Abstract

The quinolones have evolved from antibacterial agents with a limited spectrum of predominantly anti-Gram-negative antimicrobial activity and a restricted number of indications to a class of widely used oral (and, in some cases, intravenous) antibiotics with extensive indications for infections caused by many bacterial pathogens in most body tissues and fluids. This evolutionary pattern has arisen through the development of new core and side-chain structures, with associated improvements in activity, pharmacokinetics and tolerability, and through the selection of molecules that remain useful and well tolerated. This review describes the progress of the quinolones from the first to the third (IIIa and IIIb) generations. Special attention is given to gemifloxacin, currently the most developmentally advanced third-generation quinolone, which has enhanced in vitro Gram-positive antimicrobial activity and no troublesome adverse drug reactions. Preliminary data indicate that gemifloxacin should prove to be an important addition to the fluoroquinolone class. Further clinical trial data are awaited with interest.

Introduction

Since the discovery, in 1962, of the progenitor 1,8-naphthyridine, nalidixic acid,1 the utility of which was largely limited to the treatment of Gram-negative urinary tract infections, the quinolones have evolved to become important and effective agents in the treatment of bacterial infection.2

The molecular structures of the quinolones have been adapted over time in association with clinical need. The naphthyridone nucleus of nalidixic acid became the basis of a series of more active compounds; piperazine substitution at the 7-position led to compounds with significant activity against Pseudomonas aeruginosa, e.g. pipemidic acid, and, fluorination at the 6-position (giving the fluoroquinolones) and modification of other side chains led to enhanced anti-Gram-positive activity, including improved potency against the pneumococcus, improved pharmacokinetic profiles and longer serum half-lives.3,4 These compounds, which are suitable for once-daily administration and are clinically effective in pneumococcal respiratory and other Gram-positive infections, have differing adverse drug reaction profiles. In some cases, there are relationships between structure and adverse reaction, notably in terms of phototoxicity, which is more commonly associated with additional fluorine (lomefloxacin, sparfloxacin) or chlorine (clinafloxacin and sitafloxacin) substitution at the 8- position, and central nervous system (CNS) effects, which are more commonly associated with unsubstituted 7-piperazine derivatives.5,6 However, more serious reactions, such as the temafloxacin-associated haemolytic–uraemic syndrome7 and the recent serious, unpredictable hepatic reactions associated with trovafloxacin5 do not seem to have any specific structural relationship. There are also no obvious structural associations, either nuclear or substituent, with QT interval prolongation, a recently recognized class effect.8 Nevertheless, the known adverse reaction profiles and improving broad-spectrum activity have led to the evolution of safer, more clinically efficacious molecules by a process akin to the Darwinian principles of fitness of the surviving molecular ‘mutations’ and attrition of the defective ones.46,9 Thus today, newer compounds can be designed that maintain or enhance activity whilst minimizing the risk of use-limiting adverse effects.

There are, thus, two aspects to the evolution and development of the quinolones. Firstly, there is the natural history, characterized by the development of novel structures with better activity, pharmacokinetics and tolerability than previous members of the class. Secondly, there is ‘natural selection’ by prescribers and registration/licensing authorities of those agents and molecular configurations that remain useful and deselection of those that do not.

This article reviews the progress of the quinolones from the first-generation through to the more recently developed third-generation agents. Special attention is given to gemifloxacin, a novel advanced third-generation quinolone with superior Gram-positive antimicrobial activity and retained Gram-negative activity.

The fluoroquinolones and naphthyridones

The structures of the quinolones have developed along two parallel pathways (Table I): the naphthyridones (with the original naphthyridine core of nalidixic acid) and the fluoroquinolones, in which a carbon atom is substituted for nitrogen at position 8 of the naphthyridine nucleus. All have a fluorine substitution at the 6-position.

The first fluoroquinolone, flumequine,10 was used transiently until ocular toxicity was reported. Shortly afterwards, second-generation agents were developed, epitomized by ciprofloxacin (Figure 1). This agent has a wider spectrum of in vitro antibacterial activity, in particular against Gram-negative bacteria, and is effective in the treatment of many types of infection.3,1113 Despite excellent results in many respiratory infections,14 reports of failure in pneumococcal infection15 have limited its use in this area.

Subsequently, newer agents were developed that had increased antimicrobial activity against Gram-positive pathogens; these included sparfloxacin16,17 and grepafloxacin.18,19 However, sparfloxacin has now largely been abandoned because of significant phototoxicity and potential for serious cardiac dysrhythmias, secondary to its effects on the QT interval.8,12 The 8-chloro compounds, such as Bay y 3118,20,21 clinafloxacin22,23 and sitafloxacin,24 were even more active, but also photoreactive. Only sitafloxacin remains in limited development. Moxifloxacin2527 and gatifloxacin,28,29 both 8-methoxyquinolones, are the most recent and most potent fluoroquinolones.

Naphthyridone derivatives emerged in parallel with the moxifloxacin lineage. Enoxacin and tosufloxacin (available in Japan) were the first naphthyridones; they were followed by trovafloxacin30 and, more recently, gemifloxacin31,32 (Figure 2).

The quinolone generations

The characteristics of the quinolone generations are summarized in Table II. The antimicrobial activity of the fluoroquinolones and naphthyridones has increased dramatically as each generation of quinolones has been developed. The first-generation agents had anti-pseudomonal activity as a result of the addition of a piperazine substituent at position 7 of the naphthyridine core. These compounds were replaced by the second-generation agents, for example ciprofloxacin,33 which had predominantly Gram-negative activity. Improved Gram-positive activity, including that against Streptococcus pneumoniae (MICs c. 0.25–0.5 mg/L4), was the next significant step, seen with the generation IIb agents such as grepafloxacin and sparfloxacin. Generation IIIa agents (e.g. moxifloxacin, gatifloxacin, sitafloxacin, clinafloxacin and trovafloxacin) have enhanced activity against S. pneumoniae (MICs generally c. 0.12 mg/L4), at the partial expense of slightly reduced activity against P. aeruginosa. The most recent advance in in vitro activity is represented by gemifloxacin, currently the only IIIb quinolone. Gemifloxacin has a balanced spectrum of activity with Gram-negative activity similar to that of ciprofloxacin but superior Gram-positive activity (MIC for S. pneumoniae ≤0.03 mg/L).31,32

Second generation

Generation IIa.

The generation IIa quinolones have been available since the mid-1980s and were responsible for an enormous change in the clinical treatment of important infections. With the advent of ciprofloxacin, for almost the first time, serious, potentially bacteraemic Gram-negative infections, such as pyelonephritis, prostatitis and osteomyelitis, could be treated highly effectively in the outpatient setting with an oral antibiotic. Similarly, P. aeruginosa respiratory infections in children with cystic fibrosis could be treated orally. Enteric fever and salmonellosis could be treated with short-course oral therapy with minimal relapse and low carriage rates. These exceptional advances in antimicrobial chemotherapy were reflected in the approved indications for these agents.4

The main disadvantage of the IIa quinolones was their limited activity against Gram-positive pathogens, including S. pneumoniae (because of their intrinsically low activity against these species) and methicillin-resistant Staphylococcus aureus (MRSA) (because of the development of resistance).34 In addition, certain class adverse events, such as CNS effects (headache, dizziness), phototoxicity and tendinitis, became apparent, although the more serious events were rare.5 Study of this group led to a greater understanding of the metabolism of quinolones, for example their inhibition of the cytochrome P450 1A2-mediated metabolism of drugs, such as theophylline.5,35

Generation IIb.

The development of the generation IIb compounds, with a more balanced spectrum of activity encompassing the pneumococcus, resulted in the application of fluoroquinolones to respiratory tract infections. The longer half-life of these agents also permitted once-daily dosing.

The generation IIb quinolones were also associated with the class adverse drug reactions described above, but other adverse reactions were observed with individual agents. For example, haemolytic–uraemic syndrome was reported with temafloxacin and resulted in its withdrawal,7 and prolongation of the electrocardiographic QT interval corrected for heart rate (QTc interval), possibly predisposing to ventricular arrhythmias, was seen with sparfloxacin.36,37

The oral tolerance of grepafloxacin is not optimal; it interacts significantly with theophylline (via cytochrome P450 1A2) and QTc prolongation may occur.38 The occurrence of seven cardiac deaths, possibly related to grepafloxacin, led to the withdrawal of this drug by the manufacturer in October 1999. Other quinolones now have data-sheet labelling warning of possible effects on the QTc interval and associated clinical consequences, including ventricular arrhythmias and ‘torsade de pointes’.8 No clinically significant effects have been observed with gemifloxacin.

Third-generation

Generation IIIa.

. Of the IIIa compounds, moxifloxacin and trovafloxacin both have 7-azabicyclo modifications, whereas gatifloxacin retains the original 7-piperazinyl group. All are active against penicillin-resistant S. pneumoniae and have proven highly effective in the treatment of lower respiratory tract infections.4,12,39 Moxifloxacin was licensed in Germany in 1999 and both moxifloxacin and gatifloxacin are now licensed and available in the USA.

Before its withdrawal/suspension, trovafloxacin, which had excellent activity against anaerobes, had proven effective in post-surgical intra-abdominal and gynaecological infections.12 The efficacy of the other IIIa/b compounds may now be evaluated in these indications.

Members of this group share the class adverse drug reaction profile, but do not interact with cytochrome P450 1A2. Recently, however, rare but serious adverse reactions (liver failure, hepatic dysfunction and pancreatitis) have led to trovafloxacin being either restricted for use in inpatients with life- or limb-threatening infections for which no suitable safe and effective alternatives are available (in the USA) or suspended from use (in Europe). Clinafloxacin was voluntarily withdrawn by the manufacturer during the registration process, at least in part because of the excess phototoxicity and reports of hypoglycaemia. Fortunately, both of the 8-methoxyquinolones, gatifloxacin and moxifloxacin, have satisfactory adverse drug reaction profiles and appear free of significant clinical problems.12,40

Generation IIIb: gemifloxacin.

Gemifloxacin is currently the only generation IIIb quinolone in phase III development. Against S. pneumoniae, gemifloxacin has markedly better activity than its predecessors, including the IIIa quinolones.41,42 Its side-chain structure (Figure 2) includes the 1-cyclopropanyl group that is characteristic of most of the fluoroquinolones with good safety profiles, including ciprofloxacin (Figure 1), in contrast to the 1-difluorophenyl substituent of temafloxacin and trovafloxacin. In addition, gemifloxacin has a large side chain at position 7, thought to be associated with reduced CNS effects,6 and a methoxyamino group, which may account for the dramatic improvement in anti-pneumococal activity seen with this compound.

MICs for the pneumococci show a marked increase in activity compared with earlier compounds (Table III). Gemifloxacin also retains activity against penicillin-resistant and ciprofloxacin-resistant strains of S. pneumoniae.42 Its activity against quinolone-resistant S. pneumoniae43 may prove important in the light of the increasing problem of resistance to penicillins, macrolides and earlier fluoroquinolones. The small, but increasing, prevalence of quinolone resistance is discussed in more detail elsewhere.4446

Gemifloxacin is also highly active against clinically significant atypical respiratory tract pathogens such as Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae (Table IV).47,48

The safety of gemifloxacin has been studied in a continuing clinical trial programme; preliminary data indicate that it has a satisfactory adverse drug reaction profile. Gemifloxacin has been used in single doses of ≤800 mg and in multiple dosing regimens in both healthy volunteers (≤640 mg/day) and elderly patients (320 mg/day) and was well tolerated.4951 The CNS effects observed with gemifloxacin are similar to those seen with placebo and, to date, no significant/serious adverse drug reactions have been observed.

During randomized, double-blind phase II clinical trials of gemifloxacin, the incidence of CNS, gastrointestinal and dermatological class adverse drug reactions was, in general, the same or better than that of the generation IIa quinolone, ofloxacin (Figure 3).52 The incidence of nausea seen with gemifloxacin (3.8%) appears to be lower than that observed with grepafloxacin (15%; 2.6% discontinuation rate) or moxifloxacin (7.8%; <1% discontinuation rate).5 The high incidence of dizziness reported with trovafloxacin (≤11% with 200 mg dosage)5 has not been seen with gemifloxacin (1.5%) in these early trials. To date, no cardiovascular effects have been recorded in patients treated with gemifloxacin.

The phototoxic potential of gemifloxacin (320 mg od) compared with ciprofloxacin (500 mg bid) in healthy volunteers (n = 30) was shown to be low and similar to that of ciprofloxacin.53 In contrast, lomefloxacin is associated with a significant phototoxic potential.54

The interaction profile of gemifloxacin has been studied in healthy volunteers. No significant interactions were observed after absorption with digoxin,51 theophylline55 or warfarin.56 The interaction of fluoroquinolones with co-administered antacids is well known and gemifloxacin absorption is similarly reduced by the co-administration of Maalox.57 Manipulation of dosing regimens (administration either 2–3 h before or after antacid therapy)—a simple matter with the once-daily dosing regimen of gemifloxacin—can eliminate any such problems. The effect of omeprazole on gemifloxacin pharmacokinetics is not considered to be clinically significant; dose adjustment is unnecessary when these agents are administered together.58

In summary, gemifloxacin is the most active quinolone against S. pneumoniae and has a satisfactory adverse drug reaction profile. It has a favourable pharmacokinetic profile that allows once-daily dosing50 and its pharmacokinetic/pharmacodynamic profile suggests that it will be clinically effective in the treatment of respiratory tract infections.59

Conclusions

The quinolones have evolved from agents used solely for the treatment of urinary tract infections to molecules with potent activity against a wide spectrum of significant bacterial pathogens and clinical utility in many indications throughout body tissues and fluids. Progressive modifications in molecular configuration have resulted in improved breadth and potency of in vitro activity and pharmacokinetics, which have identified those agents fit to survive in today's therapeutic environment. Concomitantly, excessive incidences of class adverse drug reactions and specific ‘unexpected’ reactions with individual agents have determined the ‘deselection’ of agents such as temafloxacin, sparfloxacin, Bay y 3118 and, most recently, trovafloxacin, clinafloxacin and grepafloxacin.

Gemifloxacin is an advanced third-generation quinolone with a broad spectrum of antimicrobial activity that includes potent activity against S. pneumoniae. At present, it appears to be the most potent quinolone against this important pathogen. It also has a favourable pharmacokinetic profile, characterized by a large volume of distribution and an elimination rate that suggests it to be suitable for once-daily dosing. Preliminary data indicate that it has a low incidence of adverse drug reactions and a low phototoxic potential. Further data from clinical trials of this newly developed quinolone are awaited with interest.

Table I.

The quinolones

 Core structure 
Generation fluoroquinolone naphthyridone 
flumequine nalidixic acid 
IIa ciprofloxacin, ofloxacin, (levofloxacin) enoxacin 
IIb grepafloxacin, sparfloxacin tosufloxacin 
IIIa moxifloxacin, gatifloxacin, sitafloxacin, clinafloxacin trovafloxacin 
IIIb none yet developed gemifloxacin 
 Core structure 
Generation fluoroquinolone naphthyridone 
flumequine nalidixic acid 
IIa ciprofloxacin, ofloxacin, (levofloxacin) enoxacin 
IIb grepafloxacin, sparfloxacin tosufloxacin 
IIIa moxifloxacin, gatifloxacin, sitafloxacin, clinafloxacin trovafloxacin 
IIIb none yet developed gemifloxacin 
Table II.

Summary of the characteristics of the quinolone generations

Generation Characteristics 
*QTc, electrocardiographic QT interval corrected for heart rate. 
predominantly used for the treatment of urinary tract infections 
IIa enhanced activity, mainly against Gram-negative pathogens; limited potency against Gram-positive pathogens (pneumococcus (MIC 1–4 mg/L) and methicillin-resistant Staphylococcus aureus); ciprofloxacin most active against P. aeruginosa 
 indications: urinary tract infections, pyelonephritis, gonorrhoea, chlamydial infections, prostatitis, skin and soft tissue infections/osteomyelitis, enteric fevers, cholera and salmonellosis, infections caused by P. aeruginosa, acute exacerbations of chronic bronchitis, nosocomial pneumonia, Legionnaire's disease 
 class adverse drug reactions (CNS effects, gastrointestinal, skin rashes and allergic reactions, phototoxicity (usually <2%), cartilage damage in juvenile animals, tendinitis, usually minor renal and hepatic syndromes); cytochrome P450 interaction (theophylline, caffeine) 
 emergence of resistance (P. aeruginosa, staphylococci, pneumococci, Gram-negative bacilli) in pathogenic species with initially higher MICs, e.g. >0.5 mg/L 
IIb balanced broad spectrum of activity; increased potency against pneumococci (MIC 0.25–0.5 mg/L); less potent for P. aeruginosa 
 mode of action: frequently have two sites of action, against gyrase and topoisomerase IV 
 indicated for respiratory tract infections (plus IIa indications where licensed) 
 pharmacokinetic profile (half-life) permits once-daily dosing 
 class adverse drug reactions plus unexpected adverse drug reactions with individual agents (haemolytic–uraemic syndrome, QTc* prolongation, phototoxicity); variable cytochrome P450 interaction with theophyllines 
IIIa enhanced activity against Gram-positive pathogens (pneumococcal MIC 0.12–0.25 mg/L) 
 favourable pharmacokinetics permitting once-daily dosing; trovafloxacin is almost entirely eliminated by hepato-biliary excretion; for others there is balanced renal and hepato-biliary elimination 
 indicated for respiratory tract infections (trovafloxacin indicated for surgical and gynaecological indications) 
 class adverse reaction profile; no cytochrome P450 interaction; specific adverse drug reactions with trovafloxacin, e.g. higher incidence of CNS effects, hepatic, allergic reactions and pancreatitis; specific effects with clinafloxacin include hypoglycaemia and increased incidence and severity of phototoxicity 
IIIb markedly enhanced activity against Gram-positive bacteria (pneumococcal MIC 0.012 mg/L); retained activity against ciprofloxacin-resistant pneumococci; highly active against atypical respiratory tract infection pathogens; retained activity versus Gram-negative pathogens 
 favourable pharmacokinetics permitting once-daily dosing; high Vd and tissue penetration; balanced elimination (30% renal) 
 pharmacodynamics predict high efficacy in respiratory tract infections 
 favourable adverse drug reaction profile: low CNS adverse drug reaction rate, no phototoxicity 
Generation Characteristics 
*QTc, electrocardiographic QT interval corrected for heart rate. 
predominantly used for the treatment of urinary tract infections 
IIa enhanced activity, mainly against Gram-negative pathogens; limited potency against Gram-positive pathogens (pneumococcus (MIC 1–4 mg/L) and methicillin-resistant Staphylococcus aureus); ciprofloxacin most active against P. aeruginosa 
 indications: urinary tract infections, pyelonephritis, gonorrhoea, chlamydial infections, prostatitis, skin and soft tissue infections/osteomyelitis, enteric fevers, cholera and salmonellosis, infections caused by P. aeruginosa, acute exacerbations of chronic bronchitis, nosocomial pneumonia, Legionnaire's disease 
 class adverse drug reactions (CNS effects, gastrointestinal, skin rashes and allergic reactions, phototoxicity (usually <2%), cartilage damage in juvenile animals, tendinitis, usually minor renal and hepatic syndromes); cytochrome P450 interaction (theophylline, caffeine) 
 emergence of resistance (P. aeruginosa, staphylococci, pneumococci, Gram-negative bacilli) in pathogenic species with initially higher MICs, e.g. >0.5 mg/L 
IIb balanced broad spectrum of activity; increased potency against pneumococci (MIC 0.25–0.5 mg/L); less potent for P. aeruginosa 
 mode of action: frequently have two sites of action, against gyrase and topoisomerase IV 
 indicated for respiratory tract infections (plus IIa indications where licensed) 
 pharmacokinetic profile (half-life) permits once-daily dosing 
 class adverse drug reactions plus unexpected adverse drug reactions with individual agents (haemolytic–uraemic syndrome, QTc* prolongation, phototoxicity); variable cytochrome P450 interaction with theophyllines 
IIIa enhanced activity against Gram-positive pathogens (pneumococcal MIC 0.12–0.25 mg/L) 
 favourable pharmacokinetics permitting once-daily dosing; trovafloxacin is almost entirely eliminated by hepato-biliary excretion; for others there is balanced renal and hepato-biliary elimination 
 indicated for respiratory tract infections (trovafloxacin indicated for surgical and gynaecological indications) 
 class adverse reaction profile; no cytochrome P450 interaction; specific adverse drug reactions with trovafloxacin, e.g. higher incidence of CNS effects, hepatic, allergic reactions and pancreatitis; specific effects with clinafloxacin include hypoglycaemia and increased incidence and severity of phototoxicity 
IIIb markedly enhanced activity against Gram-positive bacteria (pneumococcal MIC 0.012 mg/L); retained activity against ciprofloxacin-resistant pneumococci; highly active against atypical respiratory tract infection pathogens; retained activity versus Gram-negative pathogens 
 favourable pharmacokinetics permitting once-daily dosing; high Vd and tissue penetration; balanced elimination (30% renal) 
 pharmacodynamics predict high efficacy in respiratory tract infections 
 favourable adverse drug reaction profile: low CNS adverse drug reaction rate, no phototoxicity 
Table III.

The in vitro activities (MICs, mg/L) of gemifloxacin and other quinolones against clinical isolates of Streptococcus pneumoniae42

 Penicillin-susceptiblea (n = 64) Penicillin-resistantb (n = 75) Ciprofloxacin-resistantc (n = 29) 
 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 
aPenicillin MICs ≤ 0.06 mg/L. 
bPenicillin MICs 2–16 mg/L. 
cCiprofloxacin MIC ≥ 8 mg/L for all strains. 
Ciprofloxacin 16 >32 
Levofloxacin 16 >32 
Sparfloxacin 0.5 0.5 0.5 16 
Grepafloxacin 0.125 0.5 0.25 0.5 
Trovafloxacin 0.125 0.5 0.125 0.25 
Gemifloxacin 0.03 0.03 0.03 0.06 0.25 0.5 
 Penicillin-susceptiblea (n = 64) Penicillin-resistantb (n = 75) Ciprofloxacin-resistantc (n = 29) 
 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 
aPenicillin MICs ≤ 0.06 mg/L. 
bPenicillin MICs 2–16 mg/L. 
cCiprofloxacin MIC ≥ 8 mg/L for all strains. 
Ciprofloxacin 16 >32 
Levofloxacin 16 >32 
Sparfloxacin 0.5 0.5 0.5 16 
Grepafloxacin 0.125 0.5 0.25 0.5 
Trovafloxacin 0.125 0.5 0.125 0.25 
Gemifloxacin 0.03 0.03 0.03 0.06 0.25 0.5 
Table IV.

The in vitro activities (MIC range, mg/L) of gemifloxacin and other quinolones against atypical respiratory tract pathogens (data taken from reference 4 unless otherwise indicated)

 Chlamydia pneumoniae Legionella pneumophila Mycoplasma pneumoniae 
aData taken from reference 47. 
bData taken from reference 48. 
Levofloxacin 0.5 0.05–0.1 – 
Sparfloxacin 0.09–0.25 0.06 0.12–0.25 
Grepafloxacin 0.5 0.016 0.25 
Trovafloxacin 0.12 0.004 0.25 
Moxifloxacin 0.06–0.1 0.015 0.06–0.12 
Gemifloxacin 0.06–0.12a 0.002–0.03a 0.05–0.11b 
 Chlamydia pneumoniae Legionella pneumophila Mycoplasma pneumoniae 
aData taken from reference 47. 
bData taken from reference 48. 
Levofloxacin 0.5 0.05–0.1 – 
Sparfloxacin 0.09–0.25 0.06 0.12–0.25 
Grepafloxacin 0.5 0.016 0.25 
Trovafloxacin 0.12 0.004 0.25 
Moxifloxacin 0.06–0.1 0.015 0.06–0.12 
Gemifloxacin 0.06–0.12a 0.002–0.03a 0.05–0.11b 
Figure 1.

The chemical structure of ciprofloxacin.

Figure 1.

The chemical structure of ciprofloxacin.

Figure 2.

The chemical structure of gemifloxacin.

Figure 2.

The chemical structure of gemifloxacin.

Figure 3.

The adverse drug reaction rates for gemifloxacin (□) and ofloxacin (▪) during randomized, double-blind phase II clinical trials.52

Figure 3.

The adverse drug reaction rates for gemifloxacin (□) and ofloxacin (▪) during randomized, double-blind phase II clinical trials.52

*
Correspondence address. 6 Gilchrist Row, Fife KY16 8XU, UK. Tel: +44-1334-476-049; Fax: +44-1334-476-6371; E-mail: peterball1@aol.com

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