Fluoroquinolones in the management of community-acquired pneumonia
T.E.Albertson,1,2N.C.Dean,3,4A.A.El Solh,5M.H.Gotfried,6C.Kaplan,7M.S.Niederman8,9
Introduction
An estimated 5.6million episodes of community-acquired pneumonia(CAP)occur in the United States each year,resulting in1.1million hospitalisa-tions(1–3).Approximately10%of these hospitalised patients will require management in an intensive care unit(ICU)(4,5).The importance of CAP-treated patients in the hospital is underscored both by its use of scarce medical resources and by its contribu-tion to mortality.The average length of hospital stay for CAP patients is5.7days,which is longer than that of patients admitted for primary diagnoses of either heart disease or diabetes mellitus(6).In addi-tion,although the mortality rate for CAP-treated outpatients ranges from<1%to5%,the mortality rate among hospitalised CAP patients outside the ICU averages12%(1).The mortality rate for CAP patients admitted to the ICU ranges from23%to 57.6%(7–9).Furthermore,CAP is associated with a signi?cant economic burden.The annual cost of antimicrobial therapy alone is approximately $100million in the United States(10),and the total costs range from an estimated$10billion to$12bil-lion,most of which can be attributed to hospital costs(10,11).
This article reviews the role of?uoroquinolones (FQs)in the management of CAP.These agents are an important monotherapy treatment option for out-patients with comorbid conditions,inpatients who do not require ICU care,patients recently treated with antibiotics and patients with suspected drug-
S UMMA RY
Aims:Review of the current guidelines for the use of respiratory?uoroquinolones in the management of community-acquired pneumonia(CAP).Methods:Data were collected from recent clinical trials on?uoroquinolone therapy in patients with CAP and from updated recommendations of antimicrobial therapy in manag-ing CAP,with a focus on current North American guidelines.Results:Randomised clinical trials of respiratory?uoroquinones(moxi?oxacin,levo?oxacin and gemi?ox-acin)in the treatment of CAP were identi?ed and analysed.The bacteriology of CAP,and susceptibility rates,resistance rates and pharmacokinetic and pharmaco-dynamic properties of?uoroquinolones against causative pathogens in CAP,and adverse event pro?les of these agents were described.Respiratory?uoroquinones have broad-spectrum antibacterial activities against common causative pathogens in CAP and provide an important treatment option as monotherapy for outpatients with comorbidities and inpatients who are not admitted to the intensive care unit (ICU),including those with risk factors of drug-resistant Streptococcus pneumoniae.For treatment of ICU patients with severe CAP,it is recommended that?uoroquinolones be used in combination with a b-lactam.Recent studies also demonstrated a more rapid resolution of clinical symptoms with the use of highly potent respiratory ?uoroquinolones.Discussion:Appropriate use of?uoroquinolone agents may shorten the duration of antimicrobial therapy and the length of hospital stay and contribute to the decreased development of resistance in patients with CAP. Adverse event pro?les of these agents should be considered to facilitate the selec-tion of an appropriate?uoroquinolone for appropriate CAP patients.Conclu-sion:The?uoroquinolone class,speci?cally those with adequate activity against respiratory pathogens,represents an important and convenient treatment option for patients with CAP.Review Criteria
Review criteria used in the development of this manuscript included recent clinical trials using respiratory?uoroquinolones in the treatment of patients with CAP,current guideline recommendations for antimicrobial therapy in managing CAP and contemporary articles discussing causative pathogens in CAP or pharmacokinetic and pharmacodynamic properties and susceptibility rates of?uoroquinolones.
Message for the Clinic
Respiratory?uoroquinolones provide an important monotherapy treatment option for outpatients with CAP and other comorbidities and for non-ICU inpatients with CAP,including those with suspected drug-resistant Streptococcus pneumoniae.For patients with CAP,appropriate use of
?uoroquinolone agents may shorten the duration of antimicrobial therapy and length of hospital stay and contribute to the decreased development of resistance.
1Department of Internal
Medicine,UC Davis School of
Medicine,Davis,CA,USA
2Division of Pulmonary and
Critical Care Medicine,UC
Davis Health System,
Sacramento,CA,USA
3Section of Pulmonary and
Critical Care Medicine,
Intermountain Medical Centre,
Murray,UT,USA
4Department of Internal
Medicine,University of Utah,
Murray,UT,USA
5Department of Medicine,
Division of Pulmonary and
Critical Care and Sleep
Medicine,University at Buffalo
SUNY,Buffalo,NY,USA
6Department of Medicine,
College of Medicine,University
of Arizona,Phoenix,AZ,USA
7Division of Pulmonary,Critical
Care&Sleep Medicine,
Department of Internal
Medicine,St.Louis University,
St.Louis,MO,USA
8Department of Medicine,
Winthrop-University Hospital,
Mineola,NY,USA
9Department of Medicine,SUNY
Stony Brook School of Medicine,
Stony Brook,NY,USA
Correspondence to:
Michael S.Niederman,MD,
Department of Medicine,
Winthrop-University Hospital,
222Station Plaza N.,Suite509,
Mineola,NY11501,USA
Tel.:+15166632381
Fax:+15166638796
Email:
MNiederman@https://www.doczj.com/doc/ee18077423.html,
Disclosures
Dr Albertson has served on
Speakers Bureau for Boehringer
Ingelheim and GlaxoSmithKline
(GSK)and Schering-Plough,and
has received research funding
from P?zer.Dr Dean has served
on Advisory boards for Forest,
Advanced Life Sciences and
Schering-Plough,and has
received research funding via
contracts with Intermountain
REVIEW ARTICLE
a2010Blackwell Publishing Ltd Int J Clin Pract,February2010,64,3,378–388 378doi:10.1111/j.1742-1241.2009.02239.x
resistant Streptococcus pneumoniae(DRSP).The arti-cle brie?y describes the bacteriology of CAP,resis-tance rates among key pathogens and the activity, pharmacokinetic?pharmacodynamic properties and adverse event(AE)pro?les of FQs.The article also discusses recent trials of FQs and the implications of their?ndings for management of CAP in the future. Bacteriology of CAP
Multiple pathogens may cause CAP and vary by the setting in which CAP is acquired.In the outpatient setting,the most common bacterial causes of CAP are S.pneumoniae,Mycoplasma pneumoniae,Haemo-philus in?uenzae and Chlamydophilia pneumoniae (12,13).Among non-ICU-hospitalised patients,com-mon bacterial pathogens include S.pneumoniae, H.in?uenzae,Legionella spp,M.pneumoniae and C.pneumoniae.Some of these patients also can be at risk for infection with enteric Gram-negative organ-isms(1,12).In ICU patients,the most common bac-terial causes of CAP are S.pneumoniae,Legionella spp,H.in?uenzae,Staphylococcus aureus and Gram-negative bacilli,including Pseudomonas aeruginosa (1,12).
Recent reports have focused on resistant bacteria such as community-acquired methicillin-resistant S.aureus(CA-MRSA)(14).Utilising an Emerging Infections Network,Kallen and colleagues found that most of the cases of S.aureus CAP were associated with current or recent in?uenza and that most cases were MRSA(15).DRSP and multidrug-resistant S.pneumoniae(MDRSP)also are important causes of CAP(16,17),although their clinical relevance and impact on outcomes are uncertain(12).Respiratory viruses,such as in?uenza A and B,adenovirus,respi-ratory syncytial virus and parain?uenza virus are other common causes of CAP(12),although treatment of these cases is beyond the scope of this article.
The bacteriology of CAP varies in different parts of the world,and in North America,MDRSP and infection with atypical pathogens are more of a con-cern than in other parts of the world,and these dif-ferences account for a different approach to therapy in North America,compared with parts of Europe and the United Kingdom(13).
Activity of FQs
The respiratory FQs moxi?oxacin,levo?oxacin and gemi?oxacin provide Gram-positive,Gram-negative and atypical pathogen coverage with a single agent taken daily(18–20).These FQs also are active against DRSP and MDRSP(16,17)Agents in this drug class have good penetration into respiratory secretions, such as the epithelial lining?uid(ELF),and into alveolar macrophages,delivering adequate concentra-
tions at the site of the infection(21).FQs have com-
parable serum levels whether administered
intravenously(IV)or orally(PO),allowing for early
switch to oral therapy(18,19).
Pharmacokinetic and pharmacodynamic
properties of FQs
Pharmacokinetic and pharmacodynamic differences
exist between the FQs,and these differences can
affect the outcome of therapy,especially in cases
caused by potentially drug-resistant pneumococci.
Differences in dosing administration,lung tissue con-
centrations and renal dosage adjustments are impor-
tant considerations that have implications for ef?cacy
and safety.Differences in pharmacodynamic parame-
ters may affect the speed of resolution of the infec-
tion and the duration of antimicrobial therapy
(22,23).
These FQs exhibit a similar spectrum of activity
against common CAP pathogens,with the exception
of pneumococcus(22).Cipro?oxacin,a?rst-genera-
tion FQ,and levo?oxacin,a second-generation FQ,
are not as active in vitro against S.pneumoniae as
moxi?oxacin and gemi?oxacin(fourth-generation
FQs).In contrast,cipro?oxacin is the most active FQ
against P.aeruginosa(22),but is not considered as a
respiratory FQ because of its poor Gram-positive
coverage.Table1presents the pharmacodynamic
properties of FQs against S.pneumoniae.
Moxi?oxacin has demonstrated greater in vitro
potency than levo?oxacin against pneumococcus,
and the clinical correlate of this could be more rapid
bacterial killing and a faster time to clinical improve-
ment in patients with CAP(17).Moxi?oxacin has an
in vitro90%minimum inhibitory concentration
(MIC90)of0.25l g?ml.Moxi?oxacin(400mg once
daily)has a24-h serum area under the curve(AUC)
to MIC90ratio(AUC?MIC90)of96,whereas gemi-
?oxacin320mg once daily has an MIC90of
0.03l g?ml and an AUC?MIC90ratio of116.Levo-
?oxacin500mg once daily has an MIC90of1l g?ml
and an AUC?MIC90of34,whereas levo?oxacin
750mg has an MIC90of1l g?ml and an AUC?
MIC90ratio of64(Table1)(18–20,22,24,25).Some
investigators have estimated that an AUC?MIC value
of at least30against pneumococcus is needed in
serum to ensure ef?cacy(18,19,26).
Achieving adequate drug concentration at the site
of infection also is an important consideration.In
a small study of47adults undergoing diagnostic
bronchoscopy,moxi?oxacin400mg exhibited equiv-
alent steady-state concentrations in ELF and macro-
phages at<12h compared with levo?oxacin
500mg,but achieved signi?cantly higher steady-state
Healthcare,Aggenix,P?zer and
Novartis,and employment from
Intermountain Healthcare.Dr El
Solh has nothing to disclose.Dr
Gotfried has served on Advisory
Boards for GSK and Schering-
Plough,and has received
research support from Ortho-
McNeil,P?zer and GSK.Dr Carl
Kaplan has nothing to disclose.
Dr Niederman has received
honoraria or consulted for
Bayer,Schering-Plough,Merck,
P?zer,Johnson and Johnson and
Nektar,and has received grants
from Nektar.
Fluoroquinolones in the management of community-acquired pneumonia379a2010Blackwell Publishing Ltd Int J Clin Pract,February2010,64,3,378–388
concentrations in both ELF and macrophages at24h (21).In other studies,the concentrations of moxi-?oxacin,levo?oxacin and gemi?oxacin in ELF following single or multiple dosing schedules were 20.7,10.9and2.69±1.96mg?l respectively,and in macrophages were56.7,27.7and107±77mg?l respectively(27).Recommended uses of FQs in CAP
According to Infectious Diseases Society of America (IDSA)and American Thoracic Society(ATS)consen-sus guidelines(Table2)(12),FQs should be considered as monotherapy in complicated(e.g.with comor-bidities or recent antibiotic treatment)outpatients with CAP and in inpatients with disease of mild to
Table1Pharmacodynamics of?uoroquinolones vs.S.pneumonia(18–20,22,24,25)
Agent MIC90
(l g?ml)
24-h serum
AUC(l g?h?ml)
Fraction
unbound
24-h free
serum AUC
(l g*h?ml)
Free serum
AUC?MIC90
Levo?oxacin500mg1480.73434 Levo?oxacin750mg1910.76464 Gemi?oxacin320mg0.03100.3–0.43–4116 Moxi?oxacin400mg0.25480.5–0.72496 Cipro?oxacin750mg twice daily140702828
Table2IDSA?ATS recommended empirical antibiotics for community-acquired pneumonia(12)
Type of treatment Antibiotic therapy
Outpatient treatment
Healthy and no use of antimicrobials within
the previous3months
A macrolide or doxycycline
Presence of comorbidities,such as chronic heart,lung,liver,or renal disease;diabetes mellitus;alcoholism;malignancies;asplenia; immunosuppressing conditions or use of immunosuppressing drugs;or use of antimicrobials within the previous3months (in which case an alternative from a different class should be selected)A respiratory FQ[moxi?oxacin,gemi?oxacin or levo?oxacin(750mg)]
A b-lactam plus a macrolide
In regions with a high rate(>25%)of infection with high-level
(MIC?16l g?ml)macrolide-resistant Streptococcus pneumoniae Alternative agents listed above for patients without comorbidities
Inpatients,non-ICU treatment A respiratory FQ or a b-lactam plus a macrolide
Inpatients,ICU treatment A b-lactam(cefotaxime,ceftriaxone
or ampicillin-sulbactam)plus either
azithromycin or a respiratory FQ
Special concerns
If Pseudomonas is a consideration An antipneumococcal,antipseudomonal b-lactam
(piperacillin-tazobactam,cefepime,imipenem or
meropenem)plus either cipro?oxacin or levo?oxacin
(750mg)or one of the above b-lactams plus an amino
glycoside and azithromycin or one of the above b-lactams
plus an aminoglycoside and an antipneumococcal FQ(for
patients allergic to penicillin,substitute aztreonam for
above b-lactam)
If CA-MRSA is a consideration Add vancomycin or linezolid
ATS,american thoracic society;CA-MRSA,community-acquired methicillin-resistant Staphylococcus aureus;FQ,?uoroquinolone;ICU,
intensive care unit;IDSA,Infectious Diseases Society of America;MIC,minimum inhibitory concentration.
Adapted from Ref.(12).
380Fluoroquinolones in the management of community-acquired pneumonia
a2010Blackwell Publishing Ltd Int J Clin Pract,February2010,64,3,378–388
moderate severity as an alternative to a b-lactam?macrolide combination regimen(12).Currently available FQs with good Gram-positive activity include gemi?oxacin,moxi?oxacin and levo?oxacin. Moxi?oxacin and levo?oxacin are available in IV and oral formulations,whereas gemi?oxacin is avail-able only in an oral formulation(18–20).The approach to therapy in the United Kingdom is not the same,with the greatest differences being the rec-ommendation for routine atypical pathogen coverage in North America and a trend to use penicillins and to avoid quinolones in the United Kingdom.In addi-tion,macrolide monotherapy is recommended more widely in the United States than in Europe.These national differences re?ect variability in the fre-quency of atypical pathogens and of DRSP in differ-ent countries(13).
Recent FQ trials in CAP
A number of trials have been recently reported inves-tigating the use of the FQs in CAP,comparing these agents in certain high-risk patient populations and with some studies designed to determine the clinical importance of a rapid response to therapy.
Ef?cacy in elderly patients
Results from the CAP recovery in the elderly(CAP-RIE)study revealed a clinical response at test-of-cure (TOC)of92.9%for elderly patients with CAP receiving moxi?oxacin400mg IV?PO once daily, compared with87.9%for patients taking levo?oxacin 500mg IV?PO once daily.This was not a statistically signi?cant difference[95%con?dence interval(CI), )1.9–11.9;p=0.2](28).However,a secondary out-come analysis in this double-blinded trial demon-strated that patients receiving moxi?oxacin experienced a statistically signi?cant faster recovery than those in the levo?oxacin group,with a higher percentage showing clinical resolution or improve-ment at3–5days[moxi?oxacin97.9%vs.levo?oxa-cin90.0%(95%CI,1.7–14.1;p=0.01)].At TOC, bacteriological eradication occurred in81%of patients treated with moxi?oxacin(17?21)and75% of patients treated with levo?oxacin(21?28;p=0.9). Although the rate of treatment-emergent AEs(e.g. diarrhoea,oral candidiasis,nausea,Clostridium dif?-cile?colitis,cardiac event)was signi?cantly higher in the moxi?oxacin arm(84.1%compared with73.4% in the levo?oxacin arm;p=0.01),the rates of drug-related(26.2%in the moxi?oxacin arm and22.6% in the levo?oxacin arm;p=0.5)and serious(23.6% in the moxi?oxacin arm and22.6%in the levo?oxa-cin arm;p=0.9)AEs were similar in both treatment groups.Ef?cacy in hospitalised patients with more severe illness[pneumonia severity index(PSI) class IV and V]
In the multicenter randomised MOxi?oxacin Treat-ment IV(MOTIV)study,748hospitalised patients with CAP requiring hospitalisation(PSI classes III, IV,or V,10%ICU patients)were randomised to either IV?PO moxi?oxacin400mg?day or the com-bination of IV ceftriaxone2g?day plus IV levo?oxa-cin500mg every12h for7–14days(29,30). Patients were strati?ed by PSI scores to either class III or classes IV–V.The primary end-point was the clinical cure at the TOC visit,which was4–14days after the?nal antibiotic dose.Of the total patient population,336(59%)were in PSI classes IV–V.The overall cure rates at TOC were similar in both groups:86.9%for moxi?oxacin and89.9%for the combination of ceftriaxone plus levo?oxacin(95% CI,)8.1–2.2%).Similar results also were obtained for both treatment groups in the subsets of patients with CAP in PSI class IV or V,CAP because of S.pneumoniae and CAP with bacteremia.For patients with PSI class IV or V,the cure rates were 84.6%for moxi?oxacin and86.8%for the ceftriax-one plus levo?oxacin group(95%CI,)8.8–6.0%). The clinical success rate for pneumococcal pneumo-nia was90%in the moxi?oxacin group and87%in the comparator group.Each treatment achieved a 75%clinical success rate in patients with bacteremia (31).Overall bacteriological success rates were83% for moxi?oxacin and85%for the comparator.AE pro?les were similar for treatment groups in the MOTIV study as well.The exception was the?nding of QT prolongation in3.5%of patients treated with moxi?oxacin,although there was no evidence of any clinical proarrhythmic effect for moxi?oxacin,even in this high-risk population(29).
In a randomised,open-label,multicenter study, oral gemi?oxacin320mg once daily was also shown to have similar clinical ef?cacy and tolerability in the treatment of patients hospitalised with moderate to severe CAP in PSI classes IV and V,compared with IV ceftriaxone followed by oral cefuroxime(with or without a macrolide)(32).
Speed of resolution
The use of respiratory FQs may have advantages that go beyond clinical cure.In an in vitro pharmaco-dynamic study,moxi?oxacin400mg proved to resolve infections faster than levo?oxacin;moxi?oxa-cin eradicated most strains of S.pneumoniae within 8h of the?rst dose,but levo?oxacin required an additional4–5h to achieve a99.9%kill of two strains(17).
Fluoroquinolones in the management of community-acquired pneumonia381a2010Blackwell Publishing Ltd Int J Clin Pract,February2010,64,3,378–388
Moxi?oxacin also achieved faster clinical resolu-tion in CAP compared with standard therapy.In the MOXIRAPID study,a controlled,multicenter,inter-national,randomised,prospective,open-label clinical trial,397patients with CAP were randomised to sequential IV?PO moxi?oxacin400mg once daily or ceftriaxone2g IV once daily,with or without eryth-romycin1g IV every6–8h for7–14days.The pri-mary end-point was the clinical response at the TOC visit5–21days after the study therapy was com-pleted.The investigators found that moxi?oxacin monotherapy resolved fever signi?cantly faster (3.0days vs.4.0days;p<0.003)than high-dose cef-triaxone with or without erythromycin.Clinical response data were available for317patients at the TOC visit;a clinical cure was achieved in138?161 (85.7%)patients in the moxi?oxacin group and 135?156(86.5%)in the ceftriaxone group(p>0.1; 95%CI,)7.9–7.1%),demonstrating equivalence for the two regimens(33).
These results suggest that FQ therapy may mini-mise the physical inconveniences associated with IV therapy while in the hospital,lead to earlier patient discharge(mean duration of hospitalisation,9days vs.11days in moxi?oxacin and comparator groups),improve patient treatment compliance (rates of continued clinical resolution,85.7%vs.
86.5%in moxi?oxacin and comparator groups)and result in cost savings(33).Faster hospital discharge rates as observed in MOXIRAPID may result in substantial savings as well as improvement in patient’s quality of https://www.doczj.com/doc/ee18077423.html,e of such agents has shown promise even in patients with pneumonia who have had prior antibiotic therapy and treat-ment failure.In63patients admitted to the hospital after failure of primary outpatient therapy for CAP, treatment with moxi?oxacin resulted in shorter duration of hospitalisation and much lower clinical failure rates and28-day failure rates than standard therapy(Figure1)(34).
The CAPRIE study also provided data on time to response.At days3–5,signi?cantly more patients had rapid clinical improvement or resolution of pneumonia with moxi?oxacin than with levo?oxacin (97.9%of patients receiving moxi?oxacin achieving clinical recovery at the visit between days3and5 compared with90.0%in the group receiving levo-?oxacin;95%CI,1.7–14.1;p=0.01)(28).
Finch et al.(35,36)explored the use of sequential IV and PO moxi?oxacin compared with sequential IV and PO amoxicillin?clavulanate with or without clarithromycin in628patients with CAP who received initial parenteral treatment.There were sig-ni?cantly more afebrile patients on day2in the moxi?oxacin monotherapy group.
The use of high-dose,short-course(5-day)levo-?oxacin was explored by Dunbar et al.(23)in a ran-domised,double-blind,active-treatment controlled study.Patients who had previously failed FQ therapy and those at high-risk of infection with P.aeruginosa were excluded from this study.The study showed that patients had an equivalent outcome[92.4%vs.91.1% (95%CI,)7.0–4.4)]but a more rapid response(as indicated by fever resolution)with a750-mg,5-day course of levo?oxacin than with a500-mg,10-day course.When defervescence was compared at day3of therapy,a signi?cantly greater number of patients showed improvement in the750-mg,5-day course group than in the500-mg,10-day course group (49.1%vs.38.5%;p=0.027).
382Fluoroquinolones in the management of community-acquired pneumonia
a2010Blackwell Publishing Ltd Int J Clin Pract,February2010,64,3,378–388
In another trial(the Finch study cited above), conducted in a hospitalised CAP population where moxi?oxacin400mg was compared with amoxicil-lin?clavulanate,58.6%of patients on moxi?oxacin therapy were reported to be apyretic on day2com-pared with46.7%of patients on the comparator reg-imen(p=0.008)(3,35).The more rapid resolution of fever observed in moxi?oxacin patients led to an earlier conversion from IV to PO therapy.Taken together,these studies suggest that the rapidity of fever resolution may be related to the degree of anti-pneumococcal activity of the FQ(Figure2).In addi-tion,the results of these studies suggest that a more rapid response to therapy is not only possible with a highly potent FQ but also may facilitate a shorter duration of therapy and be associated with an earlier switch from IV to PO therapy(3).
Resistance to FQs
Pneumococcal resistance is a serious concern in the treatment of CAP as S.pneumoniae is a leading cause of pneumonia.Resistance of S.pneumoniae to cur-rent antimicrobials is rising,but resistance to respira-tory FQs remains<1%worldwide and<2%in North America.Much higher rates have been reported in some countries(37–40).
Risk factors for resistance
A number of factors are known to predispose patients to infections with speci?c pathogens.Risk factors for infection with DRSP in patients with CAP include age>65years,b-lactam therapy within the past3months,alcoholism,the presence of multiple medical comorbidities,exposure to a child in daycare and immune system suppression from an illness or therapy such as corticosteroids(1).The likelihood that CAP is caused by enteric Gram-negative infec-tion is increased by cardiopulmonary disease,multi-ple medical comorbidities and recent antibiotic therapy.P.aeruginosa occurs more often in patients with malnutrition or structural lung disease,such as bronchiectasis,or in patients who have used corticos-teroids regularly(>10mg of prednisone per day)or broad-spectrum antibiotics for>10days within the past month(1).
A review of the literature reveals many published case reports of respiratory tract infections(RTIs) because of S.pneumoniae in which FQ treatment failure was associated with resistance(39).Fuller and Low(39)discussed cases of20patients who were treated for CAP;10were treated with levo?oxacin and?ve of these patients had received prior FQ ther-apy(all but one within the previous3months).Pre-treatment cultures,available for?ve patients,showed that resistant S.pneumoniae was present in two patients and resistance emerged during FQ therapy in the others.Strains that were resistant before therapy had parC and gyrA mutations,and strains were initially sensitive selected for these mutations during therapy.CAP guidelines recommend that patients previously treated with FQs within3months should not be prescribed the same agent(12). Vanderkooi et al.(40)performed a prospective cohort study using data from the Toronto Bacterial Infection Network,which includes3339patients of invasive pneumococcal infection.Among the563 patients in which patients received a prior course of antibiotics in the3months preceding invasive pneu-mococcal infection and the antimicrobial used was known,an association was found between pneu-mococcal resistance and the antibiotic previously used.This applied for penicillin,trimethoprim?sulfamethoxazole,macrolides and FQs(Table3) (40).A quinolone-resistant isolate(levo?oxacin was the only FQ studied)was more likely to be present if the patient was on corticosteroids[odds ratio(OR), 6.0;p=0.008],if the infection was nosocomial(OR, 5.8;p=0.009)or if the patient acquired the infec-tion while in a nursing home(OR,5.4;p<0.001) (40).
Factors to consider in antimicrobial selection The choice of antimicrobial therapy should be based on patient risk factors and likely pathogens,and treatment guidelines,such as those established by IDSA and ATS(12).If DRSP is a likely cause of CAP,therapy should be selected that will ensure ef?-cacy for organisms that may be resistant.Evidence indicates that the clinically relevant level of penicillin resistance is an MIC?4l g?ml,which is currently uncommon(12,41).Consideration of risk factors and selection of a therapy that provides coverage of likely pathogens is important not only to cure the current infection but also to manage resistance and prevent selection of further resistance among patho-gens in the community.Thus,in patients with risk factors for DRSP,a highly active antipneumococcal agent should be prescribed to minimise selection pressure for the emergence of resistant organisms (12).
Being able to predict and provide coverage for the most likely causative pathogens is essential.Evidence suggests that inappropriate initial therapy in CAP increases the rate of both morbidity and mortality (40).When selecting an FQ to treat CAP,agents with the greatest antipneumococcal activity and appropriate spectrum should be used to ensure ef?-cacy,avoid selection of resistance and avoid‘collat-eral damage’to the sensitivities of Gram-negative bacilli(42).For patients treated for CAP in the ICU,
Fluoroquinolones in the management of community-acquired pneumonia383a2010Blackwell Publishing Ltd Int J Clin Pract,February2010,64,3,378–388
consideration should be given to the increased potential for infection with drug-resistant isolates of usual CAP pathogens(e.g.,S.pneumoniae)and an increased risk of infection with hospital-acquired pathogens,such as Pseudomonas spp and MRSA.
An increasing concern in the management of CAP is pneumonia caused by MRSA,which is often rapidly progressive.Addition of vancomycin or linezolid to the empirical regimen is recommended if CA-MRSA is a consideration(12).While MRSA is a concern among patients in the ICU,CA-MRSA is becoming a growing concern among patients,espe-cially younger patients,following infections with in?uenza virus(12,43).The rising prevalence of CA-MRSA has been linked to in?uenza seasons (14,44)and addiction to drugs such as opiates(45). It is important to note that FQ monotherapy is not appropriate for severe(ICU-admitted)CAP, although results from one study do indicate that out-comes with levo?oxacin500mg IV twice daily are comparable with standard therapy in ICU patients with CAP,but the?ndings do not apply to those who have septic shock or are mechanically ventilated (46).
AE pro?le of FQs
The physiological effects of acute bacterial pneumo-nia stress the heart,demanding an increase in myocardial oxygen consumption and raising circulat-ing levels of in?ammatory cytokines(47).Patients with pneumonia caused by S.pneumoniae are at substantial risk of concurrent acute cardiac events, such as myocardial infarction,serious arrhythmia,or new-onset or worsening congestive heart failure(47). The CAPRIE study examined cardiac safety end-points in394patients?65years of age who were hospitalised for CAP and treated with either moxi?oxacin or levo?oxacin(48).A total of195 patients received moxi?oxacin and199received levo?oxacin,and the duration of antimicrobial therapy was9days for both groups.With the average age of patients in CAPRIE at78years and two-thirds of those in both groups older than75years,it is not surprising that most patients had a history of a cardiac disorder(72%for moxi?oxacin and76%for levo?oxacin).Abnormal Holter monitor?ndings were seen in8.3%of patients receiving moxi?oxacin and in5.1%of those receiving levo?oxacin(95%CI, )1.8–8.2;p=0.49).The majority of these?ndings were non-sustained ventricular tachycardia(VT). One patient in the moxi?oxacin group had multiple ectopic beat morphologies in an irregular run of slow VT,but not torsade de pointes,and one patient treated with levo?oxacin had an episode of torsade de pointes.These?ndings con?rm the lack of differ-ences in cardiac AEs between the two FQs.
Some clinicians have questioned whether?uroqui-olones can promote the emergence of C.dif?cile
Table3Multivariate analysis evaluating risk factors for antimicrobial resistance in cases of invasive pneumococcal disease(40)
Risk factor Penicillin-resistant
isolate
Ceftriaxone-resistant
isolate*
TMP-SMX-resistant
isolate
Erythromycin-resistant
isolate
Levo?oxacin-resistant
isolate
OR(95%CI)p OR(95%CI)p OR(95%CI)p OR(95%CI)p OR(95%CI)p
Year of infection 1.29(1.14–1.42)<0.001 1.20(1.04–1.39)0.01ns ns 1.11(1.04–1.96)0.002...ns Chronic organ system
disease
0.59(0.35–0.94)0.03...ns0.61(0.45–0.92)0.001...ns...ns
Drug use<3months before infection
Any penicillin 2.47(1.36–4.71)0.006…ns 1.71(1.06–2.77)0.03 1.77(1.07–2.94)0.03…ns TMP-SMX 5.97(2.71–13.2)<0.001…ns 4.73(2.73–8.23)<0.001 2.07(1.04–4.12)0.02…ns Azithromycin 2.79(0.99–7.96)0.05…ns 3.49(1.61–7.54)0.0019.93(4.95–20.3)<0.001…ns Clarithromycin…ns…ns…ns 3.93(2.16–7.16)<0.001…ns Fluoroquinolone…ns…ns…ns ns12.1(4.22–35.4)<0.001 Institution associated with acquisition
Nursing home…ns…ns…ns…ns12.9(3.95–43.9)<0.001 Hospital…ns…ns…ns…ns9.94(2.22–44.6)0.003
*In a multivariate analysis using non-susceptibility as the outcome,ceftriaxone non-susceptibility in infecting isolates was associated with date of culture,as well as with previous use of penicillin(OR,2.36;95%CI,1.30–4.38;p=0.005),TMP-SMX(OR,3.57;95%CI,1.81–7.92;p=0.002)and azithromycin(OR,2.94;95% CI,1.03–7.82;p=0.04).
Annual ORs are presented.
CI,con?dence interval;ns,not statistically signi?cant(p>0.05);OR,odds ratio;TMP-SMX,https://www.doczj.com/doc/ee18077423.html,ed,with permission,from data published in(40).
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colitis,and if so,whether speci?c agents are more likely to do this than others.Recent studies have suggested that quinolone use is only one risk factor,and that environmental and infection control factors are most important for controlling the spread of antibiotic-induced colitis (49).In addition,the CAP-RIE study showed than moxi?oxacin and levo?oxa-cin had similar risks for this complication,and current data support this ?nding,suggesting that the use of one quinolone rather than another is not likely to impact this complication (28,50).
Renal clearance
A single 400-mg dose of moxi?oxacin is used for both IV and PO for all indications,regardless of renal function status.For all other FQs,dosing must be adjusted in patients with decreased renal function (Table 4)(18–20,51).
In patients with a creatinine clearance of <50ml ?min,a dosage adjustment is required in patients prescribed levo?oxacin 500mg or 750mg after the initial levo?oxacin dose.For patients with a creatinine clearance of 20–49ml ?min,the levo?oxa-cin 500mg should be adjusted to 250mg every 24h,and the levo?oxacin 750mg should be adjusted to 750mg every 48h.For patients with a creatinine clearance of <19ml ?min (including those on dialy-sis),the levo?oxacin 500mg should be adjusted to 250mg every 48h,and the levo?oxacin 750mg should be adjusted to 500mg every 48h (19).Cip-
ro?oxacin dosage also should be adjusted in patients with creatinine clearance ￡50ml ?min (250–500mg q 12h at 30–50ml ?min,250–500mg q 18h at 5–29ml ?min and 250–500mg q 24h in patients on dialysis)(51).Gemi?oxacin should be prescribed as 160mg every 24h in patients with a creatinine clear-ance of ￡40ml ?min (20).
Additional factors affecting cap management
Current IDSA ?ATS CAP guidelines have been pub-lished (Table 2).Brie?y stated,for outpatient treat-ment in previously healthy patients with no risk factors for DRSP,a macrolide or doxycycline may be used.However,in the presence of comorbidities or recent use of an antibiotic,a respiratory FQ (gemi-?oxacin,levo?oxacin 750mg,or moxi?oxacin)is one option.Alternatively,a high-dose b -lactam plus a macrolide or doxycycline may also be used in these patients.For inpatients who receive non-ICU treat-ment,a respiratory FQ (IV levo?oxacin 750mg or moxi?oxacin)or a b -lactam plus a macrolide or doxycycline is the recommended treatment.Preferred b -lactam agents include cefotaxime,ceftriaxone and ampicillin ?sulbactam,but ertapenem may be consid-ered in selected patients.Cefepime,imipenem,meropenem and piperacillin ?tazobactam should be considered only if pseudomonal risks are present (12).For patients admitted to the ICU,a b -lactam plus either azithromycin or an FQ should be used.If Pseudomonas is suspected,an antipneumococcal,
Table 4Recommended dosage regimens for ?uoroquinolones in patients with renal impairment (18–20,49)
Renal function Recommended dosage
Cipro?oxacin Gemi?oxacin Levo?oxacin Moxi?oxacin Usual dosage
500mg q 12h*
750mg q 12h*
320mg q 24h
500mg q 24h
750mg q 24h
400mg q 24h
CL CR >50ml ?min 500mg q 12h 750mg q 12h No dosage adjustment required
CL CR 30–50ml ?min 250mg q 12h 500mg q 12h CL CR 5–29ml ?min 250mg q 18h 500mg q 18h
CL CR >40ml ?min 320mg q 24h CL CR ￡40ml ?min 160mg q 24h
CL CR 50–80ml ?min 500mg q 24h 750mg q 24h CL CR 20–49ml ?min 250mg q 24h 750mg q 48h CL CR 10–19ml ?min 250mg q 48h 500mg q 48h Hemodialysis 250mg q 24h 500mg q 24h 160mg q 24h
250
mg q 48h
500
mg q 48h
CAPD
*The recommended dosage for lower respiratory tract infection with mild ?moderate severity is 500mg and for severe ?complicated severity is 750mg. CAP of mild to moderate severity because of known or suspected S.pneumoniae ,Haemophilus in?uenzae ,Mycoplasma pneumoniae or Chlamydophilia
pneumonia e infection is recommended to use one 320-mg gemi?oxacin tablet daily for 5days;CAP because of known or suspected MDRSP,K.pneumoniae or M.catarrhalis infection,one 320-mg tablet daily for 7days.
CAP,community-acquired pneumonia;CAPD,chronic ambulatory peritoneal dialysis;CL CR ,creatinine clearance;FQ,?uoroquinolone;MDRSP,multidrug-resistant S.pneumoniae .Data from Ref.(18–20,49).
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antipseudomonal b-lactam(such as piperacillin-tazo-bactam,cefepime,imipenem or meropenem)and either cipro?oxacin or levo?oxacin(750mg)should be administered.Alternatively,these ICU-admitted patients can get the antipseudomonal b-lactam com-bined with an aminoglycoside plus either a macrolide or an antipneumococcal quinolone.Patients at risk for CA-MRSA also should receive either vancomycin or linezolid(12).As mentioned above,guidelines outside of North America are slightly different,based on data about local microbiology and the relative prevalence of MDRSP and atypical pathogens(13). Another consideration in the selection of a?uor-oquinolone is the cost of therapy.Among the respi-ratory?uoroquinolones,moxi?oxacin400mg provides a45.5%lower cost for the oral formulation, in many US markets(52).
Conclusions
The management of CAP is driven by several factors, including the patient’s medical history,the severity of symptoms,the presence of comorbid conditions, previous hospitalisations,previous antibiotic use and the potential for causative pathogens that may be resistant to commonly used antibiotics.In the outpa-tient,inpatient or ICU setting,selection of appropri-ate antibiotic therapy should cover the common pathogens seen in that particular environment.
FQs are widely used in the management of CAP and provide important treatment options as mono-therapy in non-ICU-hospitalised patients,in outpa-tients with comorbidities,in patients recently treated with antibiotics other than FQs and in cases of sus-pected DRSP.The use of FQs in combination with a b-lactam agent is recommended for treatment of CAP in the ICU.The high bioavailability of these agents provides a treatment option that could avoid hospitalisation in some‘borderline’patients by pro-viding a safe,effective and convenient outpatient reg-imen.FQs also can serve as reliable monotherapy in many non-ICU patients,including those with risk factors for DRSP,in both inpatient and outpatient settings.In hospitalised patients,the use of FQ is an alternative to more expensive and less convenient combination regimens,such as a b-lactam?macrolide combination.Furthermore,the availability of IV?PO doses provides convenient treatment options to enable earlier IV to PO switch and potentially earlier hospital discharge.
Recently published data on the ef?cacy and safety of FQs for the treatment of CAP expand our under-standing of their role.In the CAPRIE study,moxi-?oxacin400mg IV?PO provided a clinical response comparable with levo?oxacin500mg IV?PO,but demonstrated a signi?cantly faster clinical resolution at3–5days after therapy initiation.The MOXIRAPID study also demonstrated that moxi?oxacin had clini-cal cure rates comparable with a standard combina-tion regimen(ceftriaxone with or without erythromycin),but led to a signi?cantly faster fever resolution.To determine its utility in hospitalised CAP,the MOTIV study demonstrated that IV?PO moxi?oxacin400mg once daily provided ef?cacy comparable with the combination of IV ceftriaxone 2g qd plus IV?PO levo?oxacin500mg twice daily. This ef?cacy was demonstrated in patients with CAP in PSI classes IV and V,in cases of CAP with bacter-emia and in CAP because of S.pneumoniae.Few of these patients were in the ICU,however;therefore, the ability to use monotherapy in the ICU popula-tion remains uncertain.
By understanding the clinical implications of CAP-speci?c and FQ-speci?c differences in terms of pharmacokinetic?pharmacodynamic and clinical pro-?les,the management of CAP can be improved by the use of effective and rapid-acting agents,such as moxi?oxacin400mg or levo?oxacin750mg. Acknowledgements
The authors would like to acknowledge the edito-rial assistance of Ching-Ling Chen,PhD and Shab-ber Abbas in the preparation of this manuscript. Funding for this assistance was provided by Schering-Plough Corporation and this article fol-lowed from a round table discussion sponsored by Schering-Plough.The authors accept full responsi-bility for the construction and authorship of this manuscript.
Author contributions
All authors have contributed to concept?design,criti-cal revision of article and approval of article. References
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The way 的用法 Ⅰ常见用法： 1)the way+ that 2)the way + in which（最为正式的用法） 3)the way + 省略（最为自然的用法） 举例：I like the way in which he talks. I like the way that he talks. I like the way he talks. Ⅱ习惯用法： 在当代美国英语中，the way用作为副词的对格，“the way+ 从句”实际上相当于一个状语从句来修饰整个句子。 1)The way =as I am talking to you just the way I’d talk to my own child. He did not do it the way his friends did. Most fruits are naturally sweet and we can eat them just the way they are—all we have to do is to clean and peel them. 2）The way= according to the way/ judging from the way The way you answer the question, you are an excellent student. The way most people look at you, you’d think trash man is a monster. 3）The way =how/ how much No one can imagine the way he missed her. 4）The way =because
The way的用法及其含义（二） 二、the way在句中的语法作用 the way在句中可以作主语、宾语或表语： 1.作主语 The way you are doing it is completely crazy.你这个干法简直发疯。 The way she puts on that accent really irritates me. 她故意操那种口音的样子实在令我恼火。The way she behaved towards him was utterly ruthless. 她对待他真是无情至极。 Words are important, but the way a person stands, folds his or her arms or moves his or her hands can also give us information about his or her feelings. 言语固然重要,但人的站姿,抱臂的方式和手势也回告诉我们他(她)的情感。 2.作宾语 I hate the way she stared at me.我讨厌她盯我看的样子。 We like the way that her hair hangs down.我们喜欢她的头发笔直地垂下来。 You could tell she was foreign by the way she was dressed. 从她的穿著就可以看出她是外国人。 She could not hide her amusement at the way he was dancing. 她见他跳舞的姿势，忍俊不禁。 3.作表语 This is the way the accident happened.这就是事故如何发生的。 Believe it or not, that's the way it is. 信不信由你, 反正事情就是这样。 That's the way I look at it, too. 我也是这么想。 That was the way minority nationalities were treated in old China. 那就是少数民族在旧中
定冠词the的用法： 定冠词the与指示代词this ,that同源,有“那(这)个”的意思,但较弱,可以和一个名词连用,来表示某个或某些特定的人或东西. (1)特指双方都明白的人或物 Take the medicine.把药吃了. (2)上文提到过的人或事 He bought a house.他买了幢房子. I've been to the house.我去过那幢房子. (3)指世界上独一无二的事物 the sun ,the sky ,the moon, the earth (4)单数名词连用表示一类事物 the dollar 美元 the fox 狐狸 或与形容词或分词连用,表示一类人 the rich 富人 the living 生者 (5)用在序数词和形容词最高级,及形容词等前面 Where do you live?你住在哪? I live on the second floor.我住在二楼. That's the very thing I've been looking for.那正是我要找的东西. (6)与复数名词连用,指整个群体 They are the teachers of this school.(指全体教师) They are teachers of this school.(指部分教师) (7)表示所有,相当于物主代词,用在表示身体部位的名词前 She caught me by the arm.她抓住了我的手臂. (8)用在某些有普通名词构成的国家名称,机关团体,阶级等专有名词前 the People's Republic of China 中华人民共和国 the United States 美国 (9)用在表示乐器的名词前 She plays the piano.她会弹钢琴. (10)用在姓氏的复数名词之前,表示一家人 the Greens 格林一家人(或格林夫妇) (11)用在惯用语中 in the day, in the morning... the day before yesterday, the next morning... in the sky... in the dark... in the end... on the whole, by the way...
“tｈｅwａｙ+从句”结构的意义及用法 首先让我们来看下面这个句子: Ｒead the foｌloｗｉnｇpassagｅａnd talkａbout ｉt wi ｔh your classmaｔes．Try tｏｔeｌl whaｔyｏu thiｎk ｏf Tom aｎd ｏｆｔhe ｗay the chiｌｄrenｔrｅated ｈim. 在这个句子中，ｔhe waｙ是先行词,后面是省略了关系副词that或in whｉch的定语从句。 下面我们将叙述“the ｗaｙ+从句”结构的用法。 1.tｈe wａy之后，引导定语从句的关系词是tｈat而不是hoｗ,因此，<<现代英语惯用法词典＞＞中所给出的下面两个句子是错误的：Ｔhｉs is ｔｈeｗayｈowｉtｈａppened. This is the way how he ａlwａｙs treats me. 2．在正式语体中,thaｔ可被in which所代替;在非正式语体中，ｔhat则往往省略。由此我们得到theｗay后接定语从句时的三种模式：1) tｈe ｗaｙ＋ｔhａt-从句２）the way +ｉn whiｃh－从句3) the ｗay +从句 例如：Ｔｈe way(in whiｃh ，thａt) ｔhｅｓｅｃomｒade ｓloｏｋａｔｐrobｌems is wrong．这些同志看问题的方法
不对。 Ｔｈｅｗａy(that ,ｉn ｗhiｃh)yoｕ’ｒe doinｇit is comple ｔeｌy crａzy.你这么个干法,简直发疯。 Wｅａdmiｒｅd him for thｅｗay ｉｎｗhｉch he fａｃeｓdiｆficultieｓ． Waｌlａｃe ａｎd Ｄarwiｎｇreed ｏn the way ｉｎwhi ｃh ｄｉfｆｅrｅnt forms ｏf life had ｂegｕn.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 Thｉs is ｔｈe ｗaｙ（tｈａｔ) hｅdｉd it. I lｉkeｄｔhe waｙ(ｔhat) ｓｈeｏｒganized ｔhe ｍeetｉng． 3.theｗay(tｈat)有时可以与hｏw(作“如何”解）通用。例如： That’s tｈe ｗaｙ(tｈaｔ) shｅspoke. = Tｈat’s how shｅspoke.
表示“方式”、“方法”，注意以下用法： 1.表示用某种方法或按某种方式，通常用介词in(此介词有时可省略)。如： Do it (in) your own way. 按你自己的方法做吧。 Please do not talk (in) that way. 请不要那样说。 2.表示做某事的方式或方法，其后可接不定式或of doing sth。 如： It’s the best way of studying [to study] English. 这是学习英语的最好方法。 There are different ways to do [of doing] it. 做这事有不同的办法。 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句，但是其后的从句不能由how 来引导。如： 我不喜欢他说话的态度。 正：I don’t like the way he spoke. 正：I don’t like the way that he spoke. 正：I don’t like the way in which he spoke. 误：I don’t like the way how he spoke. 4.注意以下各句the way 的用法： That’s the way (=how) he spoke. 那就是他说话的方式。 Nobody else loves you the way(=as) I do. 没有人像我这样爱你。 The way (=According as) you are studying now, you won’tmake much progress. 根据你现在学习情况来看，你不会有多大的进步。 2007年陕西省高考英语中有这样一道单项填空题： ——I think he is taking an active part insocial work. ——I agree with you_____. A、in a way B、on the way C、by the way D、in the way 此题答案选A。要想弄清为什么选A，而不选其他几项，则要弄清选项中含way的四个短语的不同意义和用法，下面我们就对此作一归纳和小结。 一、in a way的用法 表示：在一定程度上，从某方面说。如： In a way he was right.在某种程度上他是对的。注：in a way也可说成in one way。 二、on the way的用法 1、表示：即将来(去)，就要来(去)。如： Spring is on the way.春天快到了。 I'd better be on my way soon.我最好还是快点儿走。 Radio forecasts said a sixth-grade wind was on the way.无线电预报说将有六级大风。 2、表示：在路上，在行进中。如： He stopped for breakfast on the way.他中途停下吃早点。 We had some good laughs on the way.我们在路上好好笑了一阵子。 3、表示：(婴儿)尚未出生。如： She has two children with another one on the way.她有两个孩子，现在还怀着一个。 She's got five children，and another one is on the way.她已经有5个孩子了，另一个又快生了。 三、by the way的用法
The way的用法及其含义（一） 有这样一个句子：In 1770 the room was completed the way she wanted. 1770年，这间琥珀屋按照她的要求完成了。 the way在句中的语法作用是什么？其意义如何？在阅读时，学生经常会碰到一些含有the way 的句子，如：No one knows the way he invented the machine. He did not do the experiment the way his teacher told him.等等。他们对the way 的用法和含义比较模糊。在这几个句子中，the way之后的部分都是定语从句。第一句的意思是，“没人知道他是怎样发明这台机器的。”the way的意思相当于how；第二句的意思是，“他没有按照老师说的那样做实验。”the way 的意思相当于as。在In 1770 the room was completed the way she wanted.这句话中，the way也是as的含义。随着现代英语的发展，the way的用法已越来越普遍了。下面，我们从the way的语法作用和意义等方面做一考查和分析： 一、the way作先行词，后接定语从句 以下3种表达都是正确的。例如：“我喜欢她笑的样子。” 1. the way+ in which +从句 I like the way in which she smiles. 2. the way+ that +从句 I like the way that she smiles. 3. the way + 从句(省略了in which或that) I like the way she smiles. 又如：“火灾如何发生的，有好几种说法。” 1. There were several theories about the way in which the fire started. 2. There were several theories about the way that the fire started.
way 的用法 【语境展示】 1. Now I’ll show you how to do the experiment in a different way. 下面我来演示如何用一种不同的方法做这个实验。 2. The teacher had a strange way to make his classes lively and interesting. 这位老师有种奇怪的办法让他的课生动有趣。 3. Can you tell me the best way of working out this problem? 你能告诉我算出这道题的最好方法吗？ 4. I don’t know the way (that / in which) he helped her out. 我不知道他用什么方法帮助她摆脱困境的。 5. The way (that / which) he talked about to solve the problem was difficult to understand. 他所谈到的解决这个问题的方法难以理解。 6. I don’t like the way that / which is being widely used for saving water. 我不喜欢这种正在被广泛使用的节水方法。 7. They did not do it the way we do now. 他们以前的做法和我们现在不一样。 【归纳总结】 ●way作“方法，方式”讲时，如表示“以……方式”，前面常加介词in。如例1； ●way作“方法，方式”讲时，其后可接不定式to do sth.，也可接of doing sth. 作定语，表示做某事的方法。如例2，例3；
t h e-w a y-的用法
The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.
way的用法总结大全 way的用法你知道多少，今天给大家带来way的用法，希望能够帮助到大家，下面就和大家分享，来欣赏一下吧。 way的用法总结大全 way的意思 n. 道路,方法,方向,某方面 adv. 远远地，大大地 way用法 way可以用作名词 way的基本意思是“路,道,街,径”,一般用来指具体的“路,道路”,也可指通向某地的“方向”“路线”或做某事所采用的手段,即“方式,方法”。way还可指“习俗,作风”“距离”“附近,周围”“某方面”等。 way作“方法,方式,手段”解时,前面常加介词in。如果way前有this, that等限定词,介词可省略,但如果放在句首,介词则不可省略。
way作“方式,方法”解时,其后可接of v -ing或to- v 作定语,也可接定语从句,引导从句的关系代词或关系副词常可省略。 way用作名词的用法例句 I am on my way to the grocery store.我正在去杂货店的路上。 We lost the way in the dark.我们在黑夜中迷路了。 He asked me the way to London.他问我去伦敦的路。 way可以用作副词 way用作副词时意思是“远远地,大大地”,通常指在程度或距离上有一定的差距。 way back表示“很久以前”。 way用作副词的用法例句 It seems like Im always way too busy with work.我工作总是太忙了。 His ideas were way ahead of his time.他的思想远远超越了他那个时代。 She finished the race way ahead of the other runners.她第一个跑到终点,远远领先于其他选手。 way用法例句
t h e_w a y的用法大全
The way 在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了 另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的
The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.
the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms. 从那天起,其他同学是夹着书本来上课,而他们却带着"失败"的思想负担来上课.
The way的用法及其含义（三） 三、the way的语义 1. the way=as（像） Please do it the way I’ve told you.请按照我告诉你的那样做。 I'm talking to you just the way I'd talk to a boy of my own.我和你说话就像和自己孩子说话一样。 Plant need water the way they need sun light. 植物需要水就像它们需要阳光一样。 2. the way=how（怎样，多么） No one can imagine the way he misses her.没人能够想象出他是多么想念她！ I want to find out the way a volcano has formed.我想弄清楚火山是怎样形成的。 He was filled with anger at the way he had been treated.他因遭受如此待遇而怒火满腔。That’s the way she speaks.她就是那样讲话的。 3. the way=according as （根据） The way you answer the questions, you must be an excellent student.从你回答问题来看，你一定是名优秀的学生。 The way most people look at you, you'd think a trash man was a monster.从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物。 The way I look at it, it’s not what you do that matters so much.依我看，重要的并不是你做什么。 I might have been his son the way he talked.根据他说话的样子，好像我是他的儿子一样。One would think these men owned the earth the way they behave.他们这样行动，人家竟会以为他们是地球的主人。
一．Way：“方式”、“方法” 1.表示用某种方法或按某种方式 Do it (in) your own way. Please do not talk (in) that way. 2.表示做某事的方式或方法 It’s the best way of studying [to study] English.。 There are different ways to do [of doing] it. 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句 正：I don’t like the way he spoke. I don’t like the way that he spoke. I don’t like the way in which he spoke.误：I don’t like the way how he spoke. 4. the way 的从句 That’s the way (=how) he spoke. I know where you are from by the way you pronounce my name. That was the way minority nationalities were treated in old China. Nobody else loves you the way(=as) I do. He did not do it the way his friend did. 二．固定搭配 1. In a/one way：In a way he was right. 2. In the way /get in one’s way I'm afraid your car is in the way， If you are not going to help，at least don't get in the way. You'll have to move－you're in my way. 3. in no way Theory can in no way be separated from practice. 4. On the way (to……) Let’s wait a few moments. He is on the way Spring is on the way. Radio forecasts said a sixth-grade wind was on the way. She has two children with another one on the way. 5. By the way By the way，do you know where Mary lives? 6. By way of Learn English by way of watching US TV series. 8. under way 1. Elbow one’s way He elbowed his way to the front of the queue. 2. shoulder one’s way 3. feel one‘s way 摸索着向前走；We couldn’t see anything in the cave, so we had to feel our way out 4. fight/force one’s way 突破。。。而前进The surrounded soldiers fought their way out. 5.. push/thrust one‘s way（在人群中）挤出一条路He pushed his way through the crowd. 6. wind one’s way 蜿蜒前进 7. lead the way 带路，领路；示范 8. lose one‘s way 迷失方向 9. clear the way 排除障碍，开路迷路 10. make one’s way 前进，行进The team slowly made their way through the jungle.
在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了 另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms.
“the way+从句”结构的意义及用法 首先让我们来看下面这个句子： Read the following passage and talk about it with your classmates. Try to tell what you think of Tom and of the way the children treated him. 在这个句子中，the way是先行词，后面是省略了关系副词that 或in which的定语从句。 下面我们将叙述“the way+从句”结构的用法。 1．the way之后，引导定语从句的关系词是that而不是how,因此，<<现代英语惯用法词典>>中所给出的下面两个句子是错误的：This is the way how it happened. This is the way how he always treats me. 2. 在正式语体中，that可被in which所代替；在非正式语体中，that则往往省略。由此我们得到the way后接定语从句时的三种模式：1) the way +that-从句2) the way +in which-从句3) the way +从句 例如：The way(in which ,that) these comrades look at problems is wrong.这些同志看问题的方法不对。
The way(that ,in which)you’re doing it is completely crazy.你这么个干法，简直发疯。 We admired him for the way in which he faces difficulties. Wallace and Darwin greed on the way in which different forms of life had begun.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 This is the way (that) he did it. I liked the way (that) she organized the meeting. 3.the way(that)有时可以与how(作“如何”解)通用。例如： That’s the way (that) she spoke. = That’s how she spoke. I should like to know the way/how you learned to master the fundamental technique within so short a time. 4．the way的其它用法：以上我们讲的都是用作先行词的the way，下面我们将叙述它的一些用法。
定冠词the的12种用法 定冠词the 的12 种用法，全知道?快来一起学习吧。下面就和大家分享，来欣赏一下吧。 定冠词the 的12 种用法，全知道? 定冠词the用在各种名词前面，目的是对这个名词做个记号，表示它的特指属性。所以在词汇表中，定冠词the 的词义是“这个，那个，这些，那些”，可见，the 即可以放在可数名词前，也可以修饰不可数名词，the 后面的名词可以是单数，也可以是复数。 定冠词的基本用法： (1) 表示对某人、某物进行特指，所谓的特指就是“不是别的，就是那个!”如： The girl with a red cap is Susan. 戴了个红帽子的女孩是苏珊。 (2) 一旦用到the，表示谈话的俩人都知道说的谁、说的啥。如：
The dog is sick. 狗狗病了。(双方都知道是哪一只狗) (3) 前面提到过的，后文又提到。如： There is a cat in the tree.Thecat is black. 树上有一只猫，猫是黑色的。 (4) 表示世界上唯一的事物。如： The Great Wall is a wonder.万里长城是个奇迹。(5) 方位名词前。如： thenorth of the Yangtze River 长江以北地区 (6) 在序数词和形容词最高级的前面。如： Who is the first?谁第一个? Sam is the tallest.山姆最高。 但是不能认为，最高级前必须加the，如： My best friend. 我最好的朋友。 (7) 在乐器前。如： play the flute 吹笛子
Way用法 A:I think you should phone Jenny and say sorry to her. B:_______. It was her fault. A. No way B. Not possible C. No chance D. Not at all 说明：正确答案是A. No way，意思是“别想！没门！决不！” 我认为你应该打电话给珍妮并向她道歉。 没门！这是她的错。 再看两个关于no way的例句： （1）Give up our tea break? NO way! 让我们放弃喝茶的休息时间？没门儿！ （2）No way will I go on working for that boss. 我决不再给那个老板干了。 way一词含义丰富，由它构成的短语用法也很灵活。为了便于同学们掌握和用好它，现结合实例将其用法归纳如下： 一、way的含义 1. 路线
He asked me the way to London. 他问我去伦敦的路。 We had to pick our way along the muddy track. 我们不得不在泥泞的小道上择路而行。 2. （沿某）方向 Look this way, please. 请往这边看。 Kindly step this way, ladies and gentlemen. 女士们、先生们，请这边走。 Look both ways before crossing the road. 过马路前向两边看一看。 Make sure that the sign is right way up. 一定要把符号的上下弄对。 3. 道、路、街，常用以构成复合词 a highway（公路），a waterway（水路），a railway（铁路），wayside（路边）
way/time的特殊用法 1、当先行词是way意思为”方式.方法”的时候,引导定语从句的关系词有下列3种形式： Way在从句中做宾语 The way that / which he explained to us is quite simple. Way在从句中做状语 The way t hat /in which he explained the sentence to us is quite simple. 2、当先行词是time时,若time表示次数时,应用关系代词that引导定语从句,that可以省略; 若time表示”一段时间”讲时,应用关系副词when或介词at/during + which引导定语从句 1.Is this factory _______ we visited last year? 2.Is this the factory-------we visited last year? A. where B in which C the one D which 3. This is the last time _________ I shall give you a lesson. A. when B that C which D in which 4.I don’t like the way ________ you laugh at her. A . that B on which C which D as 5.He didn’t understand the wa y ________ I worked out the problem. A which B in which C where D what 6.I could hardly remember how many times----I’ve failed. A that B which C in which D when 7.This is the second time--------the president has visited the country. A which B where C that D in which 8.This was at a time------there were no televisions, no computers or radios. A what B when C which D that