including penicillin- and macrolide-resistant strains. It is also active against S. pyogenes or group A streptococci (mean weighted MIC 90 0.24 mg/L) and methicillin-susceptible Staphylococcus aureus (mean weighted MIC 90 0.10 mg/L), but has more variable activity against methicillin-resistant S. aureus (MIC 90 2 to 8 mg/L) and borderline activity against ciprofloxacin-resistant strains of S. aureus (MIC 90 1 to 2 mg/L). Moxifloxacin has good activity against Enterobacteriaceae and other Gram-negative species, including Haemophilus influenzae, Moraxella catarrhalis (β-lactamase-positive or -negative strains of both species) and H. parainfluenzae (MIC 90 0.03 to 0.125 mg/L).

Moxifloxacin: a review of its clinical potential in the management of community-acquired respiratory tract infections.

Moxifloxacin is a new broad-spectrum antibacterial agent for treatment of respiratory tract infection of pathogens, including the major pathogens isolated in respiratory tract infections. The pharmacokinetic and pharmacodynamic properties of moxifloxacin are: excellent bioavailability, long half-life, and superior tissue penetration. Consequently, the 90% minimum inhibitory concentration (MIC(90)) values exhibited by moxifloxacin are generally lower than the concentrations of moxifloxacin found in circulation and in pulmonary tissues after a standard 400-mg dose given for up to 30 h. The relationship between moxifloxacin MIC(90) values and clinical response was investigated. The results of 13 clinical trials, performed in 30 countries between 1997 and 1998 and comprising 2618 patients treated with moxifloxacin or a comparator drug, were reviewed. Overall, 94% clinical success and 95% bacterial eradication was observed with moxifloxacin. These results were equivalent or superior to results seen with the comparator drugs. Clinical response rates and bacterial eradication rates with moxifloxacin were not significantly affected by bacterial resistance to other antibiotics (i.e., penicillin, clarithromycin, or amoxicillin). The majority (89%-97%) of the different bacterial strains with MICs for moxifloxacin < or =2 mg/L were successfully eradicated. In conclusion, moxifloxacin has potent in vivo bactericidal activity, and pathogen sensitivity to moxifloxacin is in accordance with US Food and Drug Administration and European suggested breakpoint values.

Evaluation of the Clinical Microbiology Profile of Moxifloxacin

Comparative in vitro bacteriostatic and bactericidal activity of trovafloxacin, levofloxacin and moxifloxacin against clinical and environmental isolates of Legionella spp.

Agar dilution minimum inhibitory concentration (MIC) methodology, according to NCCLS guidelines, was used to test the activity of three glycopeptides (LY 333328 [LY], vancomycin [VAN], and teicoplanin [TEI]), four fluoroquinolones (trovafloxacin [TRO], BAY 12-8039 [BAY], ciprofloxacin [CIP], and ofloxacin [OFL]), five macrolide-lincosamide-streptogramin antibiotics (erythromycin [ERY], azithromycin [AZI], miocamycin [MOM], clindamycin CLN], and quinupristin-dalfopristin [SYN] against 126 Streptococcus pneumoniae strains, isolated in Lozano Blesa Hospital of Zaragoza (Spain). MIC50/MIC90 (microg/ml) values for penicillin-susceptible (PS), penicillin-intermediate (PI) and penicillin-resistant (PR) strains show an excellent antipneumococcal activity of LY 333326--a new glycopeptide, for the fluoroquinolones trovafloxacin and moxifloxacin [BAY 12-8039], and for quinupristin/dalfopristin, regardless of the resistance phenotype of the strains.

P. Gómez-Lus

Papers

Comparative in vitro bacteriostatic and bactericidal activity of trovafloxacin, levofloxacin and moxifloxacin against clinical and environmental isolates of Legionella spp.

Susceptibility of penicillin-resistant and penicillin-susceptible Streptococcus pneumoniae to newer antimicrobial agents