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ISSN 1478-7210
? 2009 Expert Reviews Ltd
10.1586/ERI.09.46
In the late 1980s and early 1990s rising rates of antimicrobial resistance in common bac-terial pathogens against standard antibiot-ics were noted in many countries worldwide. For Haemophilus influenzae , a common res-piratory tract pathogen, an increasing inci-dence of b -lactamase-producing strains has been recorded in North America since the mid-1970s. Similarly, around 1990, more than 60% of strains of Moraxella catarrhalis , another common respiratory pathogen, in the USA and Europe were b -lactamase- p roducers. For Streptococcus pneumoniae , one of the most important pathogens in respiratory tract infec-tions (RTIs), the incidence of isolates with reduced susceptibility to penicillin showed a dramatic increase in the early 1990s. Still more alarming was the cross-resistance to other agents, including non-b -lactams. Cross-resistance to cephalosporins, macrolides, tetra-cyclines or cotrimoxazole was found even in pneumococci with intermediate susceptibility to penicillin. As a result, the agents traditionally
used for first-line treatment of mainly RTIs, such as pneumonia and acute exacerbation of chronic bronchitis, caused by these pathogens became less useful. This situation was the more worrisome as RTIs are the most common com-munity-acquired infections and are almost always treated empirically without a microbiological
d iagnosis [1].Overview of th
e market
The development of antibiotic resistance was an additional stimulus to search for better compounds with broader antimicrobial activ-ity within the quinolone class of antimicro-bials, which had been a field of research since the 1970s. The then-available second-generation fluoroquinolones, such as ciprofloxacin and ofloxacin, had broad-spectrum activity with a focus on Gram-negative pathogens. However, their activity against Gram-positive cocci, espe-cially S. pneumoniae , was somewhat limited [2]. The levorotatory isomer (S -enantiomer) of the racemate ofloxacin was developed as a new drug,
Olaf Burkhardt and Tobias Welte ?
?
Author for correspondence Department of Pulmonary Medicine, Medical School
Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Tel.: +49 511 532 3530 Fax: +49 511 532 3353
welte.tobias@mh-hannover.de
Moxifloxacin (MXF) is the latest broad-spectrum fluoroquinolone marketed worldwide. It has in vitro activity against a wide range of Gram-positive and Gram-negative pathogens including anaerobes and intracellular organisms, as well as strains resistant to b -lactam or macrolide antibiotics. For relevant respiratory pathogens, MXF attains the threshold values of pharmacodynamic indices predictive of clinical efficacy and minimization of resistance development. On the other hand, due to its limited activity against Pseudomonas aeruginosa , it is less suitable for ‘late-onset’ nosocomial infections. In clinical trials, it has been found to be at least as effective and safe as comparators, while often showing higher bacteriological success rates. In some randomized studies MXF has shown superiority over comparator regimens in the treatment of patients with community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis. A consistent observation in many clinical trials of respiratory tract infections is the early onset of effect and a faster resolution of symptoms compared with standard therapy, possibly resulting from its fast distribution into tissue and high bactericidal activity leading to more rapid bacterial eradication. Although originally developed for respiratory tract infections, MXF over the years as been shown to be effective, and consequently received approval for
additional indications.
10 years’ experience with the pneumococcal quinolone moxifloxacin
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levofloxacin, and approved in the USA in late 1996. It is approxi-mately twice as active as ofloxacin against Gram-positive cocci. Another fluoroquinolone developed originally by LG Chemical in South Korea at about the same time as moxifloxacin (MXF) is gemifloxacin. With the exception of a higher activity against S. pneumoniae , its in vitro profile is similar to that of MXF. But gemifloxacin has a checkered history. Following a rejected US-NDA in 2000, its oral formulation was first approved by the US FDA in 2003 for mild-to-moderate community-acquired pneumonia (CAP) and acute bacterial exacerbation of chronic bronchitis. In Europe it was filed for approval again in 2008. An intravenous formulation is still in early development. Another fluoroquinolone also designed for the intravenous and oral treat-ment of lower RTIs is gatifloxacin (Kyorin Pharmaceutical Co. Ltd, Tokyo, Japan). Owing to several safety problems, such as gastrointestinal disorders or hypo- and hyperglycemia, especially in the elderly, the substance is only approved in a few coun-tries. In the early 2000s, the des-fluoroquinolone garenoxacin was developed by Toyama Chemical in Japan. It has a high in vitro activity against common respiratory pathogens and is approved only in Japan as an oral formulation for respiratory and o tolaryngologic infections. In 2007 it was declared not-approvable by the EMEA and consequently all EU trials were closed to enrollment.
Moxifloxacin: introduction to the drug
The research that led to the development of MXF was rather targeted to achieve broad-spectrum activity with greater potency against Gram-positive bacteria, including penicillin- and mac-rolide-resistant pneumo c occi, as well as against atypicals and anaerobes, in order to ensure the coverage required for empiri-cal therapy of community-acquired RTIs. Another objective achieved in the development of MXF had been the optimization
of pharmacokinetic properties, especially a longer half-life allow-ing for once-daily administration and, thereby, possibly improv-ing compliance [3]. MXF was licensed in 1999, first in Germany then in the U S A . Mainly owing to its spectrum of activity, MXF has been categorized as a fourth generation or group 4 quinolone [4,5], but has also been labeled as a ‘respiratory or pneumococcal fluoroquinolone’.
Chemistry
Moxifloxacin (systematic name: 1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo-[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride) belongs to the quinolone class of antibacterial agents that was discovered initially as a by-product of chemical synthesis of the antimalarial chloroquine in the early 1960s [4]. Modification of this precur-sors’ structure led to nalidixic acid, viewed as the first clinically used quinolone, although chemically it is not a quinolone but a naphthyridone.
By comparison with nalidixic acid, the quinolone pharmacore in MXF has undergone several structural modifications in order to improve the potency and spectrum of antibacterial activity. The N-1 cyclopropyl moiety that was first introduced with cipro-floxacin has increased the activity against Gram-negative patho-gens. Avoiding a halogen substituent at C-8 has eliminated the phototoxicity that was present in some older quinolones such as sparfloxacin. A key modification was the insertion of the methoxy side chain at C-8 as it led to activity against bacterial topoisomer-ases II and IV and, as a result, may decrease the probability of the development of resistance [4,6]. Further structure relationships are outlined in F igure 1. Compared with earlier quinolones, these modifications led to an enhanced activity against Gram-positive and atypical pathogens and a pharmacokinetic profile that allows for once-daily dosing [3].
Microbiology
Mechanism of action
The bactericidal action of MXF results from binding to and inhibition of bacte-rial topoisomerases, enzymes that control bacterial DNA replication, transcription, repair and recombination, and are vital for chromosome function. The intra-cellular targets for MXF are topoisomer-ases II and IV in Gram-positive bacte-ria and DNA gyrase in Gram-negative bacteria. This dual target of action in Gram-positive bacteria seems to be rele-vant for the high activity of MXF against S. pneumoniae [7–12]. Unlike older fluo-roquinolones such as ciprofloxacin and levofloxacin, which primarily target the ParC subunit of topo i somerase IV in Gram-positive bacteria, MXF primarily targets the GyrA subunit of DNA gyrase as an initial lethal event. It thereby retains
Figure 1. Moxifloxacin and structure–activity relationships of fluoroquinolones. Adapted with permission from [7].
N
N
N
H
H
H
F
O
OH
O
O
H 3
C
? Mar k edly impro v ed activity against Gram-positive (pneumococci)? No interaction with theophylline ? Impedes efflux proteins
Activity against Gram-negati ve
? Lower propensity for resistance de v elopment ? Increased activity against anaerobes ? Photostability
*HCl
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high bactericidal activity against S. pneumoniae strains bearing mutations in topoisomerase IV associated with resistance to older fl uoroquinolones [6,10].Resistance In vitro resistance to MXF develops slowly via multiple-step target site mutations in both topoisomerases. In vitro and in vivo studies have demonstrated a low spontaneous mutation rate for resistance to MXF, particularly for Staphylococcus aureus (6 × 10-11), S. pneumoniae (<1.4 × 10–9) and H. influenzae [3,6]. Although cross-resistance has been observed between MXF and other fluoroquinolones in Gram-negative bacteria, some Gram-positive bacteria resistant to other fluoroquinolones may be sus-ceptible to MXF as it inhibits both topoisomerase II and IV [9]. Because of the dual targeting, the MIC of MXF for S. aureus with single-step mutations in gyrA or parC genes (encoding for GyrA and ParC subunits, respectively) are only slightly increased from wild-type and are well below the serum concentration achieved with therapeutic dosing [13]. In pharmaco d ynamic models, the potential for resistance development in S. pneumoniae secondary
to fluoroquinolone exposure was shown to be significantly lower for MXF than for levofloxacin and gatifloxacin (p < 0.05) [14].While resistance mechanisms that inactivate penicillins, cepha-losporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of MXF, other resistance mechanisms such as permeation barriers (common in Pseudomonas aeruginosa ) and drug efflux may do so. However, MXF was found to be a poor substrate for energy-dependent active efflux in S. pneu-moniae . It is probably the presence of the bulky bicycloamine substituent at the C-7 position that prevents active efflux [9,10].In vitro activity The antibacterial activity of MXF includes a broad spectrum of Gram-positive, Gram-negative and acid-fast bacteria, anaer-obes and so-called atypical pathogens (Mycoplasma, Legionella, Chlamydia spp.), and covers the key pathogens of RTIs as well as pathogens of other community-acquired infections [15]. Susceptibility of MXF is independent of susceptibility to other drug classes such as b -lactams and macrolides [16]. MXF lacks sufficient activity against P. aeruginosa [7]. T able 1 is a compila-tion of worldwide in vitro activity data from 232 original studies published up to December 2004.Data from more recent isolates suggest that susceptibility of S. pneumoniae to MXF remains largely unchanged since its launch in 1999, with exception of localized pockets of increased fluoroquinolone resistance in pneumococci in Hong Kong and South Korea [16]. Of 1776 S. pneumoniae isolates from patients in Australia (2005), 28, 23 and 17% were resistant to penicil-lin, macrolides and multiple drugs, respectively, whereas only two strains (0.1%) were resistant to MXF (MIC: 3 and 4 mg/l) [17]. Pneumococci (n = 3584) from bacteremias, collected in UK and Ireland up to 2007, had a MIC 90 of 0.24 mg/l and a susceptibility rate of 99.2% [18]. H. influenzae (n = 4635) and M. catarrhalis (n = 1283) from community-acquired RTIs, collected in UK and Ireland until 2007, both had a MIC 90 of 0.06 mg/l and a susceptibility rate of 99.9 and 100%, respectively [19]. In a nationwide study of isolates from patients hospitalized for RTI in Germany, the three mayor RTI pathogens S. pneumoniae
(n = 426), H. influenzae (n = 398) and M. catarrhalis (n = 112)
showed low MIC 90 of 0.19, 0.125 and 0.125 mg/l, respectively, and susceptibility rates of more than 99%. Klebsiella pneumoniae (n = 438) and S. aureus (n = 485) from the same cohort had a MIC 90 of 0.75 and 4.0 mg/l, respectively, and resistance rates of 5.9 and 21.2% (mainly MRSA), respectively [16].Moxifloxacin was active against 90% of 166 urogenital myco-plasmas at a MIC of 1 mg/l or less [20] and had a MIC 90 of 0.5 mg/l against 306 clinical isolates of Helicobacter pylori , collected up to 2007 [21]. Susceptibility rates for MXF were 90.8% in 350 aero-bic and 97.1% in 550 anaerobic isolates from intra-abdominal and diabetic foot infections [22]. Bacteroides fragilis (n = 135) and methicillin-resistant, but quinolone-susceptible S. aureus (n = 20) from surgical patients had a MIC 90 of 1.0 and 0.25 mg/l, respec-tively [23]. All of 50 streptococci isolates from odontogenic infections were susceptible to MXF (MIC 90: 0.19 mg/l) [24].Pharmacodynamics
Time-kill assay studies have demonstrated that MXF exhibits a rapid concentration-dependent bactericidal effect on both Gram-negative and Gram-positive organisms [25–28]. Minimum bactericidal con-centrations for S. pneumoniae, group A streptococci , M. catarrhalis, S. aureus, Escherichia coli and K. pneumoniae are in the range of the MICs [3,7,9]. For S. pneumoniae , MXF concentrations of 2–4 × MIC lead to a reduction in colony count of 2–4 log 10 within 6–12 h of incubation. At 16 × MIC (achieved at 1–2 mg/l) the killing rate was 99.9% within 4 h [26]. In vitro, MXF showed a markedly faster kill-ing of S. aureus than b -lactams or macrolides [29]. MXF exhibited a rapid bactericidal effect of respiratory pathogens in an in vitro infection model simulating a single oral 400-mg dose [30]. Against S. pneumo-niae , MXF showed faster killing than levofloxacin and sparfloxacin [31]. The bactericidal action of MXF is not significantly influenced by the presence of albumin, globulins, dead bacteria, pus or anaerobic conditions [32]. A significant postantibiotic effect that increased with higher concentrations was observed with clinical isolates of B. fragilis , S. aureus , H. influenzae , S. pneumoniae and Streptococcus pyogenes [27,28].In animal studies, in vivo and in vitro bactericidal activities of
MXF against Gram-positive and Gram-negative bacteria were shown to be comparable [7,28]. In an animal model for pneumonia with penicillin-resistant S. pneumoniae , MXF was more effective than sparfloxacin, levofloxacin and amoxicillin at concentrations equivalent to therapeutic dosing [7].For all known fluoroquinolones, the pharmacokinetic/phar-macodynamic indices that correlate best to clinical efficacy are the ratio between the 24-h area under the free serum concentra-tion versus time curve and MIC (fAUC 24/MIC) and the peak of free, protein-unbound serum concentration to MIC ratio (fC max /MIC). In hospitalized patients with Gram-negative infec-tions, a fAUC 24/MIC ratio of greater than 125 and a fC max /MIC ratio of 8–10 are predictive for clinical cure [9,33]. The target fAUC 24/MIC ratio for treating infections caused by Gram-positive bacteria is believed to be lower. Therefore, for MXF a fAUC 24/MIC
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ratio of 96 mg/h/l has been associated with a high probability of success in patients with community-acquired infections caused by S. pneumoniae [34].
Another concept that allows for com-parison of resistance development between quinolones is the so-called mutant pre-vention concentration (MPC). The MPC defines the antimicrobial drug concen-tration threshold that would require an organism to simultaneously possess two resistance mutations for growth in the presence of the drug, or simply a dosing threshold above which mutants should rarely arise [35]. With the standard ther-apeutic regimen of MXF the MPC is attained for 75% of the dosing interval, whereas with other currently available qui-nolones the MPC is attained either for a short fraction of the dosing interval or not at all [34].
Pharmacokinetics
Moxifloxacin is available in oral and intravenous formulations containing MXF 400 mg. The oral preparation is rapidly and extensively absorbed from the gastrointestinal tract, yielding an absolute bioavailability of approximately 91% [9,36]. Absorption is not significantly affected by food including dairy products [9,37]. MXF pharmacokinetics are linear for intravenous and oral administration within a dose range from 50 to 600 mg [2,9,38]. Steady-state is reached within 3 days [39]. Following a 400-mg oral dose, peak plasma concentrations of 3.1 mg/l are reached within 0.5–4 h postadministra-tion. In multiple-dose studies, peak and trough plasma concentrations at steady-state were 3.2 and 0.6 mg/l, respectively [2,9]. After a single 400-mg intravenous 1-h infusion, peak plasma concentrations of approximately 4.1 mg/l were observed at the end of the infusion. In healthy vol-unteers, mean peak and trough plasma concentrations at steady-state following 400-mg 1-h infusion once daily were 4.1–5.9 and 0.43–40.84 mg/l, respectively. In patients, mean peak plasma concentra-tions of 4.4 mg/l were achieved at steady-state [40]. In patients receiving multiple intravenous doses of MXF 400 mg once daily, trough serum concentrations were 0.7 mg/l [41]
.
Exposure to the drug is equivalent for oral and intravenous
doses of MXF, thereby allowing a switch from intravenous to oral
therapy without the need to change the drug or the dosage [42].
After a single 400-mg dose, an AUC of 30–39 mg·h/l (oral) and
of 35–39 mg·h/l (intravenous) was observed in healthy volun-
teers [25,42–44], and of 34 mg·h/l (intravenous) in diabetic patients [45]. After multiple 400-mg doses, the AUC was 34–48 mg·h/l (oral) in healthy volunteers [2,43,46]and 41 mg·h/l (oral) in
patients undergoing diagnostic bronchoscopy [46], or 27 mg·h/l
(intravenous) in ventilated patients with pneumonia [47].
Distribution
Moxifloxacin is distributed rapidly to extravascular spaces and shows a steady-state volume of distribution of 2.1–3.1 l/kg [2,9,42]. Independent of the drug concentration, only 40–42% is bound to plasma proteins, mainly to serum albumin, leaving most of the drug in an unbound, active form [9,38,42]. MXF penetrates effectively into extravascular tissue and even seems to accumulate in infected tissue areas [48,49]. In respiratory and abdominal tissues, high drug concentrations were observed, often exceeding corresponding plasma levels as shown in T able 2. Rapid penetration into the lung was even shown in mechani-cally ventilated patients [47,50]. High concentrations in epithelial lining fluid and alveolar macrophages were maintained over the 24-h dosing interval [51]. MXF also penetrates into human phagocytic and nonphagocytic cells such as alveolar macro-phages, neutrophils and endothelial cells and is able to con-centrate intracellularly in human phagocytic cells, fibroblasts, and epithelial cells, reaching intracellular concentrations several times higher than extracellular ones [46,51–53]. It remains active inside human neutrophils [52].
Elimination
Moxifloxacin undergoes Phase II biotransformation in humans and is eliminated via metabolic, renal (approximately 40%) and biliary/fecal (approximately 60%) pathways [2,9]. Its balanced excretion pattern minimizes the potential for drug accumulation in cases of renal or hepatic impairment [42]. Of an oral or intra-venous MXF 400-mg dose, 44–48% is excreted as unchanged drug in feces (25%) and urine (20%), and approximately 52% undergoes hepatic biotransformation and is excreted in urine (16.5%) or via the biliary/fecal route (36%) [40]. The only metabo-lites relevant in humans, a sulphate conjugate and a glucuronide, are both microbiologically inactive [9]. The sulphate conjugate accounts for 38% of the dose and is excreted primarily in the feces, whereas the glucuronide conjugate accounts for 14% of the dose and is excreted in the urine [42]. There is neither indication of involvement of the cytochrome P450 (CYP) system nor of oxidative metabolism [9].
In healthy volunteers, a mean elimination half-life (t
1/2) of
11–15 h after a single intravenous or oral dose and of 12–15 h after multiple doses of MXF, was observed, thereby suggesting a once-daily dosing for the drug [23,42,43]. Following a 400-mg dose, the mean apparent total body clearance and renal clear-ance ranged from 179 to 246 ml/min and 24 to 53 ml/min, respectively, suggesting partial tubular reabsorption from the kidneys [9]. Concomitant administration of ranitidine or probenecid did not alter renal clearance of MXF [9]. The rates of elimination of MXF from tissues generally parallels those from plasma [8].
Drug interactions
As the CYP system is not involved in MXF metabolism and is also not affected by MXF, metabolic interactions via CYP enzymes are unlikely [8,9]. In clinical studies, no interactions following concomitant administration of MXF with ranitidine, probenecid, oral contraceptives, calcium supplements, morphine administered parenterally, theophylline or itraconazole have been observed. There is no clinically relevant interaction between MXF and glib-enclamide or digoxine [9]. Concomitant rifampin or high-dose rifapentine administration resulted in a modest decrease in the mean MXF AUC [54,55].
An additive effect on QT interval prolongation between MXF and other QT prolonging drugs such as antiarrhythmics class IA or class III, neuroleptics, tricyclic antidepressive agents, certain antimicrobials such as intravenous erythromycin, and some older antihistaminics cannot be ruled out. As this might lead to an increased risk of ventricular arrhythmias, MXF is contraindicated in patients treated with these drugs [9].
An interval of approximately 6 h should be left between administration of agents containing bivalent or trivalent metal cations (e.g., antacids containing magnesium or aluminium, didanosine tablets, sucralfate and agents containing iron or zinc) and administration of MXF [9].
Pharmacokinetics in special patient populations Although the elderly and patients with lower than average body weight show higher plasma concentrations, no adjust-ment of dosage is required [9]. In patients with renal impair-ment, including those receiving hemodialysis, continuous renal replacement therapy or extended daily dialysis, or those with mild-to-moderate hepatic impairment (Child-Pugh class A and B) a dosage adjustment of MXF is also not required [9,56–60]. In a study of nine cirrhosis patients treated with MXF 400 mg intravenously once a day, no drug accumulation was found. The authors concluded that even in patients with severe hepatic insufficiency (Child-Pugh class C), a dose adjustment is not necessary [61].
Dosing
The daily dose of MXF is 400 mg for all indications, for tab-lets as well as for the solution for intravenous use that must be administered as a constant infusion over 60 min [40]. Recommended durations of therapy for approved indications (may vary by country) are [8]:
? CAP: 7–14 days
? Acute (bacterial) exacerbations of chronic bronchitis: 5 days ? Acute bacterial sinusitis: 7–10 days
? Uncomplicated skin and skin structure infections: 7 days
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? Complicated skin and skin structure infections: 7–21 days ? Complicated intra-abdominal infections: 5–14 days
? Mild-to-moderate pelvic inflammatory disease: 14 days [9] Clinical efficacy
In accordance with its good penetration into respiratory tract tissues and its excellent activity against respiratory tract patho-gens, the clinical development of MXF focused initially on RTIs. Consequently, the first set of approved clinical indications was for acute exacerbation of chronic bronchitis (AECB), acute bacterial sinusitis and CAP, including infections by multidrug-resistant S. pneumoniae. Continued clinical research led to approval for fur-ther indications: skin and skin structure infections, complicated intra-abdominal infections and, more recently, mild-to-moderate pelvic inflammatory disease. Beyond currently licensed indica-tions, MXF seems to be promising as a second-line drug in the treatment of (multiresistant) pulmonary TB [62–65], and odon-togenic [66,67] and Helicobacter pylori infections [68,69], all plagued by increasing resistance against standard antibiotics. Respiratory tract infections
Pneumonia/community-acquired pneumonia
There are over 3 million cases of CAP in Europe annually. Approximately 20% of patients are hospitalized [70] and of those 6–8% die [71]. Globally, a challenge to clinicians is the wide range of CAP pathogens and their changing pattern of susceptibility to available agents, in particular the increasing prevalence of penicil-lin and macrolide resistance in S. pneumoniae[72]. Fatal failures of macrolide therapy in CAP patients due to resistance have been reported [73].
In eight controlled clinical trials (T able 3) including more than 4000 randomized patients, MXF was at least as effective as compa-rator regimens in the treatment of CAP. In CAP, owing to typical and atypical pathogens, 5–15 days of oral MXF was compared with clarithromycin, amoxicillin or both combined and resulted in clini-cal success rates of 92–95%. Bacteriological success rate was numeri-cally higher for MXF therapy overall in one study (90 vs 82%) [72] and in patients with H. influenzae infection (96 vs 88%) [74].
In patients requiring initial parenteral treatment, 7–14 days of sequential intravenous/oral MXF therapy was compared with b-lactams ± macrolides or levofloxacin and with levofloxacin alone, achieving clinical success rates of 83–93%. In a study by Finch et al., more than 50% of patients had severe CAP as defined by the American Thoracic Society (ATS) criteria and the most common pathogens were S. pneumoniae (55%) and H. influen-zae (20%). Intravenous/oral MXF monotherapy demonstrated superiority over intravenous/oral amoxicillin–clavulanate with or without clarithromycin in both per-protocol and intent-to-treat analyses. Clinical cure and bacteriological success rates were sig-nificantly higher for MXF- than for comparator-treated patients. The rate of clinical cure was higher for MXF therapy in both non-severe (95 vs 86%) and severe (95 vs 86%) pneumonia. Median
time to defervescence was significantly shorter (2 vs 3 days) and
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the switch from intravenous to oral therapy (4.02 vs 4.81 days), as well as discharge from hospital (9.49 vs 10.41 days), occurred earlier with MXF therapy. In addition, there were fewer deaths in the MXF study arm [75]. This is consistent with an observational study in more than 12,000 hospital admitted pneumonia patients in the USA, which demonstrated a significant reduction in 30-day mortality in the group initially treated with fluorquinolones in comparision with b-lactam monotherapy [76].
In a similar patient population, sequential intravenous/oral MXF was found equivalent to high-dose intravenous ceftriaxone ± eryth-romycin, but led to significantly faster defervescence. Evaluation of patient diaries showed a consistently faster relief of symptoms such as chest pain, weakness and sputum color during the first days of therapy with MXF- than for comparator-treated patients [77]. In hospitalized elderly patients with CAP, of which more than two-thirds had a pneumonia severity index (PSI) score of 3 or higher, MXF therapy resulted in faster clinical improve-ment in comparison with levofloxacin. Clinical recovery rates were 98 versus 90% by day 3–5 of therapy. In patients with severe CAP, clinical cure rates were 95 versus 85% for MXF and levofloxacin, respectively. The safety profiles were compara-ble, although there were numerically more cardiac events in the comparator group [78].
In hospitalized patients with serious CAP classified as PSI score III–V and requiring intravenous therapy, intravenous/ oral MXF monotherapy was found to be noninferior to com-bination therapy of intravenous ceftriaxone 1 × 2 g/day plus high-dose levofloxacin 2 × 500 mg/day intravenously followed by 2 × 500 mg/day orally. Clinical cure rates were similar for treatment groups, irrespective of PSI score [79]. Earlier, a pooled ana l ysis of 376 patients from randomized trials had found intra-venous/oral MXF at least as effective as other fluoroquinolones and a b-lactam–macrolide combination. Clinical success and mortality rates were 88 versus 83% and 6 versus 10% for MXF and comparators, respectively. If using 2001 ATS definitions, success rates would be 89 versus 81%. Significantly more MXF-treated patients (73 vs 60%) were switched from intravenous to oral therapy by day 5 [80].
Failure of initial empiric therapy of CAP is uncommon but associated with an increased mortality. In a prospective, rand-omized, single-center study in 63 patients hospitalized after failure of primary outpatient therapy for CAP, intravenous MXF led to significantly lower rates of secondary clinical failure (6 vs 30%; p = 0.003) than intravenous standard therapies including combi-nations at the discretion of the admitting physician. Consequently, patients in the MXF group had a shorter length of stay (9 vs 12 days) and a lower day-28 mortality rate (10 vs 15%) [81].
In a pooled ana l ysis of CAP due to drug-resistant S. pneumo-niae, clinical cure rates with MXF were 100 versus 96 versus 96% for penicillin-, macrolide- and multidrug-resistant strains, respectively [82]. For the treatment of CAP caused by atypical pathogens, intravenous/oral MXF is at least as effective (success rates of 95 vs 94%) as trovafloxacin, levofloxacin and amoxicil-lin/clavulanate plus clarithromycin, as an ana l ysis of 86 evaluable patients pooled from two randomized trials has shown. Most had Mycoplasma or Chlamydia infections [83]. In the treatment of CAP due to Legionella, overall clinical success rates were higher for MXF (95 vs 79%) than for comparators according to a pooled ana l ysis of 50 patients [84].
Hospital-acquired & aspiration pneumonia
In a study evaluating MXF in the empiric treatment of mild-to-moderate hospital-acquired pneumonia, sequential intravenous/ oral MXF (1 × 400 mg/day) was as clinically and bacteriologi-cally effective as intravenous ceftriaxone (1 × 2 g/day) followed by oral cefuroxime axetil (2 × 500 mg/day) for a total of 7–14 days. In the MXF study arm, more patients had an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 15–20
(30 vs 12%) or were on mechanical ventilation (10 vs 7%) at
e nrollment. On the day o
f the switch to oral medication, cough and dyspnea were improved or resolved in a higher proportion of MXF- than ceftriaxone-treated patients (86 vs 72% and 89 vs 79%). The authors consider MXF intravenously/orally as an alternative for the treatment of patients with mild-to-moderate nosocomial pneumonia [85].
Moxifloxacin has also been studied in aspiration pneumonia and primary lung abscess and was found to be as effective and safe as ampicillin/sulbactam with clinical success rates of 59 ver-sus 64% and 80 versus 82% [86]. In an additional case series, all six patients with community-acquired lung abscesses were cured by 4–8 weeks of oral MXF treatment following a short course of standard therapy [87].
Acute exacerbation of chronic bronchitis Exacerbations of chronic bronchitis are one of the most com-mon causes of health service use and the associated symptoms can last for several weeks and negatively impact daily activi-ties [88,89]. Bacterial infection with H. influenzae, S. pneumoniae and M. catarrhalis is implicated in at least 50% of cases [90,91]. Empirical antibiotic therapy is recommened if one of these patho-gens has been detected. In addition, antibiotics should be consid-ered if two of the three following symtoms (increase in dyspnea, sputum production and sputum purulence) are present (so-called Anthonisen type I or II exacerbation) [88].
In nine randomized trials involving 5000 patients (T able 4), a 5-day regimen of oral MXF was found to be at least as effective for the treatment of AECB as standard therapies such as 5–10 days of clarithromycin (2 × 500 mg orally), azithromycin (2 × 500/250 mg orally), amoxicillin–clavulanate (3 × 625 mg orally), levofloxacin (1 × 500 mg orally) and ceftriaxone (1 × 1 g intramuscularly). The majority of patients included in these studies had type 1 Anthonisen exacerbations. Potential advantages of 5-day MXF therapy over longer regimens are improved treatment adherence, lower potential for adverse events, and less selection pressure for resistant strains [92]. Although these studies were designed to demonstrate equiva-lence – as required by regulatory authorities – differences between treatments were seen [88]. Chodosh et al. found higher bacteriologi-cal success rates (89–91 vs 83%) at follow-up and higher eradica-tion rates for H. influenzae (100 vs 83%) at the end of therapy with MXF than with clarithromycin [93]. In the study by DeAbate et al.,
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MXF therapy led to a more complete eradication of H. influenzae (97 vs 83%) and Haemophilus parainfluenzae (88 vs 62%) at test-of-cure (14–21 days post-therapy) and to overall faster eradication than azithromycin. By day 3 of therapy, eradication of the original causative pathogen was achieved in 63% of MXF- and 48% of azithromycin-treated patients [94]. Wilson et al. reported a superior bacteriological response of MXF compared with clarithromycin (77 vs 62% eradication at 7 days post-treatment). MXF therapy was associated with a markedly lower persistence rate of H. influ-enzae compared with clarithromycin (2 vs 33%) at study day 14 among microbiologically valid patients [91].
Clinical cure rates at day 14 were higher with MXF versus clari-thromycin in patients with concomitant steroid medication (88 vs 82%) or coexistent cardiopulmonary disease (84 vs 68%) [91]. In the study by Schaberg et al., the clinical failure rate was sig-nificantly lower with MXF than with amoxicillin–clavulanate in patients with less than three AECB episodes per year (2 vs 9%), with the more severe Anthonisen type I infection (4 vs 8%) and with those who were older than 60 years of age (5 vs 11%) [95]. In the study by Kreis et al., patients receiving MXF showed a more rapid resolution of their infection. This trend may have translated into the higher rate of MXF- versus azithromycin-treated patients reporting improvement of bronchitis (40 vs 27%) or returning to normal activities (36 vs 26%) within 3 days of initiation of therapy [96]. In patients who had achieved clinical cure at test-of-cure visit, Grassi et al. observed a lower relapse rate during 6-month follow-up after MXF versus ceftriaxone treatment (23 vs 28%). In this Italian study, MXF was associated with cost savings of €448 per patient per
episode from a societal perspective in comparison with ceftriaxone,
mainly due to the lower hospitalization rate [97]. In 2001, an explor-
atory ana l ysis of the workplace-related indirect costs in patients
suffering from AECB using data from a comparative clinical trial [92] found a significantly higher work productivity (less absenteeism) for MXF- compared with levofloxacin-treated patients, translating
into cost savings of US$726 per year per patient [98].
However, earlier clinical trials, with the exception of the
one by Grassi et al. [97], were somewhat limited by their focus
on short-term outcomes of therapy and the lack of informa-
tion on patient condition prior to AECB. Therefore, in the
Moxifloxacin Compared to Standard Therapy in Acute
Infectious Exacerbations of Chronic Bronchitis (MOSAIC)
study, an innovative design and novel end points, such as the
need for repeated courses of antibiotics for the exacerbation
as a surrogate marker of relapse, were used. The clinician
could choose the comparator among three options: amoxicil-
lin (3 × 500 mg), clarithromycin (2 × 500 mg) and cefuro-
xime–axetil (2 × 250 mg). As patients were enrolled prior to
AECB while being stable, it was possible to measure the post-
exacerbation return to baseline. Use of corticosteroids was taken
into account by stratification and long-term follow-up of up
to 9 months was performed. Only Anthonisen type I patients
were included. When an exacerbation occurred, patients were
randomized to either 5 days of MXF or 7 days of amoxicillin,
clarithromycin or cefuroxime–axetil [90]
.
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While clinical success rates at day 7–10 after therapy were similar for the treatment groups (T able 4), MXF showed superiority over comparators on clinical cure (return to pre-exacerbation status) in both the intent-to-treat (71 vs 63%, 95% CI: 1.4–14.9) and per-protocol (70 vs 62%, 95% CI: 0.3–15.6; p = 0.02) populations. The bacteriological success rate was significantly higher with MXF than with comparators (92 vs 81%). The need for additional anti-biotic therapy during follow-up was significantly lower in the MXF study arm than for comparators (9 vs 15%; p = 0.006). More inter-estingly, the mean AECB-free interval was significantly prolonged for MXF-treated patients (133 vs 118 days; p = 0.03) [90]. Preventing the recurrence of exacerbations – or at least prolong-ing the exacerbation-free interval – is a critical unmet need since frequent AECB episodes result in a reduced quality of life and lead to a rapid progression of lung disease [89]. The superior preventive effect of MXF might be explained by the immunomodulatory activity of the drug (see section ‘Additional effects’) as well as by the rapid and more complete eradication of pathogens, possibly leading to a reduction of epithelial damage and to a decreased number of pathogens remaining in the bronchial tract as a res-ervoir for further exacerbations [99]. By contrast, levofloxacin (1 × 500 mg/day) did not exhibit a significant effect on the exacerbation-free interval in patients with acute exacerbation of chronic obstructive bronchitis when compared with cefuroxime (2 × 250 mg) in a later study by Petitpretz et al.[100].
Acute bacterial sinusitis
Acute bacterial sinusitis is a common RTI that may become chronic or may even spread to the orbita or the intracranial cavity and cause serious, often debilitating, complications [101]. Patients with severe forms of sinusitis or a prolonged course may benefit from treatment with MXF.
In six randomized, controlled trials, oral MXF (1 × 400 mg/day) was at least as effective for the treatment of acute bacterial sinusitis as comparator regimens including cefuroxime–axetil, amoxicillin–cla-vulanate and trovafloxacin (T able 5)[102–107]. In three studies, 7-day MXF therapy was found to be equivalent to a 10-day comparator regimen [102,105,107]. In a study by Siegert et al., 7 days of MXF had a significantly higher clinical and bacteriological efficacy than 10 days of cefuroxime–axetil, which yielded a 17% bacteriological failure rate [107]. In high-risk patients with frontal or sphenoidal sinusitis, or pansinusitis, and in patients after first-line treatment failure, 7 days of MXF resulted in rapid bacteriological eradication (success rate 95–97%) and a 93% clinical success rate [101]. In a non-comparative study, baseline pathogens were eradicated in 83% of sinusitis patients by day 2 of MXF treatment [108]. Correspondingly, Rakkar et al. found MXF therapy to be associated with more rapid symptomatic relief. By day 3 of treatment, significantly more MXF-treated than amoxicillin–clavulanate-treated patients (24 vs 14%) reported feeling better (p < 0.02) [106]. In patients with radiographic evidence of acute maxillary sinusitis, MXF resulted in somewhat higher clinical and bacteriologic success rates than trovafloxacin and was better tolerated [105]. In a pooled ana l ysis of patients with acute sinusitis due to penicillin-resistant S. pneumoniae, MXF exhibited a 93% clinical and bacteriologic success rate [109].
In a retrospective health insurer database ana l ysis of sinusitis
treatment under real-life conditions in the USA over a 3-year
period, initial duration of prescription, duration of monotherapy,
odds ratio for treatment failure, hazard ratio for recurrence, and
total treatment charges were all significantly lower for MXF
therapy compared with levofloxacin [110].
Other indications
Skin & skin structure infections
Moxifloxacin has good activity against a broad spectrum of patho-
gens, including those of bite wounds, and penetrates well into
inflammatory blister fluid, muscle and sub c utaneous adipose tissue.
Hence, it appears as a reasonable option for the treatment of skin
and skin structure infections (SSSIs). In three randomized, con-
trolled trials, oral MXF (1 × 400 mg/day) was found to be as clini-
cally and bacteriologically effective as cephalexin (3 × 500 mg/day)
in the treatment of uncomplicated SSSI (T able 6). In two recent
randomized studies in hospitalized patients with complicated
SSSI (cSSSI), sequential intravenous/oral MXF (1 × 400 mg/day)
showed clinical and bacteriological efficacy comparable to that of
intravenous piperacillin–tazobactam (4 × 3.375 g) followed by oral
amoxicillin–clavulanate (2 × 800 mg) for 7–14 days or intravenous
amoxicillin–clavulanate (3 × 1.2 g) followed by oral amoxicil-
lin–clavulanate (3 × 625 mg) for 7–21 days (T able 6). The most
frequently isolated pathogen was S. aureus and the most common
cSSSI diagnoses were abscess, cellulitis, diabetic foot infection and
complicated erysipelas. Clinical cure rates were generally similar
between groups when stratified by type of infection [111–113].
An ana l ysis of the subset of patients with moderate-to-
severe diabetic foot infections requiring initial intravenous
therapy found intravenous/oral sequential MXF monotherapy
(1 × 400 mg/day) at least as effective as intravenous piperacil-
lin–tazobactam (4 × 3.375 g) followed by oral amoxicillin–clavu-
lanate (2 × 800 mg). The authors concluded that MXF may have
potential as a monotherapy regimen for diabetic foot infection [114]. In hospitalized patients with major skin abscesses requiring initial intravenous therapy and frequent surgical interventions,
sequential (intravenously/orally) MXF monotherapy was found
to have similar clinical and bacteriological efficacy as standard
combination (b-lactam plus b-lactamase inhibitor) treatment
regimens in a pooled ana l ysis from two randomized trials with
300 evaluable patients. Clinical success rates at test-of-cure visit
were similar for MXF and comparators in patients with commu-
nity- or hospital-acquired infections, with or without diabetes,
and with mono- or polymicrobial infections [115].
Intra-abdominal infections
Complicated intra-abdominal infections (cIAIs) usually require
operative intervention and antimicrobial therapy, and are typically
polymicrobial. Enterobacteriaceae are the most common patho-
gens, but other organisms including anaerobes are often present.
In two randomized Phase III trials (T able 7) of hospitalized patients
with cIAI, sequential (intravenously/orally) MXF monotherapy
(1 × 400 mg/day) was found to be at least as clinically and bac-
teriologically effective as combination regimens of intravenous
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piperacillin–tazobactam (4 × 3.375 g) followed by oral amoxicil-lin–clavulanate (2 × 914 mg) or intravenous ceftriaxone (1 × 2 g) plus intravenous metronidazole (3 × 500 mg) followed by oral amoxicillin–clavulanate (3 × 625 mg). Included were patients with intra-abdominal abscesses, secondary bacterial peritonitis, appendicitis with evidence of perforation or abscess, acute perfo-rations of stomach, duodenum or bowel, or postoperative infec-tions; excluded were patients with pancreatic processes, transmu-ral necrosis of the intestine, or unperforated appendicitis among others. E.coli and B. fragilis were the most frequent pathogens in both studies.
In the open-label study with ceftriaxone as comparator, the appendix was the most frequently involved site of infection (>50%) and efficacy between treatment groups was similar if stratified for site of infection. The rate of adverse drug reactions was slightly higher in the MXF group [116]. In the double-blind study with piperacillin–tazobactam as comparator, the most common diagnoses was complicated appendicitis (60%). Intra-abdominal abscess was diagnosed in 26% of patients. In the 15% of patients with a hospital-acquired cIAI, MXF had both a significantly higher clinical (82 vs 55%, p = 0.05) and bacte-riological efficacy (83 vs 55%, p = 0.04) than the comparator regimen. Similarly, clinical cure rates for MXF were higher than for the comparator in patients above 65 years of age (84 vs 64%), with an APACHE II score of 10 or more (76 vs 69%) or more severe community-acquired cIAI (75 vs 70%). Incidence and types of adverse events, mostly gastrointestinal, were similar for the study groups [117].Pelvic inflammatory disease
Pelvic inflammatory disease (PID) is a common infection in women of reproductive age caused by a variety of Gram-negative and Gram-positive aerobe and anaerobe organisms, including Chlamydia trachomatis. As etiologic diagnosis is difficult, treat-ment is usually empiric and requires broad-spectrum coverage. In two randomized, double-blind trials of patients with mild-to-mod-erate PID, oral MXF monotherapy (1 × 400 mg/day) was at least as clinically and bacteriologically effective as a dual combination of ofloxacin (2 × 400 mg) plus metronidazole (2 × 500 mg) and a triple combination of ciprofloxacin single dose (1 × 500 mg) plus doxycycline (2 × 100 mg) plus metronidazole (3 × 400 mg). For success rates, see T able 7. Bacteriological success rates for the most common pathogens in both studies were 88–95% for MXF and 85–86% for comparators against C. trachomatis and 92–100% for MXF and 82–90% for comparators against Neisseria gonor-rhoeae. In comparison to the dual combination, MXF was better tolerated and was associated with significantly fewer adverse drug reactions (22 vs 31%) than the comparator and significantly fewer increases in transaminase levels (2.6 vs 8.8%, p = 0.0003) [118]. Similarly, MXF-treated patients had lower rates of adverse drug reactions overall (44 vs 49%), especially of the digestive system (26 vs 37%), than patients receiving the triple combination [119]. Innovative/new aspects
Preventive antibacterial therapy post-stroke
Post-stroke antibacterial preventive treatment is an innovative
concept that has been tested with MXF as a model drug. Patients
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initially surviving an acute stroke have a high incidence of infec-tious complications; up to 65% develop fever or clinically sig-nificant infections, mainly pulmonary or urinary. Pneumonia is the most common cause of death in stroke patients. The risk is highest in the acute phase post-stroke. In animal models of experimental stroke, a stroke-induced persistent lymphopenia was observed that was later also found in stroke patients. In a mouse model of ischemic stroke, treatment with MXF either immediately or 12 h post-stroke resulted in significantly reduced mortality and improved neurological outcome [120]. This concept was tested in stroke patients in an investigator-initiated, placebo-controlled, randomized, double-blind trial (PANTHERIS). MXF was chosen for its broad-spectrum activity that includes anaerobic pathogens. A total of 80 patients with severe, nonla-cunar, ischemic stroke received either MXF (400 mg/day intra-venously) or placebo for 5 days starting within 36 h after stroke onset. At day 11, the infection rate in MXF-treated patients was markedly lower (15.4 vs 32.5%) than in the placebo group. In the per-protocol population the difference (17.1 vs 41.9%) was significant. Stroke-related infections were associated with a lower survival rate. However, survival and neurological out-come 6 months post-stroke did not differ significantly between t reatment groups [121].
Postmarketing surveillance
Up to the end of 2008, approximately 109 million patients have been treated with either oral or intravenous MXF. Since the licens-ing of MXF, several postmarketing surveillance (PMS) studies have been performed, including, overall, more than 92,000 patients treated with MXF mostly for respiratory indications. T able 8 sum-marizes basic data of nine PMS studies. In general, clinical effi-cacy in these studies was comparable to that observed in control-led clinical trials, with success rates around 95% for AECB and acute bacterial sinusitis and 89–99% for CAP. The safety profile was similar to that previously reported, with gastrointestinal dis-turbances as the most common adverse events [122–126]. Serious adverse events were rare [126,127], despite the less stringent control for comedications compared with controlled clinical trials. Overall, these data confirm the efficacy and safety of MXF in a real-world setting [89].
The rapid onset of action of MXF treatment as observed in clini-cal trials was also found in PMS studies. Of patients suffering from CAP, more than 50% improved by day 3 of therapy [123,125]. Patients with AECB showed symptom relief after a mean of 3.2–3.4 days of MXF [124,128] and at least 1 day earlier (p < 0.0001) than with macrolides [128]. Of sinusitis patients, 72% improved after 3 days of therapy [122]. In patients treated intravenously, the rapid clinical response allowed an earlier switch to oral therapy [125].
The Avelox Clinical Experience Study (ACES) was a large, safety-centered PMS study with a focus on cardiac safety. Despite a comparatively high rate of adverse events in this PMS study, the independent external expert committee that reviewed all patients with possible cardiac-related events did not find any clinical evi-dence of an increased risk of cardiac arrhythmias with MXF treatment [126].
The only non-RTI related PMS study (ARTOS) is still ongo-ing and includes patients with cSSSI, such as postsurgical wound infections, diabetic foot infections, erysipelas and skin abscesses. In an interim report tolerability was rated as good or very good in most of the patients [129].
The GIANT study, apart from its target size of 50,000 patients, addresses a scope beyond a usual PM S. The enrollment has fin-ished and data are currently under evaluation. GIANT intended to evaluate the impact of AECB on the individual patient and the community, in order to get a complete picture of the AECB patient. An interim ana l
ysis on comparing data from Europe and
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Asia–Pacific was presented at the American Thoracic Society 2007 International Conference in San Francisco, California, USA [89]. By the end of 2006, nearly 49,000 patients from 46 countries had been enrolled. MXF treatment duration was 5 days for most of the patients. Patients had more than two exacerba-tions in the past 12 months. A total of 73% of patients from Europe (9157) had an AECB of Anthonisen Class Type 1 or 2. Efficacy and tolerability of MXF therapy was rated as good or very good by physicians for approximately 95 and 96% of patients, respectively. The rate of serious adverse drug reactions was 0.05 and 0.004% for patients in Europe and Asia–Pacific, respectively. MXF was rated as being ‘better’ than previous therapy by 85% of European physicians. More than 96% of patients were satisfied with the therapeutic effect of MXF. In European AECB patients, MXF reduced the number of days with symptoms impacting daily life activities by 2.2 and the number of nights with disease-related sleep disturbances by 1.5 in comparison to the previous therapy [89].
Additional effects
Beyond its bactericidal activity, MXF exhibits numerous other effects that have been explored over the years, some of which may contribute to its clinical efficacy and its rapid clinical effect in patients. Especially interesting are immunomodulatory and anti-inflammatory effects that might be of benefit in patients suffering from acute or chronic infections such as CAP or AECB/acute exacerbations of chronic obstructive pulmonary disease.
In vitro, MXF, as well as other quinolones, reduce the synthesis of TNF, IL-1, IL-2 and IL-6. Stimulation of IL-3 and granu-locyte and granulocyte-macrophage colony-stimulating factors (G/GM-CSF) was observed ex vivo and in vivo in bone marrow and lungs of animals treated with cyclopropyl quinolones [130]. According to an in vitro study in zymogen A-stimulated human THP-1 monocytes, MXF may modify the acute-phase inflamma-tory responses through inhibition of cytokine release. Initially, MXF appears to activate monocytes to kill bacteria through the innate immune process. At a later time, this effect on cytokine release is reversed, so that lipid peroxidation and tissue destruction by the infection process is suppressed [131].
In a murine leucopenia model, MXF stimulated hemato-poiesis in the lung of cyclophosphamide-treated mice in a similar extent as G-CSF [132]. In immunosuppressed mice infected with Candida albicans, MXF exhibited protective anti-inflammatory effects by inhibiting IL-8 and TNF-a production in the lung. Lipopolysaccharide (LPS)-activated human peripheral blood monocytes and THP-1 cells also showed decreased synthesis of proinflammatory cytokines when incubated with MXF [133]. MXF was found to reduce the release of TNF-a and IL-6 from stimulated human peripheral blood mononuclear cells more effectively than levofloxacin and ceftriaxone, without showing a cytotoxic effect [134].
In an open, nonrandomized clinical study of 24 patients with lower RTI, treatment with MXF (400 mg/day intravenously/ orally) resulted in significantly lower sputum levels of IL-8 and caspase-3, an enzyme associated with apoptosis, than treatment with ceftriaxone (2 g/day intravenously) at day 3–4 [135]. Endotoxin, the LPS of Gram-negative bacteria, plays a pivotal role in the pathogenesis of sepsis and can be released from bacteria during cell lysis caused by antibiotic treatment. As antibiotics dif-fer in their propensity to release endotoxin from Gram-negative bacteria, kinetics of endotoxin liberation from E. coli under the influence of MXF were studied in vitro. Although MXF killed E. coli very rapidly, endotoxin release was rather low and com-parable to that induced by imipenem, a drug known for its low endotoxin-releasing potential. Correspondingly, release of proin-flammatory cytokines (TNF-a and IL-1b) from monocytic cells was reduced with MXF. As febrile response and time to deferves-cence might be influenced by LPS release, it may be prudent to select drugs with a low LPS-releasing potential for the treatment of critically ill patients [136]
.
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Cellular effects
Especially interesting are the rescue effects of MXF on human respiratory tract cells against pneumococci-induced damage. In a cell culture infection model, alveolar epithelial cells incu-bated with S. pneumoniae were largely protected from cellular damage by adding MXF, even when given 6 h after the bacte-rial challenge. Amoxicillin was far less effective under the same conditions [137].
Moxifloxacin seems to increase the tolerance of alveolar epithe-lial cells against mechanical stress. Alveolar type 2 cells from rats when stretched in vitro in a similar manner as under respiration release lactate dehydrogenase and show an increased portion of apoptotic cells. Exposure to MXF concentrations similar to those achieved in human epithelial lung fluid markedly decreased lac-tate dehydrogenase release as well as the percentage of apoptotic alveolar cells following stretching. This might be of benefit in respirated patients [138].
Mucociliary clearance plays a key role in airway host defense and is depressed during RTIs and chronic airway inflamma-tion. Toxins of several bacteria as well as some antibiotics such as tetracyclines and penicillins have been shown to decrease ciliary activity of human epithelium in vitro. Exposure of nasal ciliated epithelium cells from healthy volunteers to MXF resulted in a slight but significant upregulation of the ciliary beat frequency, which was even sustained for 20 min after drug wash-out. Although it is unknown whether this effect is clinically relevant, MXF at least has no adverse effect on cili-ary activity [139]. A similar observation was made in an in vitro model for mucociliary transport function, in which incubation with MXF did not impair ciliary function as measured by the rotation rate of human nasal epithelial spheroids cultured in their own mucus [140].
Biofilm
In respiratory diseases such as chronic bronchitis, chronic obstruc-tive pulmonary disease, or ventilator-associated pneumonia, biofilm formation is thought to play a key role as it enables bacteria to protect themselves from antimicrobial exposure and, eventually, to evade eradication. In an in vitro assay, effects of MXF on slime production and pre-formed biofilms of clinical strains of common pathogens were studied. MXF (0.5 mg/l) reduced slime synthesis by more than 70% in S. aureus, H. influenzae and S. pneumoniae, and by up to 70% in E. coli and M. catarrhalis. MXF concentra-tions achieved during therapy resulted in a significant breakdown of preformed biofllm from all tested organisms. Even mature (48 h) biofilms were reduced by up to 70% in all strains of S. pneumoniae, H. influenzae and S. aureus[141]. If this effect is also present in vivo, it might contribute to the superior long-term effect of MXF in patients with acute bacterial exacerbations of chronic bronchitis,
as observed in the MOSAIC study. Similarly, in an animal model
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of implant-associated infection by S. aureus, MXF therapy led to a highly significant decrease in the microbial counts in the biofilm as well as in bone and soft tissue, as compared with vancomycin treatment and to an untreated control. This was also reflected in the superior efficacy of MXF compared with vancomycin [142]. Safety & tolerability
In clinical studies, MXF has demonstrated a good safety profile and is as safe and well tolerated as other commonly prescribed antibiotics. This has been shown in meta-analyses of cumula-tive safety data from clinical trials (7368 moxofloxacin patients) and postmarketing studies (46,130 patients). Gastrointestinal disturbances such as nausea and diarrhea were the most com-mon adverse drug reactions associated with both formulations of MXF and were observed in controlled clinical trials at rates similar to those of comparator antibiotics [143,144]. In elderly patients, oral MXF was not associated with higher rates of adverse events or premature termination compared with younger patients (< 65 years) or patients treated with comparators, mostly cefuro-xime and clarithromycin, as a pooled ana l ysis of 12,231 patients (MXF and comparators) treated in randomized comparative tri-als has shown. No arrhythmias related to QTc prolongation were observed. QTc interval prolongation on study day 3 was even lower in elderly patients as compared with patients younger than 65 years of age [145].
Although MXF prolongs the QTc interval by 6 millisec-onds [146], this seems not to translate into an increased risk for cardiac adverse events as analyses of safety data (including >54,000 patients) and studies with paired electrocardiographic readings have shown [143,147]. In a double-blind, randomized Phase IV study in 387 hospitalized elderly patients (> 64 years) requiring initial parenteral antibiotic for CAP and receiving 72-h Holter monitoring, MXF had a comparable cardiac rhythm pro-file to levofloxacin. Of these high-risk patients, one treated with MXF had a sustained ventricular tachycardia and one patient treated with levofloxacin had a Torsade de Pointes [146]. In a pooled ana l ysis of Phase II/III studies including patients with RTI, the incidence of cardiovascular-related adverse events (2%) was similar between MXF (n = 4008) and comparator antibiotic-treated patients (n = 3689). In a PMS study (ACES) including more than 18,000 patients, MXF did not result in any detectable treatment-associated ventricular tachyarrhythmias [126].
Arthro- and tendinopathies are well known although uncom-mon adverse effects of quinolone therapy. Age over 60 years and concomitant steroid therapy increases the risk. As measured by spontaneous adverse event reports, levo- and pefloxacin are sig-nificantly more often associated with this risk than ciprofloxacin and MXF [147]. The risk for tendon inflammation or rupture with MXF is classified as rare and very rare, respectively [9]. Although disturbances of glucose homeostasis appear to be a quinolone class effect, MXF seems to have no clinically relevant effect on blood glucose [143]. In the FDA database, the incidence of glucose homeostasis-related adverse events was less than 2% for newer quinolones and even lower for MXF (<0.7%) [147].
A pooled ana l ysis of 32 clinical trials and five PMS studies involving more than 50,000 patients treated with MXF yielded no drug-related hypoglycemic adverse events and less than 0.1% hyperglycemic adverse events of which none were serious [148]. Allergic reactions associated with MXF are rare. In an ana l ysis of data from a large managed care organization, the incidence of any allergic reaction within 14 days after exposure per 10,000 first dispensings was lower for MXF (4.3) than for levofloxacin (8.7) or cephalosporins (7.5). The incidence of anaphylaxis was similar for the fluoroquinolones: 0.3 for MXF, 0.3 for gatifloxacin and 0.5 for levofloxacin [149].
Like most antibiotics, MXF can select for Clostridium difficile in patients already colonized with this highly-resistant anaerobic rod, leading to C. difficile overgrowth of the gut flora and eventually to C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis. Whether or not MXF use is a risk factor for CDAD or associated with an increased risk is a matter of debate and seems to depend on local conditions [147]. A population-based case–control study of outpatients prescribed fluoroquinolones did not show an increased risk of C. difficile-associated disease requiring hospitali-zation among patients prescribed gatifloxacin or MXF compared with levofloxacin [150]. Infection-control measures including the use of sporicidal cleaning agents seem to be at least as important as a judicious use of antibiotics [151].
Severe hepatotoxicity could be an important identified risk of treatment with MXF, which is well known from the first clinical trials and therefore is already described in the prod-uct information and is under close monitoring. The European Medicines Agency (EMEA) ordered a cumulative review up to 30 September 2007 of all hepatic reactions (serious and nonseri-ous) to perform an overall assessment of the risk–benefit ratio of MXF treatment. Of a total of 48 identified cases of pos-sibly MXF-related liver disorders with a fatal outcome of any cause, eight were suspected cases of MXF-induced fatal hepa-totoxicity. In three of these cases, MXF was used to treat less severe indications (sinusitis, pharyngitis and acute bronchitis). The Committee for Medicinal Products for Human Use of the EMEA reasoned that these findings and additional available data (observational study and clinical trials) suggested that serious liver injuries occurred more frequently with MXF than with the comparators. Therefore, the use of the oral formulation of MXF was restricted as described below [201].
Acute bacterial sinusitis
Acute bacterial sinusitis is generally a nonsevere infection associated with high spontaneous cure rates (90%). A substantial proportion of prescriptions for sinusitis in clinical practice may be empirical and without confirmation of bacterial origin. Although MXF has been shown to be effective, the available data is limited as studies have been mainly performed against comparators and the only placebo controlled study failed to demonstrate statistical superiority over placebo. Considering the higher incidence of serious and even life-threatening risks in the treatment of an infection that has a high spontaneous resolution rate without antibiotics was considered of concern. However, the risk–benefit ratio of MXF may be favorable if other antibiotic therapy has failed or cannot be used.
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Acute exacerbation of chronic bronchitis
The benefit of antibiotic treatment of AECB was supported by several publications including a meta-ana l ysis and a recent sys-tematic review from The Cochrane Centre suggesting a mor-tality benefit with the use of antibiotics in this indication in comparison with placebo and a beneficial effect on lung func-tion. However, it was noted that until recently antibiotic com-parative trials in AECB designed to show equivalence between medicinal products did not demonstrate clinical superiority of any class of antibiotics over another. Additionally, most of the Phase III studies designed for noninferiority of MXF did not use the recommended agent of choice. Therefore, since the impact of the choice of an antibiotic therapy for AECB on the outcome of the patients remains unclear, the safety profile of the different antibiotic therapy options must be considered. MXF can only be recommended in cases suspected to be of bacterial origin, in which no other antibiotic treatment (i.e., with penicillin d erivates) seem to be succesful.
Community-acquired pneumonia
Clinical trial and published data indicate that MXF generally has benefits in CAP. Furthermore, when taking into account other antibiotic therapies available and resistance, advantages over other therapies are observed in the treatment of CAP of mild-to-moderate severity. However, considering the safety profile with an observed increased incidence of risks, MXF should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection.
Expert commentary
Hepatic toxicity is a well known side effect of all antibiotics [152]. Hepatic failure as the most severe form of drug-induced liver injury is a very rare event, which has been reported for a number of fluoroquinolones, but also for macrolides, b-lactams and other classes of antibiotics. Even after a careful ana l ysis of the published data, it is hard to understand why this should be mainly a problem of fluoroquinolones and especially MXF. It may be that antibiotics that were approved recently and that offer a broad postmarketing surveillance are under more observation than older ones, which have been used in clinical practice for decades. The EMEA noted that due to this liver toxicity the risk–benefit ratio of MXF for milder infections is doubtful. However, even in moderate AECB or CAP there is a remark-able mortality, which is by far more important than the low number of reported liver toxicities. Mortality is closely related to age and comorbidities, and it has been clearly demonstrated that appropriate first-line treatment is a key factor for long-term survival [153].
In conclusion, there is no doubt that fluoroquinolones and especially MXF will be necessary for more severely ill patients who are at risk for an increased mortality. We are afraid that the above described restriction for MXF could lead to a dangerous undertreatment of more severly ill patients.
Five-year view
Moxifloxacin will probably be approved in more countries as the company aims to achieve approval for all indications in all countries. Interesting results may come out of the two large international studies of MXF in AECB, Pulsed Moxifloxacin Usage and its Long-term Impact on the Reduction of Subsequent Exacerbations (PULSE) and MAESTRAL, as well as many cur-rently ongoing or planned investigator-sponsored trials testing for innovative treatment concepts.
Regulatory affairs
The oral formulation of MXF is approved in 109 countries worldwide, including Japan. The intravenous formulation is approved in 90 countries, including the USA, Canada and many European countries. The indications may vary from country to country. Approved indications are RTIs, cIAIs, SSSIs and PID.
Financial & competing interests disclosure
Tobias Welte has received fees for lectures from Bayer Healthcare and is a member of the national and international advisory board. Olaf Burkhardt has received a travel grant from BAYER. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or m aterials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.
https://www.doczj.com/doc/1312429231.html,661
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