key: cord-0855080-decokpqi
authors: Shams, Wael E.; Evans, Martin E.
title: Guide to Selection of Fluoroquinolones in Patients with Lower Respiratory Tract Infections
date: 2012-09-19
journal: Drugs
DOI: 10.2165/00003495-200565070-00004
sha: 11a5e6ef8d4c839c60d9a530b8181f4d28a1385f
doc_id: 855080
cord_uid: decokpqi

Newer fluoroquinolones such as levofloxacin, moxifloxacin, gatifloxacin and gemifloxacin have several attributes that make them excellent choices for the therapy of lower respiratory tract infections. In particular, they have excellent intrinsic activity against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and the atypical respiratory pathogens. Fluoroquinolones may be used as monotherapy to treat high-risk patients with acute exacerbation of chronic bronchitis, and for patients with community-acquired pneumonia requiring hospitalisation, but not admission to intensive care. Overall, the newer fluoroquinolones often achieve clinical cure rates in ≥90% of these patients. However, rates may be lower in hospital-acquired pneumonia, and this infection should be treated on the basis of anticipated organisms and evaluation of risk factors for specific pathogens such as Pseudomonas aeruginosa. In this setting, an antipseudomonal fluoroquinolone may be used in combination with an antipseu-domonal β-lactam. Concerns are now being raised about the widespread use, and possibly misuse, of fluoroquinolones and the emergence of resistance among S. pneumoniae, Enterobacteriaceae and P. aeruginosa. A number of pharmacokinetic parameters such as the peak concentration of the antibacterial after a dose (C(max)), and the 24-hour area under the concentration-time curve (AUC(24)) and their relationship to pharmacodynamic parameters such as the minimum inhibitory and the mutant prevention concentrations (MIC and MPC, respectively) have been proposed to predict the effect of fluoroquinolones on bacterial killing and the emergence of resistance. Higher C(max)/MIC or AUC(24)/MIC and C(max)/MPC or AUC(24)/MPC ratios, either as a result of dose administration or the susceptibility of the organism, may lead to a better clinical outcome and decrease the emergence of resistance, respectively. Pharmacokinetic profiles that are optimised to target low-level resistant minor subpopulations of bacteria that often exist in infections may help preserve fluoroquinolones as a class. To this end, optimising the AUC24/ MPC or Cmax/MPC ratios is important, particularly against S. pneumoniae, in the setting of lower respiratory tract infections. Agents such as moxifloxacin and gemifloxacin with high ratios against this organism are preferred, and agents such as ciprofloxacin with low ratios should be avoided. For agents such as levofloxacin and gatifloxacin, with intermediate ratios against S. pneumoniae, it may be worthwhile considering alternative dose administration strategies, such as using higher dosages, to eradicate low-level resistant variants. This must, of course, be balanced against the potential of toxicity. Innovative approaches to the use of fluoroquinolones are worth testing in further in vitro experiments as well as in clinical trials.

Newer fluoroquinolones such as levofloxacin, moxifloxacin, gatifloxacin and Abstract gemifloxacin have several attributes that make them excellent choices for the therapy of lower respiratory tract infections. In particular, they have excellent intrinsic activity against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and the atypical respiratory pathogens. Fluoroquinolones may be used as monotherapy to treat high-risk patients with acute exacerbation of chronic bronchitis, and for patients with community-acquired pneumonia requiring hospitalisation, but not admission to intensive care. Overall, the newer fluoroquinolones often achieve clinical cure rates in ≥90% of these patients. However, rates may be lower in hospital-acquired pneumonia, and this infection should be treated on the basis of anticipated organisms and evaluation of risk factors for specific pathogens such as Pseudomonas aeruginosa. In this setting, an antipseudomonal fluoroquinolone may be used in combination with an antipseudomonal β-lactam.

Concerns are now being raised about the widespread use, and possibly misuse, of fluoroquinolones and the emergence of resistance among S. pneumoniae, Enterobacteriaceae and P. aeruginosa. A number of pharmacokinetic parameters such as the peak concentration of the antibacterial after a dose (Cmax), and the 24hour area under the concentration-time curve (AUC24) and their relationship to pharmacodynamic parameters such as the minimum inhibitory and the mutant prevention concentrations (MIC and MPC, respectively) have been proposed to predict the effect of fluoroquinolones on bacterial killing and the emergence of resistance. Higher Cmax/MIC or AUC24/MIC and Cmax/MPC or AUC24/MPC ratios, either as a result of dose administration or the susceptibility of the organism, may lead to a better clinical outcome and decrease the emergence of resistance, respectively. Pharmacokinetic profiles that are optimised to target lowlevel resistant minor subpopulations of bacteria that often exist in infections may help preserve fluoroquinolones as a class. To this end, optimising the AUC24/ MPC or Cmax/MPC ratios is important, particularly against S. pneumoniae, in the setting of lower respiratory tract infections. Agents such as moxifloxacin and gemifloxacin with high ratios against this organism are preferred, and agents such as ciprofloxacin with low ratios should be avoided. For agents such as levofloxacin and gatifloxacin, with intermediate ratios against S. pneumoniae, it may be worthwhile considering alternative dose administration strategies, such as using higher dosages, to eradicate low-level resistant variants. This must, of course, be balanced against the potential of toxicity. Innovative approaches to the use of fluoroquinolones are worth testing in further in vitro experiments as well as in clinical trials.

Lower respiratory tract infections include acute ma often occur together because both are frequent bronchitis, acute exacerbations of chronic bronchitis results of aetiological factors such as exposure to (AECB), community-acquired pneumonia (CAP) cigarette smoke. These two disease entities reand hospital-acquired pneumonia (HAP).

present the spectrum of chronic obstructive pulmonary disease (COPD), which afflicts 30 million indi-Acute bronchitis is an inflammatory condition of viduals in the US alone. [6] AECB in these patients is the tracheobronchial tree in which cough, with or characterised by increased cough and sputum prowithout sputum production, is a predominant feature duction and worsening dyspnoea resulting in respirin the absence of physical and radiographic findings atory decompensation without an objectively docuof pneumonia. [1] It is one of the most commonly mented cause such as pneumonia. [1, [6] [7] [8] The role of encountered disease entities in clinical practice. [2] bacterial infection as an underlying aetiology for Acute bronchitis may be due to underlying infec-AECB has been debated. [9, 10] Increases in the protious or noninfectious triggers. [3] Microbiological duction of purulent sputum, the presence of neutrostudies of acute bronchitis identify aetiological phils and bacteria in the sputum and the appearance pathogens in only 40% of cases at most. Of these, of an acute antibody response to respiratory pathobacteria are only responsible for 5-20% of episodes, gens suggest that bacteria play a central role in this while viruses are thought to be the underlying aetiprocess. [11] [12] [13] [14] [15] [16] [17] Also of note, several placebo-conology in the remainder. [3] Important viruses include trolled trials have documented a better outcome for the influenza viruses, parainfluenza viruses, respirapatients with AECB treated with antibacterials. [18] [19] [20] tory syncytial virus and common cold viruses such One remarkable study performed in Tunisia comas the corona viruses and the rhinoviruses. [1, 3, 4] Bacpared the use of ofloxacin to placebo for patients terial causes of acute bronchitis are less common.

with exacerbations of COPD requiring mechanical Important aetiologies include Bordatella pertussis, ventilation. The combined frequency of death in Mycoplasma pneumoniae and Chlamydophila hospital and the need for additional antibacterials (Chlamydia) pneumoniae. Streptococcus pneumoniwas significantly lower in the patients given ofloxae and Haemophilus influenzae do not seem to be acin (absolute risk reduction 45.9%; 95% CI 29.1, causative agents in acute bronchitis, although they 62.7; p < 0001), and the duration of mechanical may play a role in secondary infection since they are ventilation and hospital stay was shorter in the treata part of the resident respiratory flora. [1, 3, 5] The ed group (absolute difference 4.2 days, 95% CI 2.5, diagnosis of acute bronchitis depends mainly on the 5.9 and 9.6 days, 95% CI 3.4, 12.8, respectively). [21] physical examination and radiography to exclude signs of pneumonia. [1] Routine sputum Gram-stain A recent review of several longitudinal studies of and culture are of low yield in detecting B. pertussis, groups of patients with COPD concluded that 80% M. pneumoniae or C. pneumoniae. [3] of AECB episodes were infectious in origin, with Chronic bronchitis is defined as the presence of a 40-60% caused by bacteria such as H. influenzae, productive cough for 3 months in each of 2 succes-Moraxella catarrhalis, S. pneumoniae, H. parainsive years in a patient in whom other causes of fluenzae and Pseudomonas aeruginosa. [12, 14, 22] Pacough, such as infection with Mycobacterium tuber-tients with significant structural lung impairment, as culosis, carcinoma of the lung, bronchiectasis, cystic manifested by a forced expiratory volume in 1 secfibrosis or chronic congestive heart failure, have ond (FEV1) <50%, were more likely to be infected been excluded. [6] Chronic bronchitis and emphyse-with H. influenzae or P. aeruginosa. [14] Approxi-mately 30% of infections were caused by viruses tered in particular settings (see section 7.3). [28, 43, 44] such as the influenza and respiratory syncytial vi-Pneumocystis jiroveci (formally carinii) and endemruses, and 5-10% were caused by atypical bacteria ic fungi (Cryptocococcus neoformams, Histoplasma such as Legionella spp., M. pneumoniae or C. capsulatum, Blastomyces dermatiditis, Coccidioides pneumoniae. [12] immitis) constitute other aetiological agents that are often dependent on epidemiological and host fac-Pneumonia ranks first as the cause of death from tors. [26, 45, 46] The frequency of these pathogens varies infection and sixth as the leading cause of death in with the setting in which the infection was acquired. general in the US. More than 2 million cases of CAP Variables include the season of the year, geographioccur each year in the US, resulting in approximatecal location, environmental exposure and host facly 10 million physician visits, more than 500 000 tors such as age, smoking, alcohol use and underlyhospitalisations and 50 000 deaths. [23] [24] [25] The Infecing illnesses. [26, 39, 44] tious Diseases Society of America (IDSA) practice guidelines define CAP as "an acute infection of the HAP is defined as an inflammatory condition of pulmonary parenchyma that is associated with at the lung parenchyma occurring ≥48 hours after hosleast some symptoms of acute infection, accompa-pital admission and caused by infectious agent(s) nied by the presence of an acute infiltrate on a chest not present or incubating at the time of admission. radiograph or auscultatory findings consistent with HAP is the second most common nosocomial infecpneumonia (such as altered breath sounds or local-tion and the leading cause of hospital morbidity and ised rales), in a patient not hospitalised or residing in mortality. [47, 48] HAPs are mainly bacterial in aetioloa long-term-care facility for ≥14 days before onset gy. Gram-negative pathogens, Gram-positive pathoof symptoms". [26] Symptoms of acute lower respira-gens and polymicrobial infections are responsible tory infection often include two or more of the for 55-85%, 20-30% and 40-60% of the cases, following: fever or hypothermia, rigors, sweats, new respectively. Causative Gram-negative bacteria incough with or without sputum production or change clude P. aeruginosa, Enterobacter spp. and in colour of respiratory secretions in a patient with Acinetobacter spp., while causative Gram-positive chronic cough, chest discomfort or the onset of bacteria include Staphylococcus aureus and S. dyspnoea. Many patients also have nonspecific pneumoniae. [47, 49] HAP developing on the third or symptoms, such as fatigue, myalgias, abdominal fourth day of hospitalisation, i.e. early-onset HAP, is pain, anorexia and headache. [26] usually caused by the same pathogens as CAP.

CAP may be viral, bacterial or fungal in aetiolo-A number of antimicrobial agents have been used gy; however, a causative pathogen may not be iden-for the treatment of lower respiratory tract infectified in up to 50-60% of patients despite extensive tions, but perhaps the newest and most efficacious laboratory testing. [26] [27] [28] [29] Aetiological viruses include antibacterials are the fluoroquinolones. Lesher et the influenza viruses, respiratory syncytial virus, al. [50] introduced the prototype quinolone, nalidixic adenovirus, parainfluenza virus, herpes simplex vi-acid, in 1962. Nalidixic acid became a commonly rus, Hantavirus and the SARS coronavirus. [30] [31] [32] [33] [34] [35] The used antibacterial for the treatment of uncomplicatmost commonly encountered bacteria include S. ed urinary tract infections because it reliably covpneumoniae (20-60%), H. influenzae (2-31%), M. ered the Enterobacteriaceae. However, nalidixic accatarrhalis (2-13%) and 'atypical bacteria' such as id use in systemic infections was limited because of M. pneumoniae (13-37%), C. pneumoniae (6-17%) its low serum and tissue concentrations, narrow and the Legionella species (1-16%). [24] [25] [26] [36] [37] [38] [39] [40] Co-antibacterial spectrum and the emergence of bacteriinfection with atypical bacterial pathogens is esti-al resistance. [51, 52] Numerous quinolone derivatives mated to occur in up to 48% of all patients with of nalidixic acid were developed and studied over CAP. [41, 42] Enteric Gram-negative bacteria are not the subsequent two decades until fluoroquinolones common causes of CAP, yet they may be encoun-with improved pharmacokinetic and pharmacody- namic properties were introduced and approved for These agents possess excellent activity against clinical use. Placement of a fluorine atom at the 6 S. pneumoniae and atypical respiratory pathogens position of the quinolone nucleus (figure 1) and such as Legionella pneumophilia, M. pneumoniae replacement of the 7-methyl side-chain of nalidixic and C. pneumoniae. [55] However, concerns are now acid with a piperazine group markedly enhanced being raised about their widespread use, and possimicrobiological activity. [53, 54] These fluoroquibly misuse, because of increasing reports of fluoronolones, such as ciprofloxacin, had an extended quinolone resistance among S. pneumoniae, Enter-Gram-negative spectrum, but still lacked reliable coverage of important Gram-positive respiratory obacteriaceae and P. aeruginosa. [56] [57] [58] pathogens such as S. pneumoniae. This limited their

Recently, several excellent reviews of the use of role to clinical settings such as AECB, nosocomial fluoroquinolones in respiratory tract infections have pneumonia and cystic fibrosis, where Gram-negaappeared. [59] [60] [61] [62] The following is an update of data in tive bacilli were the predominant pathogens. Rethis rapidly evolving field with an emphasis on the cently, fluoroquinolones such as levofloxacin, moxifloxacin and gatifloxacin have been introduced. use of fluoroquinolones in clinical practice.

• excellent Gram-negative activity including According to Structure and P. aeruginosa; and Microbiological Spectrum • only modest activity against methicillin-resistant S. aureus (MRSA), weak activity against The following classification system is based on S. pneumoniae and no significant anaerobic acthe integration of both microbiological susceptibilitivity. ties and pharmacokinetic data. [63] Early agents had This group includes norfloxacin, lomefloxacin, moderate activity against Gram-negative bacteria enoxacin, ofloxacin and ciprofloxacin. The addition but their pharmacokinetics relegated them to the of a fluorine atom at the 6 position of the quinolone treatment of urinary tract infections and sexuallynucleus and replacement of the 7-methyl side-chain transmitted diseases. Chemical modifications to the of nalidixic acid with a piperazine group (figure 1) quinolone nucleus led to agents with enhanced acmarkedly enhance microbiological activity of these tivity against Gram-negatives and improved pharagents and allow coverage of a wide range of Grammacokinetics. This was followed by alterations negative bacteria, including P. aeruginosa. [53, 54] which led to improved activity against Early members of this group, such as norfloxacin, S. pneumoniae and anaerobes, while retaining the lomefloxacin and enoxacin, are only available oralimproved pharmacokinetic properties.

ly, and have been relegated to the treatment of urinary tract infections because they do not achieve • lack significant activity against P. aeruginosa, their widespread use in urinary tract as well as Gram-positive bacteria and anaerobes. systemic infections. They are also concentrated in This group includes the original quinolones, pulmonary alveolar macrophages. This gives them nalidixic acid and cinoxin, which share either a enhanced activity against intracellular pathogens bicyclic quinolone nucleus, or the naphthyridone such as Chlamydia, Mycoplasma and Legionella derivative of this nucleus with a nitrogen atom at the spp. Despite these advances, the second-generation 8 position (figure 1). These agents are available for agents lack adequate activity against important oral use only. Their use has been limited to uncom-Gram-positive bacteria, such as MRSA and plicated urinary tract infections because they do not S. pneumoniae, and have no clinically useful activity achieve adequate serum and tissue concentrations, against anaerobic bacteria. [64, 65] and they lack significant activity against P. aeruginosa, Gram-positive bacteria and anaerobes. [64, 65] 1.3 Third-Generation Quinolones 1.2 Second-Generation Quinolones

The key features of third-generation quinolones The key features of second-generation quiare: nolones are:

• improved pharmacokinetics allowing once daily • late members achieve adequate serum and tissue dose administration; and concentrations and can be used to treat systemic infections;

• enhanced activity against S. pneumoniae. This group includes levofloxacin, sparfloxacin, addition to coverage of aerobic Gram-positive and grepafloxacin, gatifloxacin and gemifloxacin. Gram-negative organisms. Although moxifloxacin Levofloxacin is the l-isomer of ofloxacin. Other is active in vitro against anaerobes, its efficacy in agents in this group have further structural changes treating anaerobic infections has not been estabsuch as a modification of the piperazine group at C7 lished and its use for such infections is not approved of the quinolone nucleus with addition of methyl by the US FDA. [64, 71] The US FDA has advised groups, alkylation of the ring structure at the 7 reserving trovafloxacin therapy for life-threatening position, and the addition of a methoxy group at the infections requiring inpatient treatment because of 8 position (figure 1). These structural changes im-the risk of hepatotoxicity. [72] Clinafloxacin has been prove the pharmacokinetics of these compounds, withdrawn from the market because of its significant allowing single daily dose administration, and en-phototoxicity. hance their activity against S. pneumoniae. [53, 64, 65] Garenoxin is a novel des-fluoro(6) quinolone These drugs also have enhanced antimicrobial activwith a broad antimicrobial spectrum of coverage ity against Legionella, Chlamydia and Mycoplasma similar to trovafloxacin. The removal of fluorine spp. [66, 67] On the basis of minimum inhibitory conatom at C6 differentiates this drug from other centrations (MICs), third-generation quinolones fluoroquinolones and may decrease toxicity. [73] [74] [75] It such as levofloxacin may be less active than secondhas not yet been released on the market. Despite generation quinolones such as ciprofloxacin against initial reports of a favourable safety profile, [76] hypo-P. aeruginosa. [65] However, reports of clinical failtension was encountered more with garenoxacin ures with levofloxacin in P. aeruginosa infections than with its comparator drugs in phase III clinical are rare. This may be because the in vitro disadvantrials. The clinical significance of this adverse effect tage of levofloxacin may be compensated for by a has not yet been determined. After a re-evaluation of pharmacokinetic profile in patients which results in its antibacterial research and development priorities, superior blood and tissue concentrations. [68] [69] [70] the developing company (Bristol-Myers Squibb) re-Grepafloxacin has been removed from the market cently announced that the product will be reacquired because of its significant potential for life-threatenby the initial licensing company (Toyama Chemiing tachyarrythmias caused by corrected QT (QTc) cal). [77] interval prolongation, and sparfloxacin has been removed from the market because of unacceptable 2. Mechanism of Action and Resistance phototoxicity. Gemifloxacin is the most recent Quinolones kill bacteria when they bind and inmember in this group with enhanced activity against hibit the activity of bacterial topoisomerases, partic-S. pneumoniae, and variable activity against anaerularly topoisomerase II (DNA gyrase) and toobes. It has recently gained US FDA approval for poisomerase IV. These enzymes are essential for use in CAP and AECB.

bacterial DNA synthesis and maintenance. DNA gyrase, encoded by the gyrA and gyrB genes, in-

duces negative supercoils in DNA, whereas to-The key feature of fourth-generation quinolones poisomerase IV, encoded by the parC and parE is enhanced activity against anaerobes.

genes (designated grlA and grlB in S. aureus), is involved in DNA decatenation. [61, 78] DNA gyrase is This group includes trovafloxacin, clinafloxacin, the primary target for most quinolones against moxifloxacin and garenoxacin. Further structural Gram-negative bacteria, and topoisomerase IV is the modification, such as a halogen substitution at the 8 primary target for most Gram-positive bacteria, alposition of the quinolone (clinafloxacin) or the use though exceptions occur. [79] [80] [81] [82] [83] [84] of a naphthyridone nucleus in place of the quinolone nucleus, results in enhanced antimicrobial activity Resistance to quinolones arises when spontaneagainst anaerobes such as Bacteroides fragilis, in ous mutations occur in the parC/E (grlA/B) or gyrA/ B genes. [85, 86] It is not due to acquisition of resis-acin, gemifloxacin, trovafloxacin, levofloxacin, tance genes as is the case in macrolide (ermAM or moxifloxacin, gatifloxacin or garenox-mefE genes) or methicillin (SCCmec) resistance. acin. [91, 94, 95, [103] [104] [105] [106] It also selects resistant variants of Thus, fluoroquinolone resistance can arise de novo methicillin-sensitive or -resistant S. aureus more from many different geographic foci rather than frequently than levofloxacin, trovafloxacin, gatifrom the spread of a single clone. The appearance of floxacin or garenoxacin. [90, 92, 93, [107] [108] [109] Overall, the 8ciprofloxacin resistance in Canada, for instance, is methoxy quinolones, gatifloxacin and moxifloxacin, thought to be due to the selective pressure of fluoroand the des-fluoro(6) quinolone, garenoxacin, apquinolone use upon multiple indigenous, unrelated pear to select resistant mutants of S. pneumoniae and strains throughout the country. [87] The horizontal S. aureus at a lower rate than the older quispread of a resistant clone may still occur, although nolones. [103, 104, 110, 111] It is not clear why these differthis appears to be uncommon to date. [88] ences exist, but it may be a function of the intrinsic activity of the compounds themselves against the In Gram-positive organisms, single-step mutabacteria. For instance, one study showed that the tions in the parC/E (grlA/B) genes cause low-level most active compound against S. pneumoniae was resistance to ciprofloxacin, and mutations in the gemifloxacin (MIC = 0.03 μg/mL), followed by gyrA/B genes alone are usually not associated with a clinafloxacin (MIC = 0.06 μg/mL), trovafloxacin change in phenotype. High-level resistance occurs (MIC = 0.12 μg/mL), grepafloxacin and moxifloxonly when there are mutations in both parC/E (grlA/ acin (MIC = 0.25 μg/mL), gatifloxacin (MIC = 0.5 B) and gyrA/B genes. [89] GyrA may be the primary μg/mL), levofloxacin (MIC = 1 μg/mL) and target with other fluoroquinolones and bacteria. Data from in vitro assays show that single-step ciprofloxacin (MIC = 2 μg/mL). [112] These intrinsic mutations occur in S. aureus and S. pneumoniae activities of the compounds combined with their with frequencies often ranging from 10 -6 to pharmacokinetic profiles may be the key to under-10 -8 . [90] [91] [92] [93] [94] [95] Thus, single-step, low-level resistant varstanding their ability to thwart (or foster) the emeriants are probably common in many pulmonary ingence of resistance (see discussion on pharmacodyfections since the bacterial numbers can often exnamics in section 3). ceed 10 8 colony forming units (cfu)/g of tissue. [96] If

The insights into resistance seen in in vitro assays these variants are not eradicated, a second mutation have been predictive of the performance of fluoromay lead to high-level resistance.

quinolones in clinical practice. For instance, failures Resistance may also be the result of decreased of ciprofloxacin to cure pneumococcal infections outer membrane permeability or efflux pumps. [55] have been well documented (table I) . Several pa-The latter is an energy-dependent process that limits tients developed meningitis while on therapy, and in the intracellular accumulation of antibacterials. It some clinical trials employing ciprofloxacin for the results in low-level resistance, and may or may not treatment of AECB, S. pneumoniae was found to occur in conjunction with mutations in topoisomerpersist in the sputum in up to 50% of treated patients ase genes. [55, 61, 97, 98] Efflux affects the activity of and 57% of treatment failures were due to the organnorfloxacin and ciprofloxacin more than levofloxism. [113] The US FDA subsequently modified the acin, gatifloxacin and gemifloxacin. The activity of package insert to suggest that ciprofloxacin not be moxifloxacin and trovafloxacin are affected the used as a drug of first choice for the treatment of least. [99] [100] [101] [102] presumed or confirmed pneumonia due to S. pneumoniae. [114] Failures with levofloxacin have also Important differences may exist in the ability of been reported (table II) . As with ciprofloxacin, sevspecific fluoroquinolones to select resistant variants eral of the patients developed meningitis while on among Gram-positive respiratory pathogens. For intherapy, leading one group to suggest that a βstance, ciprofloxacin selects resistant variants of lactam drug be used along with levofloxacin until S. pneumoniae in vitro more readily than grepaflox- [127] Weiss et al. [117] Montreal [128] USA, 1999

Kuehnert et al. [129] Georgia [134] 1999

Levofloxacin 500mg po od 7/9 failures AECB = acute exacerbation of chronic bronchitis; bid = twice daily; CAP = community-acquired pneumonia; COPD = chronic obstructive pulmonary disease; F = female; IV = intravenous; M = male; ND = no data, od = once daily, po = oral.

the results of susceptibility testing become availa-resistant to ciprofloxacin. [136] However, when this ble. [115] Of note, many patients in this study who group compared isolates collected during the failed levofloxacin therapy had been previously ex-1997-8 respiratory season with those collected in posed to fluoroquinolones. This has also been re-1998-9, they found a statistically significant inported by others. [116, 117] Failures to other fluoroquicrease in levofloxacin resistance from 0.1% to nolones have not been reported to date, but may 0.6%. [137] (table III) . Others have also examined occur with increased use of the drugs. resistance to the newer fluoroquinolones among S. pneumoniae. For instance, Brueggemann et al. ex-One area of particular concern is cross-resistance amined a large group of isolates from the US collectamong fluoroquinolones. The use of one agent can ed in 1994-5 and 1999-2000, and found that resislead to class resistance to all fluoroquinolones.

tance rates to levofloxacin, gatifloxacin and mox-Johnson noted that 88% (29/33) of isolates with ifloxacin were low and had remained stable. [138] ciprofloxacin MICs >8 μg/mL in one study were Doern et al. found that only 0.3% of a large number also resistant to moxifloxacin, [135] and Weiss reportof isolates were resistant to levofloxacin and that ed an outbreak of fluoroquinolone-resistant S.

there was no change over 5 years of observation. [139] pneumoniae in a hospital ward where ciprofloxacin Thornsberry and Sahm found the same results when was often used as empirical therapy for lower respircomparing isolates collected during the respiratory atory tract infections. This outbreak involved 16 seasons of 1998-9 and 1999-2000. [140] The same patients with organisms that had either single (parC) group found that resistance to levofloxacin among or double (parC and gyrA) mutations leading to lowchildren was low, perhaps reflecting the relative level (4 μg/mL) or high-level (16 μg/mL) resistance lack of use of fluoroquinolones in this populato ciprofloxacin, respectively. Cross-resistance with tion. [141] The US Centers for Disease Control and levofloxacin (MIC 8 μg/mL), moxifloxacin and ga-Prevention (CDC) reported isolates recovered from tifloxacin (MIC 2 μg/mL) was observed. [117] In another study, Urban and coworkers reported two painvasive pneumococcal disease and found that tients who failed levofloxacin therapy. The isolates ofloxacin resistance had increased from 2.6% in from these patients had increased MICs to gatiflox-1995 to 3.8% in 1997, but there was no increase in acin, moxifloxacin and trovafloxacin. No data was levofloxacin resistance during that interval. [142] available about prior exposure to ciprofloxacin. [131] Sahm et al. [143] reported a slightly higher rate of These reports mirror the cross-resistance among levofloxacin resistance in isolates collected in the fluoroquinolones seen after in vitro exposure of S. 2001-2 respiratory season. An analysis of isolates pneumoniae to ciprofloxacin, [95, 109, 112] and raise concollected from community-based practices in the US cerns that misuse of older fluoroquinolones may instead of hospital-based laboratories showed no select low-level resistant variants that then become resistance to either levofloxacin or gatifloxacin. [40] highly resistant to all fluoroquinolones with a sec-Karchmer [144] reported the results of the PROTEKT ond mutation. [131, 132] US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the Although resistance to fluoroquinolones has been United States) study where 10 103 isolates were reported in vitro and in isolated patients, the prevacollected during the 2000-1 respiratory season from lence of resistance among S. pneumoniae and other 206 sites in 41 states. Overall, levofloxacin resisrespiratory pathogens in large geographic areas over tance rates were low and varied geographically from time has remained low (table III). Sahm and co-0% (in the Southeast) to 1.3% (in the Northeast). workers [136, 137] were some of the first to examine However, resistance rates were higher in some areas fluoroquinolone resistance rates among respiratory of the country. Rates were highest in Massachusetts pathogens. They reported that only 0.3% of 5640 S.

(4.8%), Colorado (4.6%) and Alaska (2%), and in pneumoniae isolates collected from 1997 and 1998 after 10 years of ciprofloxacin use in the US were cities such as Salem, Massachusetts (21.8%), Stam- [140] Karlowsky et al. [141] 2000 Johnson et al. [135] 1998-9 England and 807 (surveillance) ND ND 0.9

Wales 462 (referred) ND ND 5.8

Glatz et al. [149] ford, Connecticut (11.8%), Dayton, Ohio (5.9%) workers [112] examined almost 7000 S. pneumoniae and Denver, Colorado (5.6%). [145] isolates collected throughout Canada from 1997 through 2002 and found that ≤1.1% were resistant to Fluoroquinolone resistance trends have also been levofloxacin. However, they noted that cross-resisexamined in other countries. In a longitudinal study tance among the fluoroquinolones was common. in Canada, Chen et al. [56] reported that the prevalence of ciprofloxacin-resistant S. pneumoniae Isolates that were resistant to levofloxacin had instrains increased from 0% in 1988 to 1.7% in 1997 creased MICs to ciprofloxacin, gatifloxacin, moxiand 1998. This was seen most commonly in adults floxacin, gemifloxacin and garenoxacin. Powis and and not children, reflecting the use of fluoroqui-coworkers [147] examined 2539 isolates collected as nolones in Canada. The resistance to the newer part of the Canadian Bacterial Surveillance Network fluoroquinolones remained low. Zhanel and co-in 2002 and reported levofloxacin resistance rates of 2.17%. This was an increase from 1.0% reported 2 TEKT surveillance study was around 1%. The exception was Hong Kong, where more than 14% of years before.

the isolates were resistant to the two antibacteri-An analysis of 1385 S. pneumoniae strains colals. [158] Similar high resistance rates in Hong Kong lected in Austria from 1994 to 1996 showed that were also reported by Ho and colleagues. [159, 160] levofloxacin resistance was rare, and there was no In summary, resistant S. pneumoniae can readily resistance to moxifloxacin or gatifloxacin. [148] In the be selected in vitro and failures among patients UK, Johnson et al. [135] found a high prevalence of treated with ciprofloxacin and levofloxacin have moxifloxacin resistance among isolates referred for been well documented. However, to date resistance additional testing because of resistance to 'first-line rates to the newer fluoroquinolones among S. pneuagents', but the prevalence of resistance was much moniae appear to be low, although several studies lower among isolates collected in routine surveilsuggest that rates are increasing in localised areas of lance activities. Glatz and coworkers [149] from Hunthe world. Studies have shown that fluoroquinolone gary also found higher rates of fluoroquinolone resistance is more common among persons ≥65 (levofloxacin) resistance among isolates that were years of age in contrast to penicillin resistance, resistant to other agents (in this case penicillin). A which is more common in children. This may reflect low level of resistance to the newer fluoroquithe relative use of the antibacterials in these age nolones was reported from several other small colgroups. [142] This may change if fluoroquinolones are lections of isolates from other European countries, approved for paediatric use. Cross-resistance among and a relatively low level of levofloxacin resistance fluoroquinolones has been seen and is of conwas reported in a small series from Taiwan. [150] [151] [152] [153] cern. [112] Thus, overuse of older agents may result in Song et al. [155] reported resistance rates of S. loss of efficacy of the newer agents. Also of note, pneumoniae isolates collected from 11 Asian counfluoroquinolone resistant isolates are often resistant tries during the 2000-1 respiratory season and reto other classes of antibacterial as well. [135, 138, 149] ported that resistance was higher with levofloxacin Among the organisms resistant to levofloxacin reand gatifloxacin than with moxifloxacin. ported by the CDC, 60% were also resistant to Several large studies have attempted to monitor penicillin, 53% were resistant to cefotaxime, 33% the prevalence of fluoroquinolone resistance among were resistant to erythromycin and 60% were resis-S. pneumoniae worldwide. For instance, Sahm and tant to co-trimoxazole (trimethoprim/sulfamethoxcoworkers [154] reported on a large number of isolates azole). [142] Similar trends have been reported by collected from China, Japan and several European others. [163] H. influenzae has been reported to be countries during the winter of 1997-8. They found a resistant to ciprofloxacin. [164] To date, H. influenzae low prevalence of resistance to levofloxacin among and M. catarrhalis have remained sensitive to the S. pneumoniae. Hoban et al. [161] reported data from newer fluoroquinolones. [140, 154, 156, 165, 166] the SENTRY Antimicrobial Surveillance Program, and found a low worldwide prevalence of resistance 3. Pharmacokinetics and to levofloxacin and gatifloxacin. However, when the Pharmacodynamic Considerations data from North America were examined for trends in resistance, it was found that the rate of resistance

The efficacy of an antibacterial against pathogens to levofloxacin among S. pneumoniae had increased is often expressed in terms of the MIC. The MIC is from 0.3% in 1997-8 to 0.9% in 1999. [162] In another defined as the concentration of antibacterial that study, resistance was more common in the Asiaresults in no net growth of an inoculum of 5 × 10 5 Pacific region (0.8-0.9%), followed by North bacteria after incubation for 18 hours. Laboratory America (0.4-0.5%) and Europe and Latin America techniques for determining the MIC as well as the (0.1-0.2%). [157] The worldwide prevalence of resisinterpretive breakpoints used for labelling an organtance to levofloxacin and moxifloxacin in the PROism as sensitive, intermediate or resistant to the antibacterial have been published and are currently used by most clinical laboratories. [167] Although the MIC has been used successfully for the management of patients in the past, this statistic is proving to be of limited value for predicting the emergence of resistance to fluoroquinolones.

Recently, investigators have focused on the effect of antibacterials on the selection of resistant variants, and proposed that environments providing small differences in antibacterial concentrations could have a selective effect on bacterial cultures comprised of subpopulations of heterogenous resistance phenotypes. These 'selective windows' or compartments are bounded by the concentration that inhibits susceptible bacteria (MIC) and the concentration that inhibits organisms with low-level resis-(MIC or MPC) have been proposed to predict the tance. [168] Negri and coworkers [169, 170] examined the effect of fluoroquinolones on bacterial killing and effect of antibacterial exposures on mixtures of penthe emergence of resistance. The most common icillin-susceptible and -resistant S. pneumoniae and pharmacokinetic values examined are the peak con-TEM-1 and TEM-12 β-lactamase-producing Escentration of the antibacterial after a dose (Cmax) cherichia coli having different MICs, and showed and the 24-hour area under the concentration-time that resistant strains were most readily selected at curve (AUC24). Experimental evidence has shown antibacterial concentrations within the selective that, in many cases, the quinolones kill most rapidly compartment.

when their concentrations are appreciably above the Dong and colleagues [171] suggested that similar MIC of the target microorganism. This is known as principles govern the selection of resistant variants concentration-dependent or dose-dependent killing of S. aureus exposed to fluoroquinolones. They de-(in contrast to time-dependent or concentration-infined a 'mutant selective window' as the antimicrodependent killing often seen with β-lactams and bial concentration range that falls between the MIC macrolides). [63] Efforts have been made to quantify and the mutant prevention concentration or MPC the relationship between pharmacokinetic parame-(the concentration that inhibits growth of first-step ters (Cmax, AUC24) and the pharmacodynamic pamutants) [figure 2]. They reported experimental data rameter, MIC, to optimise dose administration stratand theoretical analyses suggesting that regimens egies. To date, there have been no clinical trials providing fluoroquinolone concentrations that fall examining ratios using the MPC as the divisor. within the selective window select resistant S. aureus strains, whereas regimens providing concentra-

The value of pharmacodynamic ratios (AUC24/ tions above the MPC prevent the emergence of MIC and Cmax/MIC) for predicting the outcome of resistant strains. [171] [172] [173] [174] This work has been expandfluoroquinolone therapy has been examined in a few ed into a theoretical analysis of the effect of fluorostudies. Forrest and coworkers analysed the results quinolones on S. pneumoniae, [172] but to date, the of ciprofloxacin therapy in seriously ill patients with exact relationship between pharmacokinetic profiles a variety of infections and concluded that an AUC24/ and the bacterial MIC and MPC (delimiting the MIC ratio of >125 was an important predictor of selective window) have not been defined.

clinical and microbiological cure. The applicability of this conclusion to lower-respiratory tract infec-A number of pharmacokinetic parameters and tions is uncertain, however, because infections of their relationship to pharmacodynamic parameters wounds and the urinary tract were included in the pathogens causing respiratory, skin and urinary tract analysis, and there were no patients infected with infections treated with levofloxacin, Preston and S. pneumoniae. The majority of patients were infectcoworkers concluded that both clinical and microbied with S. aureus, P. aeruginosa or other Gramological outcomes were more likely to be favourable negative aerobes. The conclusions of the study reif the Cmax/MIC ratio was >12.2. [179] garding the efficacy of ciprofloxacin may also have Others have examined pharmacodynamic ratios been confounded by the concomitant use of rifampin specifically for fluoroquinolones and S. pneumoniand azlocillin in some patients. [175] These investigaae. Lacy et al. [180] studied the effects of ciprofloxtors later examined the effect of three different oral acin and levofloxacin against four isolates in an in grepafloxacin doses in patients with AECB. The vitro infection model and found that bacterial patients were infected with a wide variety of Gramgrowth was suppressed by levofloxacin with negative and Gram-positive bacteria of varying sus-AUC24/MIC ratios in the range of 30-55. Regrowth ceptibilities to the antibacterial. The authors occurred with ciprofloxacin up to the highest analysed the aggregate data and concluded that AUC24/MIC ratio tested of 28.4. In another in vitro AUC24/MIC values of <75 were inadequate, but model, Lister and Sanders [181] showed that levofloxvalues of >175 were sufficient for bacteriological acin eradicated eight strains if the AUC 24/MIC raand clinical cure. However, the AUC24/MIC values tios were in the range of 32-64. Ciprofloxacin eradiassociated with bacteriological and clinical cure vacated five of the strains with AUC24/MIC values of ried with the organism examined. For instance, only 44. Craig and Andes [182] examined the effect of grepafloxacin-sensitive organisms such as M. catarfluoroquinolones on S. pneumoniae in a murine rhalis and Haemophilus spp. were eradicated rethigh infection model and found that there was a gardless of the AUC24/MIC value, and 88%, 100% and 75% of the S. pneumoniae isolates were eradi-2-2.5 log10 kill of the organisms and 80-90% surcated at AUC24/MIC values of 0 to 92, >92 to 230 vival if the AUC24/MIC was >25-35. In a study and >230, respectively. In contrast, only 31% of examining the effect of levofloxacin or gatifloxacin more resistant organisms such as P. aeruginosa on patients with CAP or AECB caused by S. were eradicated at the lowest AUC24/MIC range, pneumoniae Ambrose et al. [183] found 100% bacteriand only 50% were eradicated at the highest al eradication if the free-drug AUC24/MIC ratio was range. [176] Another study performed in patients re->33.7. ceiving ciprofloxacin or a β-lactam for nosocomial Overall, the data from clinical trials are limited lower-respiratory tract infections concluded that cuand the conclusions from these trials are confusing re was more likely if the AUC24/MIC was >100.

for the clinician. The studies do suggest that, in However, the applicability of this conclusion for general, higher Cmax/MIC or AUC24/MIC ratios, patients with S. pneumoniae or M. catarrhalis infeceither as a result of dose administration or the sustions remains uncertain because no patient in the ceptibility of the organism, lead to a better outstudy was infected with these organisms. [177] Anothcome. [184] [185] [186] The exact value of the pharmacodyer study that analysed the data from a trial of namic ratio that should be targeted for rapid killing levofloxacin (sometimes with other drugs) adminisor to prevent resistance remains elusive, probably tered for the treatment of nosocomial pneumonia because of the wide variety of organisms and andue to a range of Gram-positive and -negative bactetibacterials studied, the limited number of isolates ria concluded that an AUC/MIC ratio ≥87 was optitested and the use of different systems (in vitro, mal for eradication of the pathogens involved. [178] animal and clinical trials). A more systematic ap-Only one trial has examined the ability of the Cmax/ proach using a limited number of organisms under MIC ratio to predict the outcome of fluoroquinolone tightly controlled conditions might be more useful therapy. On the basis of the results of a large, multicentre trial involving patients with a variety of for gaining insights into broad pharmacodynamic principles that could then be applied in tightly con-gemifloxacin, moxifloxacin and garenoxacin are trolled clinical trials. [187] more active than ciprofloxacin against pathogens such as S. pneumoniae and S. aureus, and appear to New insights into the evolution of resistance have less of a propensity to select resistant variants among bacteria exposed to fluoroquinolones, and in using clinical dose administration regimens in an in the use of novel dose administration regimens, have vitro system. This may be because the newer fluorobeen gained through a series of experiments in an in quinolones have better pharmacokinetic profiles vitro pharmacodynamic system. In these experithan older agents (higher Cmax/MPC or AUC24/ ments, S. aureus was exposed to simulated clinical MPC ratios), or because of properties intrinsic to the and experimental regimens of ciprofloxacin, and the compounds themselves. [108, 109] The increased activiresponse of the bacteria was monitored over time.

ty (lower MIC and MPC) of several of the newer With exposure to clinical regimens (400mg twice or fluoroquinolones, such as moxifloxacin, may allow three times daily), the initially sensitive bacteria the clinician to exceed the MPC without producing became resistant, as evidenced by a change of their toxicity. [172] MIC from 0.5 to 8-16 μg/mL. It was observed that whenever the bacteria were grown to high numbers Pharmacokinetic parameters of the most comfor the inoculum of the system (2 × 10 8 cfu), small monly encountered fluoroquinolones on the market numbers of bacteria with low-level resistance (MICs are presented in table IV. There are potentially imin the range of 2-4 μg/mL) would invariably be portant differences among these agents. For inpresent. These appeared as a result of spontaneous stance, the half-life (t 1 /2) of the newer fluoroquimutation in the QRDR of grlA in many cases. Mathnolones ranges from 4.5 to 13.3 hours; their C max ematical modeling of bacterial killing and regrowth varies from 2.97 to 8.6 μg/mL; and the AUC24 at in the system as a function of dose administration steady state (AUC24ss) varies from 9.0 to 91 mg • h/ was done, and the model was used to predict a L. Some controversy exists about these values beregimen that would eradicate the culture. This regicause some investigators believe that only a drug men consisted of a single high dose to eradicate the that is not protein bound is biologically active. If low-level resistant variants present in the inoculum protein binding is taken into account, Cmax values of followed by standard dose administration to eradisome compounds, such as gemifloxacin and garecate the sensitive majority. When the regimen was noxacin, must be reduced by 60% and 87%, respectested in the in vitro system, the culture was eraditively. [189] In contrast, other investigators have cated. These experiments suggested that the key to shown that protein binding has little effect on bacterial eradication was to target low-level resisfluoroquinolone activity. [190, 191] The fact that all the tant variants present in the inoculum. [107, 187] compounds are concentrated in alveolar macrophages (ranging from 11.8-fold of serum Cmax for This strategy fits in well with the concept of the ciprofloxacin to 18.2-fold for gatifloxacin) and MPC, which is the concentration of antibacterial bronchial epithelial fluids (ranging from 0.63-fold that prevents the appearance of first-step mutants. It of serum Cmax for ciprofloxacin to 4.6-fold for has been shown that pharmacokinetic profiles that moxifloxacin) may be important clinically. Howevkeep antibacterial concentrations above the MPC er, these data must be interpreted in the context of prevent the selection of resistant variants and ultithe MICs and MPCs of pathogens likely to be enmately lead to bacterial eradication in in vitro syscountered in lower respiratory tract infections. tems. [107, 188] However, the exact relationship of When ciprofloxacin and the newer fluoroquinolones pharmacokinetic profiles to the MPC has yet to be are compared on the basis of their pharmacokinetic elucidated. Simply keeping the concentration of anparameters (Cmax and AUC24 with standard dose tibacterial above the MPC may result in unacceptadministration regimens) with the MICs and MPCs able toxicity. As mentioned earlier, newer fluoroquinolones such as levofloxacin, gatifloxacin, of large collections of S. pneumoniae, it becomes evident that ratios differ considerably among fluoroquinolones (table V) . For instance, the Cmax/MIC90 values range from 1.0 to 21.4 and the AUC24/MIC90 values range from 9.5 to 106 (for ciprofloxacin at 500mg and gemifloxacin at 400mg, respectively). Similar differences are apparent when the MPC is used as the divisor and when ratios are calculated for alveolar macrophages and bronchial epithelial lining fluid. At present, interpretation of these values and their application to patient care has yet to be clarified. In general, higher pharmacodynamic ratios in serum, alveolar macrophages and epithelial lining fluid will probably lead to less selection of resistance and better patient outcomes. The exact values that delimit the probabilities of cure or failure remain to be defined.

Zhanel et al. [59] reviewed four studies published prior to the first quarter of 2000 where levofloxacin in dosages of 250-500mg each day were compared with cefuroxime axetil or cefaclor for the treatment of AECB. Bacterial eradication rates for levofloxacin ranged from 63% to 68% with clinical success rates ranging from 78% to 95%. The clinical success rates with the cephalosporins were in the range of 48-93%. [59] Four studies have been published since this review comparing the efficacy of levofloxacin and other agents (table VI). Masterton and Burley [203] compared 5-and 7-day courses of oral levofloxacin in patients with AECB from 48 centres in ten countries. They found equivalent clinical and microbiological success (more than 80%) for both regimens. Weiss [204] examined the relative efficacy of levofloxacin, clarithromycin and cefuroxime axetil in patients with AECB. The efficacy and tolerability of the three agents were similar and in all cases was ≥80%. File et al. [205] reported the results of studies comparing levofloxacin with an enhanced amoxicillin/clavulanic acid formulation (2000mg/ 125mg) designed for the treatment of penicillinresistant S. pneumoniae. Both regimens were 100% Ciprofloxacin [192, 193] Levofloxacin [193, 194] Gatifloxacin [195, 196] Moxifloxacin [197, 198] Gemifloxacin [199, 200] successful in eradicating S. pneumoniae from the sputum and curing the patients. [205] Amsden and coworkers [206] studied patients recruited from 21 medical centres in the US from August 1999 through May 2000 and showed equivalence of azithromycin and levofloxacin with success rates of more than 80% when the endpoints were clinical cure or improvement of AECB. The numbers were too small to show any difference in the rates of bacterial eradication. Both drugs were equally well tolerated. [206] 

Fogarty and colleagues [207] summarised the results of four studies commissioned by the R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey to study the efficacy of levofloxacin in CAP caused by erythromycin-sensitive and -resistant S. pneumoniae (table VI) . These studies were independently reported from 1997 through 1999, and the results of one of these studies was commented upon in a previous review of levofloxacin efficacy. [59] The overall microbiological and clinical success was good (97% and 98%, respectively) and there was no difference among patients infected with erythromycin-sensitive or -resistant organisms. In another study reported by Fogarty et al., [210] levofloxacin was compared with ceftriaxone plus erythromycin given intravenously followed by amoxicillin/clavulanic acid plus clarithromycin given orally. The overall clinical success rates and bacteria eradication rates were comparable. Gotfried and coworkers [208] examined the relative efficacy of oral levofloxacin and an extended-release formulation of clarithromycin for ambulatory patients with CAP during 1999 and 2000. Both agents appeared to be equally efficacious, with microbiological eradication rates ≥80% in most cases and clinical cure or improvement seen in more than 85% of patients. [208] From 1997 to 1999, Frank and coworkers [209] compared levofloxacin with a combined regimen of ceftriaxone and azithromycin for patients hospitalised with moderate-to-severe CAP. Both regimens were given for at least 10 days, although ceftriaxone was administered for only the first 2 days to prevent bacteraemia due to S. pneumoniae. Both regimens [59] and Hansen et al.; [202] MPC values from Hansen et al. [202] b Free drug. c Ratio calculated using Cmax obtained after single oral dose of 400mg.

d Ratio calculated using Cmax obtained after single oral dose of 600mg. 61% (57/94) hours followed by ciprofloxacin 750mg po every 12 hours for 7-15 days bid = twice daily; db = double-blinded; dd = double dummy; IM = intramuscular; IV = intravenous; mc = multicentre; nb = nonblind; ND = no data; od = once daily; p = prospective; pl = parallel; po = oral; r = randomised.

were equally efficacious with bacterial eradication cacy to trovafloxacin with clinical and bacteriologiand clinical cure or improvement rates exceeding cal success rates of 91.5% and 87% for gemifloxacin 90%. [209, 210] In a multicentre, postmarketing assess-versus 87.6% and 82% for trovafloxacin. These ment of levofloxacin efficacy for the treatment of authors also reviewed the preliminary results of the CAP, Akpunonu and coworkers, [211] reported excel-GLOBE (Gemifloxacin Long term Outcomes of lent success against a variety of respiratory patho-Bronchitis Exacerbation) study in which the efficagens.

cy and safety of a 5-day course of gemifloxacin were compared with those of a standard 7-day regimen of

clarithromycin in patients with AECB (table Only one clinical trial has been published which VII). [214] Clinical and bacteriological cure rates were examined the efficacy of one of the new respiratory comparable in both groups. However, when the imfluoroquinolones in nosocomial pneumonia. This pact of treatment on the long-term (26 weeks) trial compared a high dose of levofloxacin (750mg clinical outcome was assessed, significantly more given intravenously, then orally) with imipenem/ patients receiving gemifloxacin than clarithromycin cilastatin followed by oral ciprofloxacin. Other anremained free of AECB recurrences (71.0% vs tibacterials could be added if the patient was infect-58.5%, respectively). [214] ed with P. aeruginosa or MRSA. The clinical cure Since the review by Zhanel et al., [59] at least four and microbiological eradication rates were similar more studies have been published addressing the use (table VI) . [212] of gemifloxacin for AECB and comparing it with other conventional antibacterial regimens (table

and amoxicillin/clavulanic acid in the treatment of Zhanel et al. [59] reviewed the results of two re-600 patients with AECB in a randomised, doubleports on the use of gemifloxacin for AECB. The first blind, multicentre study. The two drugs had compawas a randomised, double-blind, multinational study rable clinical cure rates (>90%), although the microthat compared the efficacy and safety of gemiflox-biological efficacy of the penicillin regimen was acin with trovafloxacin in the treatment of somewhat less. [221] More recently, Wilson and co-AECB. [213] Gemifloxacin demonstrated similar effi-workers [216] compared the use of oral gemifloxacin given once daily for 5 days with intravenous cef-was also compared. There was no significant differtriaxone followed by oral cefuroxime axetil (given ence in the incidence or the type of adverse drug for a maximum of 10 days) in the treatment of effects, and none of the patients in this study had a hospitalised patients with AECB. The clinical suc-QTc interval change that was outside the normal cess rates at follow-up (21-28 days post-therapy) in range. [216] In another open-label, noncomparative the clinical per-protocol population were signifistudy, Ball et al. [213] assessed the clinical and bactecantly higher for gemifloxacin than for ceftriaxone/ riological efficacy of gemifloxacin in AECB and cefuroxime (87% [105/121] [217] studied difference = 5.5; 95% CI -3.9, 14.9]). The correoral gemifloxacin and oral levofloxacin in 360 sponding clinical results in the intention-to-treat adults in 60 medical centres in the US, UK and population were 82.6% (114/138) versus 72.1% (98/ Germany, and found that the clinical response to 136), respectively (treatment difference = 10.5; 95% CI 0.7, 20.4). The safety of the two drug regimens both drugs was comparable. [213] nb, nc, mc Gemifloxacin 320mg po od for 7 days Overall, 91% (52/57) 83% (217/261) Sethi et al. [217] r, db, dd, Gemifloxacin 320mg po od for 7 days ND 85% (155/182) mc, pl Levofloxacin 500mg po od for 7 days 78% (139/178)

Lode et al. [218] [220] dd, pl Amoxicillin/clavuanate 1g/125mg tid for 88% 10 days bid = twice daily; c = comparative; db = double-blinded; dd = double-dummy; GLOBE = Gemifloxacin Long term Outcomes of Bronchitis Exacerbation; IV = intravenous; mc = multicentre; nb = nonblind; nc = noncomparative; ND = no data; od = once daily; pl = parallel group; po = oral; r = randomised; tid = three times daily.

The short gatifloxacin course resulted in clinical Zhanel et al. [59] reviewed the results of a study by cure rates comparable to those of the longer ga-File et al. [222] comparing the efficacy of gemifloxtifloxacin and clarithromycin courses. The microbiacin with trovafloxacin in the treatment of CAP. ological eradication rates were reported as >90% in This evaluation demonstrated similar efficacy, both all treatment groups. Another group assessed the clinically and microbiologically. [59] Three more efficacy and tolerability of gatifloxacin in an openstudies have subsequently been published examinlabel, noncomparative, post-marketing trial. Overall ing the use of gemifloxacin for CAP (table VII) . clinical cure was demonstrated in up to 92% of Lode and coworkers [218] compared the use of oral patients. [226] Nicholson et al. [227] found a 90-93% gemifloxacin with sequential therapy with intraveclinical cure rate in patients with ages ranging from nous ceftriaxone and oral cefuroxime with or with-18 to ≥80 years old. out a macrolide in the treatment of patients hospitalised with CAP in a randomised, open-label, multi-

centre study. The clinical and bacteriological Three randomised, double-blind trials comparing efficacy of oral gemifloxacin were high and were the efficacy of gatifloxacin to ceftriaxone (with or comparable to the β-lactam regimen (with or withwithout erythromycin), clarithromycin or levofloxout a macrolide). [218] Ball and coworkers [213] found acin in patients with CAP have been reviewed previthat gemifloxacin achieved clinical and microbioously. [59] In these trials, gatifloxacin achieved slightlogical success in a subset of patients with CAP.

ly better clinical cure and bacteriological eradication Leophonte et al. [220] randomised 324 patients with rates (95% vs 91%), compared with its comparators CAP in 102 medical centres in France, Poland and (98% vs 93%), respectively. [234] [235] [236] At least seven South Africa to either gemifloxacin orally each day more studies addressing the use of gatifloxacin in for 7 days or amoxicillin/clavulanic acid orally for CAP have since been published (table VIII) . Franca 10 days. The clinical cure rate in both groups was and Carvalho, [231] and Casillas and coworkers [228] Both demonstrated clinical cure rates of ≥95%.

Nicholson et al. [229] evaluated gatifloxacin in elderly Zhanel et al. [59] reviewed an analysis by Ramirez patients and found good clinical success rates with and coworkers [223] in which the results from two S. pneumoniae infections (90%) as well as bacterial randomised, double-blind studies, and one noneradication rates (>94%). There was less of an effect blinded study evaluating the efficacy of gatifloxacin (71%) in patients ≥80 years old. [229] In another study in the treatment of AECB were pooled. The clinical reported by the same authors, clinical cure rates and bacteriological cure rates seen with gatifloxacin were >90% regardless of age. [227] The bacteriologiwere comparable to either levofloxacin or cefuroxcal eradication rate (documented or presumed) was ime axetil (91% vs 88% and 93% vs 88% for clinical 95% for S. pneumoniae. No data were given for H. and bacteriological cure, respectively). [59, 223] Howinfluenzae. Gotfried et al. [208] reported the results ever, superior bacteriological eradication rates from TeqCES, a community-based, open-label, proagainst S. pneumoniae and H. influenzae were seen spective, noncomparative study of oral gatifloxacin with gatifloxacin (100% and 96%) versus its compause in outpatient CAP. The drug achieved clinical rators (77% and 86%), respectively. [59, 224] and microbiological cure rates of >90%. In two large Three studies addressing the use of gatifloxacin trials, Lode et al. [232, 233] demonstrated the therapeuin AECB have been published recently (table VIII) .

tic equivalency of oral gatifloxacin with either One group compared 5-day gatifloxacin, 7-day gaclarithromycin or amoxicillin/clavulanic acid. tifloxacin and 10-day clarithromycin courses. [225] 4.4 Moxifloxacin rather than serology. Unfortunately, C. pneumoniae could be recovered from the nasopharyngeal secretions of only 19 (2.8%) of the 670 enrolled patients.

Five additional patients were eliminated from the Two studies were recently reviewed in which analysis because no follow-up cultures were done moxifloxacin 400 mg/day was compared with after treatment. Of the small number of patients clarithromycin for the treatment of AECB. The treated, clarithromycin appeared to be more efficaclinical success rates for moxifloxacin ranged from cious than moxifloxacin, although the numbers were 89% to 95%, and the clinical success rates for too small for formal statistical comparison, and clarithromycin ranged from 88% to 94%. [59] Five many of the patients were co-infected with S. studies have been published since this review compneumoniae, H. influenzae and other bacteria. [242] paring the efficacy of moxifloxacin and other agents Petitpretz and coworkers [243] compared the efficacy (table IX) . DeAbate et al. [237] reported the results of of moxifloxacin and high-dose amoxicillin (3000 a large clinical trial involving 37 centres in the US mg/day) in patients with CAP in a large study inwhere moxifloxacin was compared with azithrovolving 82 centres in 20 countries. They found that mycin. Both agents produced excellent eradication rates of key respiratory tract pathogens with corre-both agents gave good results, although bacterial spondingly high clinical cure success rates. The eradication rates and clinical cure rates were slightly authors concluded that a 5-day course of moxifloxhigher with the fluoroquinolone. The frequency of acin was equivalent to azithromycin for AECB. adverse effects was also comparable in both Schaberg et al. [238] reported the findings of a large groups. [243] Another large, multinational, multicentrial involving 68 centres in 12 countries comparing tre study was carried out by Hoeffken et al. [244] to moxifloxacin (one 400mg tablet daily for 5 days) compare the efficacy of two doses of moxifloxacin therapy with that of amoxicillin/clavulanic acid (200 and 400 mg/day) with clarithromycin (500mg (three 625mg tablets daily for 7 days). Overall, twice a day). All regimens were well tolerated with patients did well on either regimen. [238] Miravitlles discontinuation rates of only 3-5%. The overall and coworkers [239] followed 5737 Spanish patients clinical cure rates were approximately 94% for all with ACEB on moxifloxacin and found that 93% of three regimens. The higher moxifloxacin dosage the assessable patients were cured after 1 week of regimen was slightly superior in eradicating pathotherapy. The adverse effects were low (3.5%). [239] In gens than were either of the other regimens. [244] an Italian study, Grassi and coworkers [240] found that Finch and coworkers [245] examined the relative oral daily moxifloxacin was equally efficacious to efficacies of moxifloxacin and a penicillin plus daily administration of intramuscular ceftriaxone. macrolide regimen for patients with CAP who were Therapeutic equivalency between moxifloxacin and ill enough to require parenteral therapy. Intravenous amoxicillin/clavulanic acid was demonstrated by moxifloxacin was switched to oral therapy as soon Starakis et al. [241] as possible after a mandatory 3-day period, and given for an additional 7-14 days. This regimen was

compared to high-dose amoxicillin/clavulanic acid Two previously reviewed studies examined the 1.2g, initially given intravenously for at least 3 days efficacy of moxifloxacin 400 mg/day for the treatand then switched to oral administration. Clarithroment of CAP. [59] Clinical success rates were mycin could be added at the discretion of the treat-93-95%. Five studies have been published since that ing physician to cover atypical pathogens, although review (table IX) . Hammerschlag and Roblin [242] these were diagnosed serologically in only 13.8% of attempted to assess the relative efficacy of moxthe 326 patients enrolled. Overall, moxifloxacin ifloxacin and clarithromycin in the treatment of therapy was superior to the penicillin plus macrolide CAP caused by C. pneumoniae. Unlike other studregimen in terms of rates of clinical and bacteriologies, they defined infection on the basis of culture [227] age group (n = 2234)

Anzueto [226] nb, nc 

Casillas [228] nb, nc, mc Gatifloxacin 400mg po od for 7-14 days ND 96% (3182/3322) Nicholson nc, mc Gatifloxacin 400mg po od for 14 days Overall >71% Overall 92-96% et al. [229] S. pneumoniae, 94 [231] Lode et al. [232] M. catarrhalis, 90% bid = twice daily; db = double-blinded; dd = double-dummy; mc = multicentre; nb = nonblind; nc = noncomparative; ND = no data; od = once daily; p = prospective; po = oral; r = randomised; tid = three times daily. ical cure, time to resolution of fever (2 vs 3 days), involved 14 centres throughout the world, Torres et the proportion of patients switching to oral therapy al. [246] compared oral moxifloxacin with either within 3 days (50% vs 18%) and length of hospital amoxicillin or clarithromycin or both, given for stay (9.5 vs 10.4 days). [245] In a large trial that 5-15 days. Seventeen percent of the comparator group received amoxicillin alone, 24% received um, confusion, psychosis, abnormal vision and, clarithromycin alone and 59% received both drugs. rarely, seizures. Seizures may be encountered more The clinical success rate of all tested regimens was often when quinolones are used to treat patients with approximately 94%. Moxifloxacin was better toler-a history of strokes or seizure disorders, and in ated than the comparator regimens. [246] The thera-patients in whom potentially epileptogenic medicapeutic equivalence of moxifloxacin and a combina-tions such as NSAIDs or theophylline are concomition of ceftriaxone, azithromycin and metronidazole tantly administered. CNS adverse effects have an for patients initially requiring intravenous therapy overall incidence of 1-2%, and are most common for CAP was shown by Katz and coworkers. [247] with trovafloxacin and least common with levofloxacin and gemifloxacin. [55, 64, 251] 4.5 Summary of Clinical Trials 5.3 Dermatological

Overall, the newer fluoroquinolones often achieve clinical cure rates in ≥90% of patients with Dermatological adverse effects include rash, pru-AECB or CAP. Rates may be lower in HAP, but no ritus, photosensitivity, hyperpigmentation and urticlinical trials of gatifloxacin, gemifloxacin or moxi-caria. Phototoxicity has been linked primarily to the floxacin for nosocomial pneumonia have been pub-presence of a halogen atom at the C8 position of the lished to date. No comparative clinical trials of any quinolone nucleus in compounds such as sparfloxkind have been reported with garenoxacin. In the acin and clinafloxacin. Substitution of methyl studies reviewed, there is little difference in the groups at the C8 position, as in gatifloxacin and clinical success rates of the fluoroquinolones com-moxifloxacin, has significantly reduced the pared with the macrolides or β-lactams tested.

phototoxic potential. The dermatological adverse effects range in incidence from 0.05% to 19%, being 5. Adverse Drug Effects seen most often with clinafloxacin and sparfloxacin (which were taken off the market), and least often The currently marketed US FDA-approved quiwith trovafloxacin, gatifloxacin and moxifloxnolones are considered to be relatively safe and well acin. [55, 64, 251] The recently US FDA-approved tolerated. However, like any other class of drugs, fluoroquinolone, gemifloxacin, has a 2.8% inciadverse effects may be encountered (table X) . [248, 249] dence of rash which occurs more commonly among Gastrointestinal and CNS effects are the most frewomen under 40 years of age. [199] quent adverse events. [55, 250, 251] 

Musculoskeletal adverse effects include arthrop-Gastrointestinal adverse effects include altered athy, chondrotoxicity, tendonitis and tendon ruptaste, anorexia, nausea, vomiting and diarrhoea. ture. Arthropathy and chondrotoxicity have mainly These effects range in incidence from 2-20% acbeen shown in immature laboratory animals, and cording to the quinolone used and are most common seem to be very rare in humans, perhaps because of with trovafloxacin. [55, 64, 251] The overall rates among limited use of these agents among children. Howevthe newer fluoroquinolones is similar (1-3%), aler, arthralgias or arthritis has been reported to occur though nausea, vomiting and diarrhoea may be with an incidence of 1-1.5% in children and higher with moxifloxacin and gatifloxacin comjuveniles treated with ciprofloxacin. [252, 253] On the pared with levofloxacin. [248] other hand, there are case reports of tendonitis and rupture of the Achilles tendon with the use of

ciprofloxacin, ofloxacin, norfloxacin and levoflox-CNS adverse effects include dizziness, headache, acin. [55, 64, 254, 255] Risk factors for tendinopathy insomnolence and, less commonly, agitation, deliri-clude renal failure and corticosteroid use. [256] 

Hammerschlag r, db Moxifloxacin 400mg po od for 10 days Chlamydophila pneumoniae, 70% (7/10) 100% (10/10) and Roblin [242] Clarithromycin 500mg po bid for 10 days C. pneumoniae, 100% (4/4) 100% (4/4) Ceftrixone 2g IV ± azithromycin 500mg IV Overall, 69% (9/13) 80% (90/113) od ± metronidazole 500mg IV every 6 S. pneumoniae, 78% hours then switch to cefuroxime 500mg po H. influenzae, 50% bid ± azithromycin 250mg po od ± metronidazole 500mg po every 6 hours bid = twice daily; db = double-blinded; IM = intramuscular; IV = intravenous; mc = multicentre; nb = nonblind; nc = noncomparative; ND = no data; od = once daily; p = prospective; po = oral; r = randomised; tid = three times daily.

the study. [258] In another study, Demolis and coworkers [259] compared the effect of moxifloxacin The fluoroquinolones can cause hypotension, 400mg and 800mg versus placebo on the QTc intertachycardia and prolongation of the QTc interval of 18 healthy men and women in a double-blind, val. [257] The latter effect, although rarely encounrandomised, placebo-controlled, crossover study. tered, may lead to cardiac arrhythmias in patients ECGs were recorded at rest and with exercise. There with hypokalaemia, underlying heart disease, or in was a 2.3% ± 2.8% and 4.5% ± 3.8% (mean ± SD) those who are receiving antiarrhythmic drugs that increase relative to placebo for the two doses across prolong the QTc interval such as quinidine, proa wide range of RR intervals. Although these cainamide, disopyramide, sotalol or amiodarone. A changes were statistically significant, the authors recent double-blinded, randomised, four-period, concluded that the risk of moxifloxacin-induced torfour-treatment, four-sequence, crossover trial comsades de pointes would be low with moxifloxacin pared the effect of placebo, levofloxacin 1000mg, 400mg. However, they advised caution when using moxifloxacin 800mg and ciprofloxacin 1500mg on the drug in patients with predisposing factors for QTc interval prolongation. The drug doses were torsades de pointes such as electrolyte disturbances twice that recommended by the US FDA for routine and bradycardia, or during coadministration of clinical use. Increases in QT or QTc interval comproarrhythmic drugs. [259] QTc interval prolongation pared with placebo were statistically significant for has also been reported with sparfloxacin and all three antibacterials and were consistently greater grepafloxacin, both of which have been removed with moxifloxacin (16.34-17.83ms over placebo) from the market. [55, 64, 72, [260] [261] [262] than with either levofloxacin (3.53-4.88ms) or Blood pressure changes including hypertension, ciprofloxacin (2.27-4.93ms). However, no adverse effects were experienced by any of the volunteers in hypotension and postural hypotension have been Table X . Adverse drug effects of quinolone antibacterials [192, 194, 195, 197, 199] Drug

Gastrointestinal CNS Dermatological Musculoskeletal Cardiovascular Idiosyncratic reactions

Moxifloxacin ++ + ± ± + + Gemifloxacin ± ± ++ ND ± ND ND = no data; ±, +, ++ indicate relative incidence (lowest to highest).

reported in an incidence of <1% with the use of the 5.8 Summary of Adverse Drug Effects currently marketed quinolones. [192, 194, 195, 197, 199] Histamine release has been postulated as one of the In summary, the currently marketed fluoroquiresponsible mechanisms for hypotension. [263] Severe nolones appear to be a safe and well tolerated class hypotension may occur after a single dose of the of drugs, although several compounds have either currently restricted quinolone trovafloxacin. [260] As been withdrawn from the market (temafloxacin), mentioned in section 1.4, hypotension has occurred restricted (trovafloxacin) or never released (sparmore with the new quinolone garenoxacin than its floxacin, grepafloxacin and perhaps garenoxacin). comparators in phase III trials.

The most common adverse effects are gastrointestinal but the overall rate is low (1-3%). Discontinua-

tion rates among the newer fluoroquinolones are about the same. [248] Perhaps the adverse effect of Gatifloxacin has been shown to have no marked most concern is prolongation of the QTc interval effect on glucose tolerance or pancreatic β-cell funcsince this can lead to dangerous arrhythmias. Protion. However, it did cause a brief increase in serum longation appears to be greatest with moxifloxacin. insulin levels. [264] Severe and persistent hypogly-Unfortunately, there is no known threshold for QT caemia caused by gatifloxacin interactions with oral interval prolongation above which arrhythmias will hypoglycaemic agents were reported in at least three occur and below which it is known to be safe. [249] It case reports. [265] Ciprofloxacin may also cause slight is known that in post-marketing trials of ciprofloxfluctuations in blood sugar levels in patients receivacin and levofloxacin, arrhythmias occurred at a rate ing oral hypoglycaemic drugs. [266] of less than one per million patients. [190] Whether this rate will be higher with gatifloxacin, gemifloxacin and moxifloxacin will only be known after the 5.7 Idiosyncratic Reactions drugs are used more extensively. Of interest, QTc interval prolongation has been reported with a num-There have been reports of asymptomatic and ber of other antimicrobials including the macrolides symptomatic hepatitis, pancreatitis, severe hepatoand imidazoles. [267] toxicity and death associated with trovafloxacin. As noted earlier, the US FDA has advised restricting the use of this drug to patients with life-or limb-threat-6. Important Drug Interactions ening infections. Clinicians are advised to monitor serum transaminases and other indices of hepatobili-Other drugs may alter serum fluoroquinolone ary function in patients receiving hepatically concentrations, or the fluoroquinolones may alter metabolised quinolones such as trovafloxacin and moxifloxacin. [64, 72, 260] their metabolism.

Multivalent cations such as iron, zinc, calcium, 7.1 Acute Bronchitis aluminium and magnesium may form insoluble The use of antibacterials in acute bronchitis is complexes with orally administered fluoroquidiscouraged because the aetiology is most often nolones in the gastrointestinal tract and decrease the viral. [5] The use of antibacterials in this syndrome absorption of the antibacterial by >90%. Examples results in unnecessary costs, adverse drug effects of these drugs include multivitamins and mineral and the potential for selection of resistant bactesupplements, antacids and sucralfate. When these ria. [3, 4] Further clinical evaluation, radiographic drugs are necessary, they should be administered at imaging and microbiological studies should be carleast 4 hours before or 2 hours after oral administraried out for those patients with presentations sugtion of a fluoroquinolone to avoid interactions. The gesting more serious illness such as pneumonia or in antiretroviral drug didanosine also impairs the abthose with severe or prolonged duration of illness. [1] sorption of quinolones because the drug formulation Antibacterials may be used if an underlying bactericontains calcium carbonate and magnesium hydroxal aetiology is found. In this case, a macrolide or a ide buffers. [65, 250, 268, 269] Probenecid, loop diuretics tetracycline may be appropriate. [5] Fluoroquinolones and cimetidine increase serum fluoroquinolone conshould be reserved as second-line agents for patients centrations. [192, 194, 195, 197, 199] with resistant bacteria. Following local trends in antibacterial resistance may be of value.

The quinolones inhibit the cytochrome P450 sys-Several guidelines addressing the management of tem leading to increased serum concentrations of AECB have been published. [8, [270] [271] [272] [273] Stratification of drugs such as theophylline, caffeine, digoxin, patients allows identification of patients who are at high risk for infection with resistant bacteria, treatciclosporin (cyclosporin) and warfarin. Newer ment failure and a complicated course. High-risk fluoroquinolones such as levofloxacin, gatifloxacin factors include significant impairment of lung funcand moxifloxacin have less of an effect on theophyltion with an FEV1 of <50%, four or more episodes line pharmacokinetics than older agents. Fluoroquiof AECB per year, oral corticosteroid use, age >65 nolones should be used with caution in patients years and co-morbid conditions such as diabetes receiving Class Ia (procainamide, quinidine, dismellitus, heart disease or renal failure. In these paopyramide) and Class III (amiodarone, bretylium, tients, an aggressive approach including sputum sotalol, dofetilide, ibutilide) antiarrhythmic drugs, Gram-stain and cultures, and the initial, empirical as well as erythromycin, cisapride, antipsychotics use of broad-spectrum antibacterials is justified to and tricyclic antidepressants that prolong the QTc avoid treatment failure. [8, 271, 273] interval, because of the increased potential for fatal When deciding whether to use a fluoroquinolone tachyarrhythmias. [63, 65, 268] Concurrent use of cortior an alternative class of antibacterial for patients costeroids may increase the risk of tendon rupture, with AECB, it is helpful to have information on especially in elderly patients. [192, 194, 195, 197, 199] Some local bacterial resistance rates. Unfortunately, data fluoroquinolones, such as gatifloxacin and to a are often available only from large national (or lesser extent ciprofloxacin, interact with oral hypointernational) surveys and may differ depending upglycaemic agents which may result in serious hypoon the source of the isolates (hospital vs communiglycaemia. [265, 266] ty). For instance, in one large study of hospital isolates collected in the US during the 1999-2000 ation cephalosporin (e.g. ceftazidime or cefepime) and an aminoglycoside if P. aeruginosa is suspectrespiratory season, more than 30% of H. influenzae ed, until sputum culture results and antibacterial strains were resistant to ampicillin and 14% were sensitivity data are available. [271, 272, 274] One author resistant to co-trimoxazole. Less than 1% of the suggested that fluoroquinolone monotherapy proisolates were resistant to either clarithromycin or vides good clinical outcomes, higher quality of life azithromycin. A full 34% of the S. pneumoniae and lower costs in this setting. [8] isolates were non-susceptible (intermediate plus resistant) to penicillin, and this varied by geographic 7.3 Community-Acquired Pneumonia region (ranging from 44% in the South Atlantic to 24% in New England). [140] A study of isolates col-

The IDSA recently published guidelines for the lected from 2795 primary care providers in the US management of CAP and provided recommendashowed that penicillin non-susceptibility among S.

tions for choosing antimicrobial therapy. These recpneumoniae was about the same (33%), but up to ommendations include pathogen-specific treatment 7.3% of the H. influenzae isolates were resistant to for cases in which an aetiological diagnosis is estabclarithromycin. [40] In another study of S. pneumonilished, and empirical treatment for patients in whom ae isolates collected in 1999-2000, intermediate and an aetiological diagnosis is not known. Whenever an resistant rates were 34.2% for penicillin, 26.2% for aetiological organism is determined, changing to the the macrolides, 35.9% for co-trimoxazole and antimicrobial agent that is most cost effective, least 16.6% for tetracycline. [139] toxic and has the most narrow spectrum is en-COPD patients with AECB and no high-risk faccouraged. [26] Recommendations for treating patients tors are usually treated on an outpatient basis. In this who require empirical antibacterial selection are setting, sputum Gram-stain and culture do not seem based on the likely pathogen, local resistance patto be cost effective and are not recommended. [272, 274] terns, comorbid conditions, the severity of illness In our opinion, amoxicillin/clavulanic acid or newer and the site of care. It was recommended that a macrolides such as clarithromycin or azithromycin decision to hospitalise the patient should be based should be used as first-line therapy and fluoroquion an assessment of pre-existing conditions that may nolones reserved as second-line agents. Data showcompromise the safety of the patient if they are sent ing recent in vitro trends in macrolide resistance home; a PORT (Pneumonia Outcomes Research among S. pneumoniae and clinical failures with Team) Severity Index (PSI) score greater than class these agents are of concern. [40, 140, 156, [275] [276] [277] However, III, and clinical judgment. Although there was concontroversies about the relevance of in vitro data to cern that misuse and overuse of fluoroquinolones clinical outcomes, [278, 279] and the lack of superior could lead to increasing pneumococcal resistance outcomes when fluoroquinolones are compared with and more clinical failures, the use of fluoroquithe newer macrolides or β-lactam/β-lactamase comnolones alone was recommended in several inbinations in clinical studies (see tables VI to IX) stances (table XI). suggest that the latter agents can still be used suc-

The American Thoracic Society (ATS) guidecessfully.

lines for the management of CAP have also included High-risk patients with AECB are usually treated recommendations on choosing antimicrobial therin the hospital setting. In these patients, sputum apy (table XI). [39] As with the IDSA guidelines, the Gram-stain and cultures are cost effective because ATS recommendations are based on patient stratifithey help in directing antibacterial therapy. This is cation according to site of care (outpatient, inpatient because these patients are often at risk for infection ward or intensive care unit [ICU]), the presence of with antibacterial-resistant enteric Gram-negative cardiopulmonary disease and the presence of 'modibacteria and P. aeruginosa. Empirical therapy may fying factors'. Modifying factors define clinical setbe started with an intravenous third-or fourth-gener-tings that place the patient at risk for infection with [26] ATS recommendations, 2001 [39] Outpatient Previously healthy with no recent antibacterial therapy → a macrolide a or doxycycline No cardiopulmonary disease and no Previously healthy with antibacterial therapy within the last 3 months → a respiratory modifying factors f → an advanced macrolide c fluoroquinolone b alone, an advanced macrolide c + high-dose amoxicillin (1g tid), or an or doxycycline advanced macrolide plus high-dose amoxicillin/clavulanic acid (2g bid) Cardiopulmonary disease and/or modifying Comorbidities d and no recent antibacterial therapy → an advanced macrolide or a factors f → a β-lactam g + an advanced respiratory fluoroquinolone macrolide or doxycycline/or → a respiratory Comorbidities and recent antibacterial therapy → a respiratory fluoroquinolone alone or fluoroquinolone alone an advanced macrolide + a β-lactam e Suspected aspiration with infection → amoxicillin/clavulanic acid or clindamycin Influenza with bacterial superinfection → a β-lactam e or a respiratory fluoroquinolone

No recent antibacterial therapy → a respiratory fluoroquinolone alone or an advanced Cardiopulmonary disease and/or modifying macrolide plus a β-lactam h factors → an IV β-lactam i + po or IV Recent antibacterial therapy → an advanced macrolide + a β-lactam h or a respiratory advanced macrolide c or doxycycline/or → an fluoroquinolone alone (regimen selected will depend on nature of recent antibacterial IV respiratory fluoroquinolonealone therapy)

No cardiopulmonary disease or modifying factors → an IV advanced macrolide c alone or → an IV β-lactam + po or IV advanced macrolide c or doxycycline/or → an IV respiratory fluoroquinolone alone

Pseudomonal infection unlikely → a β-lactam h + either an advanced macrolide or a No risk factors for Pseudomonal infection → respiratory fluoroquinolone an IV β-lactam i + an IV advanced macrolide c Pseudomonal infection unlikely but patient has a β-lactam allergy → a respiratory or an IV respiratory fluoroquinolone fluoroquinolone, with or without clindamycin Risk factors for Pseudomonal infection → Pseudomonal infection likely j → either: (i) an antipseudomonal agent k + ciprofloxacin; or either: (i) an antipseudomonal agent k + (ii) an antipseudomonal agent + an aminoglycoside + a respiratory fluoroquinolone or a ciprofloxacin; or (ii) an antipseudomonal macrolide agent + an aminoglycoside + a respiratory Pseudomonal infection likely but the patient has a β-lactam allergy → either: (i) fluoroquinolone or a macrolide aztreonam + levofloxacin; or (ii) aztreonam + moxifloxacin or gatifloxacin, with or without an aminoglycoside

Receiving treatment in nursing home → a respiratory fluoroquinolone alone or No particular recommendations amoxicillin/clavulanic acid + an advanced macrolide Hospitalised → same as for medical ward and ICU a Erythromycin, azithromycin or clarithromycin.

b Moxifloxacin, gatifloxacin, levofloxacin or gemifloxacin (gemifloxacin is only available orally).

c Azithromycin, or clarithromycin. d Chronic obstructive pulmonary disease, diabetes mellitus, renal or congestive heart failure or malignancy. e High-dose amoxicillin, high-dose amoxicillin/clavulanic acid, cefpodoxime, cefprozil or cefuroxime.

f See text section 7.3. g Selected oral β-lactam antibacterials include oral cefpodoxime, cefuroxime, high-dose amoxicillin, amoxicillin/clavulanic acid.

h Cefotaxime, ceftriaxone, ampicillin-sulbactam or ertapenem; ertapenem was recently approved for such use (in once-daily parenteral treatment) but there is little experience thus far.

i Selected IV β-lactam antibacterials include cefotaxime, ceftriaxone, ampicillin/sulbactam. ATS-defined risk factors for infection with Pseudomonas aeruginosa include any of the following: structural lung disease (bronchiectasis), antibacterials for >7 days in the past month, corticosteroid therapy with >10 mg/day of prednisone or malnutrition.

j Risk factors for Pseudomonal infection include severe structural lung disease (e.g. bronchiectasis), and recent antibacterial therapy or stay in hospital (especially in the ICU).

k Piperacillin, piperacillin-tazobactam, imipenem, meropenem or cefepime. bid = twice daily; ICU = intensive care unit; IV = intravenous; po = oral; tid = three times daily.

drug resistant S. pneumoniae, enteric Gram-negative fifth day of hospitalisation or later should be asbacteria or P. aeruginosa. Risk factors for infection sumed to be a result of organisms acquired in the with drug-resistant S. pneumoniae include age >65 hospital and treated accordingly. years, β-lactam therapy in the past 3 months, alco-Empirical, early and adequate antibacterial therholism, immunosuppressive illness (including cortiapy based on the knowledge of the most likely costeroid therapy, but not HIV infection), multiple infecting organisms has been shown to reduce mormedical comorbidities and exposure to a child in a bidity and mortality in HAP. [47, [282] [283] [284] [285] The ATS dedaycare centre. Risk factors for infection with enterfines pathogens that are the most likely aetiologies ic Gram-negative bacteria include residence in a for HAP in the absence of specific risk factors (see nursing home, underlying cardiopulmonary disease, below). These bacteria include E. coli, Enterobacter multiple medical co-morbidities and recent anspp., Klebsiella spp., Proteus spp., Serratia marcestibacterial therapy. Risk factors for infection with P. cens, H. influenzae, methicillin-sensitive S. aureus aeruginosa include structural lung disease (bronchiand S. pneumoniae. Risk factors for additional ectasis), antibacterial therapy for more than 7 days pathogens include witnessed aspiration, recent abin the past month, corticosteroid therapy at the dominal surgery, coma, head trauma, recent influenequivalent of >10 mg/day of prednisone and malnuza, history of intravenous drug use, diabetes, renal trition. Recommended antibacterial regimens are failure, high-dose corticosteroids, prolonged ICU given in table XI. As with the IDSA guidelines, stay, structural lung disease, antibacterial use before fluoroquinolones were often recommended as single the onset of pneumonia and prolonged mechanical agents.

ventilation. The presence of these risk factors in-Other organisations have made recommendations creases the probability of infections due to for the treatment of CAP. The CDC, focusing prima-P. aeruginosa, Acinetobacter spp., MRSA, anaerrily on drug-resistant S. pneumoniae (defined as an obes and Legionella spp. [47] MIC ≥4μg/mL) recommended an oral β-lactam plus For the initial empirical therapy for HAP or vena macrolide or tetracycline, even if pneumococcal tilator-associated pneumonia in patients with no resistance was a concern. An intravenous β-lactam known risk factors for multidrug-resistant pathogens plus a macrolide was recommended for empirical and of early onset, the ATS recommends monothertherapy of hospitalised patients with CAP. The CDC apy with a ceftriaxone, ampicillin/sulbactam, emphasised that fluoroquinolones should not be ertapenem or a quinolone (ciprofloxacin, levofloxused routinely to treat CAP, but should be reserved acin or moxifloxacin). For patients with late onset for those patients who have failed other regimens or disease or risk factors for multidrug-resistant bactewho have documented high-level, drug-resistant S. ria, the ATS recommends that patients be treated pneumoniae. [280] In contrast to the American recomwith an antipseudomonal cephalosporin (cefepime mendations, the Canadian guidelines call for a 'reor ceftazidime), or an antipseudomonal carbapenem spiratory' fluoroquinolone as the first choice for all (imipenem/cilastin or meropenem), or a β-lactam/βpersons admitted to hospital. [281] lactamase inhibitor combination (piperacillin/ tazobactam), plus an antipseudomonal fluoroqui-7.4 Hospital-Acquired Pneumonia nolone (ciprofloxacin or levofloxacin) or an aminoglycoside. Linezolid or vancomycin should be The ATS guidelines for management of HAP are used when MRSA is suspected. [47] based on the time of onset during hospitalisation, Studies on the use of fluoroquinolones in HAP disease severity and the presence of risk factors for mainly involved the use of ciprofloxacin. [286] [287] [288] One specific organisms. [47] It is recommended that HAP study showed equivalence of high-dose levofloxacin beginning on the third or fourth day of hospitalisawith imipenem/cilastatin followed by oral ciprofloxtion be treated as CAP (see section 7.3). In contrast, acin (table VI) , [212] but the use of other newer fluoroit is recommended that HAP encountered on the quinolones such as gatifloxacin and moxifloxacin increased prevalence of levofloxacin resistance has not been evaluated in this setting. While among pneumococcal isolates collected from across ciprofloxacin remains the most active quinolone the US, with figures exceeding 4.6% in certain states against P. aeruginosa in vitro, levofloxacin may be such as Massachusetts and Colorado, is very worrias effective in the clinical setting, given its superior some. [144] Of greater concern is cross-resistance pharmacokinetics. [68] [69] [70] Despite activity against among fluoroquinolones. This has clearly been P. aeruginosa, however, use of a fluoroquinolone as shown to occur when pathogens are exposed to monotherapy in HAP cannot be justified, since high older, less potent agents that select single-step, lowclinical failure rates and the evolution of resistance level resistant mutants. These mutants may have in P. aeruginosa have been observed with ciprofloxdecreased susceptibility to newer fluoroquinolones, acin monotherapy. [286, 287] Fluoroquinolones may be and may acquire high-level resistance with additionused as an alternative to an aminoglycoside in comal mutations in a second target gene. Because of this, bination with an antipseudomonal β-lactam when some investigators have suggested that less potent there are concerns about renal dysfunction. These fluoroquinolones (ciprofloxacin and levofloxacin) drugs are not reliably synergistic with β-lactams be abandoned in favour of more potent ones (gaagainst P. aeruginosa as are the aminoglycotifloxacin, moxifloxacin or gemifloxacin) for the sides. [289, 290] treatment of CAP in an effort to prevent class resistance. [39, 56, 58, 114, 236, 292, 293] Clinical failures have been 8. Conclusion documented with ciprofloxacin leading the US FDA to suggest that the drug not be used for lower respir-Newer fluoroquinolones such as levofloxacin, atory tract infections caused by S. pneumoniae. It is moxifloxacin, gatifloxacin and gemifloxacin have of interest that a similar number of levofloxacin several attributes that make them good choices for failures have also been reported but no such recomthe therapy of lower respiratory tract infections. mendations have been forthcoming. Theoretically, They have excellent intrinsic activity against ciprofloxacin would be expected to be less effica-S. pneumoniae, H. influenzae, M. catarrhalis and cious for infections caused by S. pneumoniae bethe atypical respiratory pathogens; their cause its pharmacodynamic ratios are <20% of the pharmacokinetics allows single daily dose adminisnewer agents (table V) . The pharmacodynamic ratration, and they are generally well tolerated and tios of levofloxacin and gatifloxacin are <60% of have a good safety profile. Clinical trials have those of moxifloxacin or gemifloxacin. Whether this shown that they achieve high microbiological eradiwill make a difference in patient outcomes remains cation and clinical success rates, and they compare to be seen. Data published from recent clinical trials favourably with β-lactams and the newer involving levofloxacin, gatifloxacin, moxifloxacin macrolides. Unfortunately, bacteria can become reand gemifloxacin suggest that there is little differsistant to these agents through a series of simple ence among these fluoroquinolones in the eradicaspontaneous mutations. Numerous studies ranging tion rates of S. pneumoniae (tables VI to IX). from in vitro experiments to case reports, and large An approach, originally recommended for consurveillance databases have shown that resistance servation of β-lactam efficacy against S. pneumonican, and does, occur. Currently, the overall prevaae, also seems appropriate for the fluoroquinolones. lence of resistance to the newer fluoroquinolones is This approach entails: (i) reduction of prescribing of low, but this is not necessarily reassuring. As Austin drugs whose consumption correlates strongly with et al. pointed out, there is typically a long period of resistance; (ii) development of new formulations or very low-level resistance that precedes a rapid inadministration strategies to deal with resistant crease in resistance. [291] This has been the case with strains; and (iii) use of antibacterials with the maxi-MRSA, vancomycin-resistant Enterococci and penimal capacity for bacterial eradication. [294] In our cillin-resistant S. pneumoniae. The recently reported opinion, ciprofloxacin should not be used for lower Acknowledgements respiratory tract infections. Of concern is the newly Dr Shams has no conflicts of interest that are directly released Cipro ® XR. 1 This formulation consists of a relevant to the content of this manuscript. Dr Evans has received funding for basic research in quinolones from Ortho-bilayer matrix. The first layer releases ciprofloxacin

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Ciprofloxacin extended-release tablets (CiproXR) [package inof Infectious Diseases

West Haven (CT): Bayer Corporation Pharmaceutical Division

The authors are very grateful to Rajia Hassib, the illustration are approximately 50% of those achieved with tor who helped us complete figure 1 in this article. administration of the conventional formulation. Cipro ® XR 500mg has been approved by the US References FDA solely for once-daily treatment of urinary tract