Resistance to moxifloxacin

Moxifloxacin has a broad spectrum of activity which includes Gram-positive cocci, atypical pathogens and anaerobic bacteria responsible, inter alia, for infections of the respiratory tract. Moreover, moxifloxacin is one of the most effective fluoroquinolones against pneumococci, including the penicillin- and macrolide-resistant strains. The development of resistance to moxifloxacin is slower than that of the other fluoroquinolones. 

The quinoline antibiotics are relatively late arrivals on the antibiotic scene. The parent compound of this class of drugs is nalidixic acid. The downside of this molecule is the rapid development of resistance by pathogenic bacteria. A major step forward was the introduction of a single fluorine atom at a key position, to yield new molecules such as ciprofloxacin, ofloxacin, levofloxacin, andmoxifloxacin. Of these, levofloxacin and moxifloxacin have the best combinations of spectrum of action, potency, and pharmacokinetic properties. In time, they are likely to largely replace the current quinoline antibiotic of choice, ciprofloxacin. Since these molecules work by a different mechanism than do the p-lactams, organisms that become resistant to the latter are generally susceptible to the former. 

Moxifloxacin hydrochloride was approved for the peroral treatment of AECB, CAP and ABS, and is also available as an infusion solution for the sequential treatment of CAP. In 2004, it was additionally approved by the FDA as the first intravenously and perorally administrable antibiotic for treating CAP, which is caused by multidrug-resistant S. pneumoniae (MDRSP). MDRSP is understood to include those strains of S. pneumoniae that are resistant to two or more of the following classes of antibiotics penicillins and second-generation cephalosporins such as cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole. 

The powerful activity of the more recent fluoroquinolones moxifloxacin, gati-floxacin and levofloxacin against clinical isolates of S. pneumoniae, H. influenzae and M. catarrhalis isolated in various European countries in 2000-2001 and the low rates of resistance to these compounds have been demonstrated in a clinical study [190]. 

Clinafloxacin, moxifloxacin, sparfloxacin, and trovaflox-acin were significantly more active in vitro than ciprofloxacin and levofloxacin against Stenotrophomonas maltophilia, a microorganism with inherent resistance to many antibiotics new-generation quinolones may become very useful in the treatment of certain severe or life-threatening infectious conditions due to this bacterium (113). 

The first quinolone, nalidixic acid, was isolated as a byproduct of the synthesis of chloroquine. It has been available for the treatment of urinary tract infections for many years. The introduction of fluorinated 4-quinolones, such as ciprofloxacin (Cipro), moxifloxacin (Avelox), and gatifloxacin (Tequin) represents a particularly important therapeutic advance because these agents have broad antimicrobial activity and are effective after oral administration for the treatment of a wide variety of infectious diseases. Relatively few side effects appear to accompany the use of these fluoroquinolones, and microbial resistance to their action does not develop rapidly. Rare and potentially fatal side effects, however, have resulted in the withdrawal from the market of temafloxacin (immune hemolytic anemia), trovafloxacin... 

Complicated exacerbation FEV, less than 50% predicted Comorbid cardiac disease Greater than or equal to 3 exacerbations per year Antibiotic therapy in the previous 3 months Above organisms plus drug-resistant pneumococci, P-lactamase-producing H. influenzae and M. catarrhalis, Escherichia coli, Proteus spp., Enterobacter spp., Klebsiella pneumoniae Oral P-Lactam/P-Iactamase inhibitor (amoxicil 1 i n-clavulanate) Fluoroquinolone with enhanced pneumococcal activity (levofloxacin, gemifloxacin, moxifloxacin) Intravenous P-Iactam/P-Iactamase inhibitor (ampicillin-sulbactam) Second- or third-generation cephalosporin (cefuroxime, ceftriaxone) Fluoroquinolone with enhanced pneumococcal activity (levofloxacin, moxifloxacin)... 

Due to its powerful specific activity against commonly isolated community-acquired respiratory tract pathogens [33,149-158], including penicillin-sensitive and -resistant Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus, Haemophilus spp., Moraxella catarrhalis and atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila and Klebsiella pneumoniae and anaerobic bacteria [159-162], moxifloxacin was developed as a respiratory tract anti-infective [163-168]. 

The effectiveness of moxifloxacin (MIC,) 0.06-0.125 mg L ) against methicil-lin-sensitive S. aureus (MSSA) is four- to eight-fold greater than that of ciprofloxacin, ofloxacin, and levofloxacin, although its in vitro activity against methicillin-resistant S. aureus (MRSA) is less powerful (MIQo 1-8 mg L 1) [33,149,150, 182,186],... 

In the treatment of tuberculosis, resistant strains of M. tuberculosis (multidrug-resistant tuberculosis, MDRTB) present a growing problem, so that new antituber-culotic agents are required which act according to a different mechanism to that of standard agents such as isoniazid, rifampicin, pyrazinamide, and ethambutol. The more modern fluoroquinolones are of particular interest, and in particular moxifloxacin, which has powerful in vitro and in vivo activity and, in contrast to sparfloxacin and clinafloxacin, is not photo toxic [191]. 

Moxifloxacin s MIC90 value of 1 mg L"1 means that it has the same in vitro activity against M. tuberculosis as levofloxacin, and is more effective than ofloxacin (MIC90 = 2 mg L"1) and ciprofloxacin (MIC90 = 4 mg IT1) [192-194]. A combination of moxifloxacin and isoniazid proved to be more effective in vivo than the individual compounds [195,196], whereas a combination with ethambutol was less effective [196]. Based on the mutant prevention concentration (MPC), which is a parameter for the selection of resistant pathogens during antibiotic treatment, moxifloxacin was found to be the most effective fluoroquinolone against M. tuberculosis [197]. 

All the available ophthalmic fluoroquinolones are indicated for bacterial conjunctivitis with a treatment regimen of usually one to two drops four times a day. However, because the newer gatifloxacin and moxifloxacin have wider spectra and less resistance, they should probably be reserved for treatment of the more serious infection, bacterial keratitis. 

Three-day courses of trimethoprim-sulfamethoxazole or a flu-oroquinolone (e.g., ciprofloxacin, levofloxacin, norfloxacin, or gatifloxacin) are superior to single-dose therapies." " The flnoro-qninolone moxifloxacin is not recommended for nse in UTIs owing to the inadequate urinary concentrations. The use of amoxiciUm and sulfonamides is not recommended because of the high incidence of resistant coli. For most adult females, short-course therapy is the treatment of choice for uncomplicated lower UTIs. Short-conrse therapy is inappropriate for patients who have had previons infections caused by resistant bacteria, for male patients, and for patients with complicated UTIs. If symptoms do not respond or recur, a urine cniture should be obtained and conventional therapy with a snitable agent instituted. ... 

The quinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin) inhibit MAC bacteria in vitro. M. fortuitum and M. kansasii also are sensitive to these quinolones but M. chelonae usually are resistant. Single-agent therapy o/M. fortuitum infection with ciprofloxacin has led to resistance. Ciprofloxacin, 750 mg twice daily or 500 mg three times daily, has been used in a... 

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