Advances in the Research and Development of Chemotherapeutic Agents for Respiratory Tract Bacterial Infections

Pulmonary Pharmacology & Therapeutics (2001) 14, 367–381

doi: 10.1006/pupt.2001.0302, available online at http://www.idealibrary.com.on

PULMONARYPHARMACOLOGY& THERAPEUTICS

Review

Advances in the Research and Development ofChemotherapeutic Agents for Respiratory Tract BacterialInfections

Mario Cazzola∗, Francesco Blasi†, Stefano Centanni†, Claudio Ferdinando Donner‡,Luigi Allegra†

∗A. Cardarelli Hospital, Department of Respiratory Medicine, Unit of Pneumology and Allergology,Naples, Italy, †University of Milan, Institute of Care and Research, Polyclinic Hospital,Institute of Respiratory Medicine, Milan, Italy, ‡S. Maugeri Foundation, Institute of Care and Research,Medical Centre of Rehabilitation, Unit of Pneumology, Veruno, Italy

SUMMARY: The activity of existing antibiotics is diminishing due to the increasing number of resistant strainsand by the increase of infections with naturally resistant microorganisms. New agents are urgently needed to meetthis challenge and the molecular strategies adopted for the discovery of these compounds must focus on minimizingthe emergence of future resistance to them. Novel compounds can be grouped on the basis of their mechanism of action:inhibitors of nucleic acid synthesis (fluoroquinolones), inhibitors of protein synthesis (ketolides, oxazolidinones,streptogramins, and glycylcyclines), inhibitors of peptidoglycan synthesis (�-lactams and glycopeptides), and agentsinterfering with membrane function (cationic peptides, and lipopeptides). Regarding the agents that are already inthe research and development pipeline, only the oxazolidinones, the cationic peptides and the lipopeptide antibioticscan be truly considered as structurally novel inhibitors because the other agents are analogues of existing compoundsthat have been in use for many years.

2001 Academic Press

KEY WORDS: Antimicrobial resistance, Cationic peptides, Fluoroquinolones, Glycopeptides, Glycylcyclines,Ketolides, Lipopeptides, Lower respiratory tract infections, Novel compounds, Oxazolidinones, Streptogramins,�-lactams.

INTRODUCTION Haemophilus influenzae are some important examplesthat are frequent in respiratory tract infections. Glyco-Over the past decade, the dramatic escalation in anti-

microbial resistance among common respiratory peptide intermediately susceptible S. aureus (GISA)and coagulase-negative staphylococci (CNS) are otherpathogens has begun to pose obstacles to antibiotic

choices. This is an important finding, as 67% of potential resistant respiratory pathogens.According to NNIS data, in 1975 the rate of MRSAantibiotic use in adults and 87% of that in children is

for the treatment of such infections.1 In particular, 70% was only 2.4%, but it has risen today to 29%, andsuch resistance is particularly acute in larger hospitalsof the oral antibiotic prescriptions in the community in

the top 10 markets are intended for treating res- (>500 beds).2 MRSA is resistant to aminoglycosides,often to fluoroquinolones, and indeed to all antibioticspiratory tract infections (Fig. 1). Methicillin-resistant

Staphylococcus aureus (MRSA), penicillin-resistant except the glycopeptides, although there are reportsthat some strains are becoming resistant to these. InStreptococcus pneumoniae (PRSP), and non-�-lac-

tamase producing ampicillin-resistant (BLNAR) fact, recently there have been reports of S. aureusclinical isolates with intermediate susceptibilities to

∗Author for correspondence: Dr M. Cazzola, Via del Parco, Margh-vancomycin (MIC=8 �g/ml) in Japan3 and the Unitederita 24, 80121 Napoli, Italy. Fax +39 081 7473331; E-mail:

[email protected] States.4

1094–5539/01/050367+15 $35.00/0 2001 Academic Press367

368 M. Cazzola et al

Enterobacter spp,20 Pseudomonas aeruginosa,21, andAcinetobacter baumannii.22 Epidemic and endemic in-fections caused by these multiple resistant strainsfollowed intense antibiotic use in many hospitals,particularly in intensive care units.18,23 In a recentEuropean hospital survey, 23% of isolates of Kleb-siellae were resistant to third generation ce-0

100

%

RTI UTI SSTI Other

102030405060708090

phalosporins by production of plasmid encodedFig. 1 Oral community antibiotics in the market by indication. extended spectrum �-lactamases.19 In many cases, epi-100%=$11.2 bn. Adapted from White.129

demic strains of these Gram-negative bacilli showedresistance to nearly all available antibacterial drugsand caused serious nosocomial infections – such as

Pneumococci were once among the most highly pneumonia and bacteraemia – which were associatedpenicillin-susceptible bacteria. However, reports of with increased mortality.22

multidrug-resistant strains have been published since Obviously, the activity of existing antibiotics isthe late 1970s. Currently, 30% to 44% of pneumococci diminishing due to the increasing number of resistantin the United States have an intermediate or high- strains and by the increase of infections with naturallygrade resistance to penicillin.5,6 Between various Euro- resistant microorganisms. This phenomenon has ledpean countries, there are remarkable differences in to the development of several new agents active againstprevalence of strains susceptible to penicillin. Euro- organisms resistant to earlier drug generations.24 Inpean rates of PRSP range from 50% or more in Spain the past 20 years the pharmaceutical industry hasand France to about 10% in the UK, Switzerland, and been relatively successful in containing problems dueGermany.7 Unfortunately, PRSP are often resistant to to single resistance determinants; however, the adventnon-�-lactam antibiotics, including macrolides, tetra- of multiple resistance mechanisms has severely limitedcyclines, chloramphenicol, and trimethoprim/sulfa-

the effective use of many major classes of drugs.methoxazole.8

Research strategies for the discovery of new anti-The worldwide prevalence of infections caused by

bacterial drugs are heavily influenced by the needpneumococci resistant to penicillin, macrolides, and

to discover and develop new agents active againstother antimicrobials has increased at an alarming ratemultidrug resistant organisms.25,26

during the past 2 decades. Multidrug-resistant (MDR)Two general strategies for the development of anti-strains of S. pneumoniae, first noted in South Africa,9

infectives have appeared in the past decade: the ‘broad-are now endemic in many countries.10–12 Currently, inspectrum’ antibiotic approach (e.g. carbapenems, ce-the United States, 9% to 25% of pneumococci arephalosporins, and fluoroquinolone antibacterials) andMDR.13 Risk factors for MDR include prior antibioticthe ‘narrow-spectrum’ antibiotic approach (e.g. theuse, extremes of age, and hospitalization.14 Alsoglycopeptides, lipopeptides, everninomicin, strep-patients with COPD are at high risk of acquiringtogramin, and oxazolidinone antibacterials). Bothmultidrug resistant pneumococci.15 Penicillin-resistantstrategies have provided the clinical community withstrains are feature in the vast majority of hospitalnew drugs for today’s most pressing infections. Butoutbreaks, whether presenting as clinically manifestphysicians cannot rest on their laurels, for it seemsinfection or a simple colonization.16

certain that the introduction of new antibacterialFor H. influenzae, the principal mechanism of re-agents will usher in a new generation of antimicrobialsistance is the production of �-lactamase enzyme.resistance factor(s).26

Isolates of BLNAR H. influenzae are generally veryThe screening of isolated biochemical targets anduncommon, with only Barcelona (Spain) consistently

intact bacteria using high-throughput technologies,associated with rates in excess of 1%. A nationalthe modifying of existing compound classes to createmulticentre surveillance study of antibiotic resistancemore powerful compounds capable of overcomingamong clinical isolates of H. influenzae in the Unitedpathogen resistance, and the introduction of com-States in 1994 and 1995 found 39 out of 1537 clinicalpletely new classes of antibiotics represent three areasisolates that were �-lactamase-negative but ampicillin-that have been partially exploited in the past andintermediate or -resistant and, even more surprisingly,continue to represent fertile fields for further in-17 �-lactamase-positive isolates that were resistant tovestigation. In addition, a number of investigators areco-amoxiclav.17

working to develop inhibitors of new bacterial targetsMultiple antibiotic resistance to useful classes ofand to develop inhibitors of genes relating to virulenceantibiotics, including penicillins, cephalosporins,or pathogenesis.27aminoglycosides, and fluoroquinolones, has gradually

Chopra28 has grouped the various antibacterialincreased among a number of Gram-negative hospitalpathogens, especially Klebsiella pneumoniae18,19 agents on the basis of their mechanism of action:

New antibiotics and LRTIs 369

Table 1 Classification of antibacterial agents on the basis of The newer compounds are characterized by in-their mechanism of action.

creasing structural novelty and complexity. The N-1Inhibitors of nucleic acid synthesis cyclopropyl group, which was originally described

1. Fluoroquinolones for ciprofloxacin, remains one of the most effective2. Nitroimidazoles

characteristics for providing broad-spectrum activity3. Rifamycinsagainst aerobic organisms. Enhanced bactericidal ac-Inhibitors of protein synthesistivity against S. pneumoniae has been attributed to1. Aminoglycosides

2. Macrolides the presence of a 2,4-difluorophenyl moiety at the N-3. Tetracyclines 1 position in an investigational series of compounds.294. Ketolides

Additional studies have shown that target specificity5. Oxazolidinones6. Streptogramins in S. pneumoniae could be altered by adding a variety7. Glycylcyclines of benzenesulfonamide groups at the C-7 position of

Inhibitors of peptidoglycan synthesis ciprofloxacin, resulting in lower MIC values and a shift1. �-lactams (cephalosporins and arbacephalosporins,

in preferential inhibition of DNA gyrase compared tocarbapenems, trinem antibiotics)topoisomerase IV.30 However, at this time, none of2. Glycopeptides

the compounds based on the modifications describedAgents interfering with membrane function1. Cationic peptides above appear to be viable clinical candidates.2. Lipopeptides Compounds containing a combination of N-1 cy-

Other agents clopropyl with C8-methoxyl group are particularlylethal, and incubation of wild-type cultures on agarcontaining C8-methoxyl fluoroquinolones producesno resistant mutant, whereas thousands arise during

inhibitors of nucleic acid synthesis, inhibitors of pro- comparable treatment with control compounds lack-tein synthesis, inhibitors of peptidoglycan synthesis, ing the C8 substituent.31 Moxifloxacin, gatifloxacin,and agents interfering with membrane function. This and clinafloxacin are three new quinolones.subdivision is simple and allows a rational description Moxifloxacin is a new 8-methoxy-fluoroquinoloneof new compounds (Table 1). with broad-spectrum Gram-positive and Gram-neg-

ative activity, launched in 2000. The MIC50/MIC90

values for moxifloxacin are lower than those for otherINHIBITORS OF NUCLEIC ACID SYNTHESIS quinolones (moxifloxacin, 0.06/0.125 �g/ml; cipro-

floxacin 0.25/1 �g/ml; ofloxacin 1/2 �g/ml; sparfloxacinMany clinically useful antibacterial agents that target 0.25/0.5 �g/ml).32 Its activity is unaffected by resistancesteps in DNA or RNA synthesis have already been or susceptibility to penicillin or to other antimicrobialdeveloped. These include the fluoroquinolones (in- agents.32 Moxifloxacin is also active against mosthibiting enzymic processes in DNA synthesis), the S. aureus isolates tested (MIC90=1 �g/ml for cipro-nitroimidazoles (introducing DNA strand breakage) floxacin-resistant isolates) and is little influencedand rifamycins (inhibiting DNA-dependent RNA by known mutations in the grl and gyr loci.33 This ispolymerase). Recently, there have been further ad- an important finding because quinolone resistancevances in the research and development of each drug determinants seem essentially chromosome encoded.34

class, but fluoroquinolones are at present the most In Gram-negative bacteria, the gyrase protein is thepromising class. major target for mutations, in particular the gyrA

subunit. In addition, mutations for the topoisomeraseIV can further increase the level of resistance. InFluoroquinolonesGram-positive bacteria, the inverse situation is often

The primary target of most Gram-negative pathogens observed with topoisomerase IV being the primaryis the bacterial gyrase, which is encoded by gyrA and target. At a concentration of eight times the MIC,gyrB genes, but in many Gram-positive bacteria, the the frequency of spontaneous resistance ranged fromprimary target appears to be the corresponding sub- 2.5×10−7 to <4×10−8.33 Integration of phar-unit of topoisomerase IV encoded by parC and parE macokinetics and antibacterial activity of mox-genes (or grlA and grlB for S. aureus). Targeting both ifloxacin in in vitro and in vivo pharmacodynamicGyrA and topoisomerase IV with about the same models established that this compound was highlyactivity is the strategy behind the development of a effective against both Gram-negative and Gram-posi-new generation of fluoroquinolones. The existence of tive bacteria, particularly against causative pathogenstwo targets and stepwise accumulation of resistance of respiratory tract.35 Moxifloxacin’s in vitro activityimplies that these new fluoroquinolones would require translates into potent in vivo efficacy in multiplecells to obtain two topoisomerase mutations before animal infection models. Moxifloxacin is efficacious

in murine infection models of both typical and atypicalthey can display resistance.


respiratory infections, and experimental lung inthat bacterial protein synthesis is a suitable target fordrug intervention. Recently, there has been con-fections in guinea-pigs and mice, treating Mycoplasma

pneumoniae, Chlamydia pneumoniae, Legionella pneu- siderable progress in the discovery and developmentof new protein synthesis inhibitors which has focusedmophila and S. pneumoniae36

Gatifloxacin, a novel 6-fluoro-8-methoxy quinolone on other drug classes: ketolides, oxazolidinones, strep-togramins, and glycylcyclines.launched at the end of 1999, and clinafloxacin, another

novel C-8-substituted fluoroquinolone, have beenshown active against multi-resistant Gram-positive Ketolidesspecies.37 In particular, gatifloxacin has greater activity

Ketolides are semi-synthetic derivatives of the 14-against quinolone-resistant S. pneumoniae, selectedmembered ring macrolides, in which a keto group atGram-negative quinolone-resistant strains and quin-position 3 of the ring system replaces the L-cladinoseolone-resistant S. aureus.36

moiety, which appears necessary for the induction ofIt has been suggested that moxifloxacin, ga-MLSB resistance phenotype. Further modifications oftifloxacin, and clinafloxacin are more active than ci-the macrolactone backbone have led to the de-profloxacin against Gram-positive cocci, probablyvelopment of three different series of 9-oxime, 11,12-because they carry an azabicyclo (moxifloxacin), 3-carbamate, and 11, 12-hydrazonocarbamate ketolides.amino-pyrrolidinyl (clinafloxacin) or 3-methyl-piper-The aromatic rings of these compounds could allowazinyl (gatifloxacin) moiety at position C-7.38

tighter ribosomial subunit binding by intercalation ofGemifloxacin and sitafloxacin are two novelthe aromatic ring into stacked RNA bases, or byfluoroquinolones under development. Gemifloxacin isshared hydrogen binding to the aromatic amino acidhighly potent against Streptococcus spp. and retainsresidue in ribosomal proteins. They increase the drug’shigh activity against strains of S. pneumoniae resistantbinding to the 50S ribosome subunit 6- to 7-times thatto ciprofloxacin.39 Gemifloxacin’s potent Gram-posi-of clarithromycin and 10-times that of erythromycin.tive activity is superior to trovafloxacin, grepafloxacin,Ketolides are very active against penicillin/ery-and sparfloxacin36. Against most members of the fam-thromycin-resistant pneumococci and non-inducers ofily Enterobacteriaceae, with the exception of Proteusmacrolide-lincosamide-streptogramin B (MLSB) re-mirabilis, it is more active than moxifloxacin andsistance in staphylococci and streptococci.46displays nearly identical activity to ciprofloxacin.40

The 11,12-substituted ketolide (HMR 3004) dem-Moreover, gemifloxacin shows greatly improved po-onstrates a potent activity against multiresistant pneu-tency against Chlamydia species compared to ci-mococci associated with a well-balanced activityprofloxacin and either ofloxacin or levofloxacin.41 Theagainst all bacteria involved in respiratory infectionsactivity of sitafloxacin compares favourably with thatincluding H. influenzae, M. catarrhalis, group A strep-of levofloxacin, trovafloxacin, clinafloxacin, ga-tococci, and atypical bacteria. In addition, HMR 3004tifloxacin, and moxifloxacin against clinically im-displays high therapeutic activity in animals infectedportant Gram-negative pathogens42 and is superior toby all major strains, irrespective of their resistancethat of the other quinolones against Gram-positivephenotype.47 HMR 3647 (telithromycin) is anothercocci.43

ketolide. It is more active than HMR 3004 against S.All these new quinolones have similar phar-pneumoniae.48 In fact, it was found to be effectivemacokinetic features to many earlier fluoro-against pneumococci harbouring high level MLSBquinolones, including excellent oral bioavailability,resistance with MIC90 values being 0.06 �g/ml.49 Themoderate clearance and elimination half-lives, andcorresponding MIC90 value for other macrolides wasvolumes of distribution above 1.5 l/kg (Table 2).44

32 �g/ml. When compared with other macrolides, clin-Pazufloxacin (T-3761) is another new quinolonedamycin and pristinamycin, telithromycin selected forwhich is awaiting registration following successfulresistant mutants of S. pneumoniae less often afterclinical trials. However, although it is active againstserial in vitro passage than did the other drugs.50 Thea range of respiratory pathogens, including H. in-drug has favourable pharmacokinetics following oralfluenzae, Moraxella catarrhalis and Legionella species,administration (Table 3). It is well absorbed, achievesits activity against pneumococci seems no better thangood plasma levels and is highly concentrated inthat of ciprofloxacin, which may put it at a dis-pulmonary tissues.51advantage relative to the other new quinolones.45

ABT-773 is a novel 11,12 carbamate, 6-O alkylarylketolide derived from erythromycin A. Its activity has

INHIBITORS OF PROTEIN SYNTHESIS been attributed to its increased binding affinity toribosomes, reported to be up to 100-fold greater (lower

The discovery and development of clinically useful Ki) than erythromycin A.52 It is more potent in vitroantibiotic classes such as the aminoglycosides, ma- than erythromycin and ciprofloxacin against My-

coplasma pneumoniae and susceptible and MDR S.crolides, and tetracyclines have clearly demonstrated


Table 2 Comparative pharmacokinetics and in vitro activity of novel fluoroquinolones against S. pneumoniae.

Agent Oral dose AUC0-24 Cmax S. pneumoniae(mg) (mg/l perh) (mg/l) MIC90 (mg/l)

Clinafloxacin 200 bd 45 2.8 0.06Moxifloxacin 400 od 34 3.2 0.12Gatifloxacin 400 od 30 3.4 0.5Gemifloxacin 600 od 24.4 3.8 0.03

Table 3 Pharmacokinetics of multiple dose (800 mg) community-acquired pneumonia requiring hos-telithromycin. Adapted from Yassin and Dever.51

pitalization, linezolid was effective also when theyParameter Median value were bacteraemic. Moreover, linezolid and van-

comycin were equivalent in the treatment of hos-Cmax 2.27 mg/l

pitalized patients with nosocomial pneumonia.58Tmax 1.0 hAUC(0-24) 12.5 mg(h)/l The oxazolidinones possess a unique mechanismRenal clearance (0–24) 12.5 l/h of bacterial protein synthesis inhibition.59 Cell-freeTerminal t1/2 9.81 h

transcription/translation systems from Escherichia coliwere used to demonstrate that the activity of the drugsas inhibitors of translation decreased as the amount ofmRNA (phage MS2 RNA) in the assay was increased.pneumoniae.53 However, it has recently been observedThese data indicate that the mechanism of action ofthat macrolide-resistant strains of S. pneumoniae havethis class of drug involves interference with the bindinga wide range of ABT-773 values from 0.008 to 16 �g/of mRNA to the ribosomes at the initiation phase ofml.54

translation. In particular, they inhibit the formationSeveral other ketolides are reported to be under-of the initiation complex in bacterial translationgoing pre-clinical evaluations: A-184656, a 6-O-sub-systems by preventing formation of thestituited ketolide which displays good activity againstN-formylmethionyl-tRNA-ribosome-mRNA ternaryerythromycin A resistant S. aureus, Streptococcus py-complex.60 There is a uniform susceptibility in sensitiveogenes, and S. pneumoniae, but is inactive against H.bacteria independent of resistance to other antibiotics.influenzae, and A-241550, a haloketolide with a 2-Extremely rare resistance has been associated withfluorine substituent that slightly improves the in vivoamino acid substitutions in the 23S rRNA. The ox-efficacy and enhances the potency in H. influenzaeazolidinones have bacteriostatic activity against ainfections,55,56 together with the haloketolides TE-802number of important Gram-positive pathogens in-and TE-810, and CP-227182, a C-11,12 carbonyl ke-cluding MRSA and PRSP, although a bactericidaltolide active against S. pyogenes and S. pneumoniaeeffect has been described for strains of S. pneumoniae.resistant to erythromycin A, but inactive againstLinezolid is 2-fold more active than teicoplanin andMLSB strains.vancomycin against S. aureus.61 Neither the presenceof modifying enzymes (LinA, LinA′, LinB, Vgb, Vat,

Oxazolidinones SatA, ANT(4′) (4′′)-I, AAC(6′)-APH(2′′), APHA-3and Cat), nor the presence of an efflux mechanismDuPont researchers reported the first oxazolidinones(MsrA, MefE, MefA, MreA, Vga, TetK and TeL), norin 1987 that had limited activity against Myco-the modification or protection of antimicrobial targetbacterium tuberculosis.57 Introduction of the fluorine(because of ribosomal methylases or TetM and TetO )substituent endowed oxazolidinones with excellentaffect linezolid activity as demonstrated by similar inactivity against resistant Gram-positive cocci (Tablevitro activity against resistant isolates and sensitive4). The susceptibility of Gram-positive organisms tocontrol isolates.62oxazolidinones can be attributed to a lack of Gram-

The oxazolidinones are also active against the atyp-positive transmembrane pumps with an oxazolidinoneical bacteria. Both eperezolid and linezolid appearspecificity. The most advanced agents in this class,to be efficacious and well tolerated both orally andsuch as eperezolid (formerly U-100592) and linezolidparenterally at doses, which produce plasma con-(formerly U-100766), which is in Phase III US clinicalcentrations in excess of the levels predicted to betrials for evaluation in pneumonia and bacteremianecessary for efficacy.63 In particular, linezolid dem-with 80% clinical and microbiologic responses, are aonstrated 100% bioavailability after oral dosing.64 Innew chemical class of synthetic antibacterial agentsgeneral, linezolid produces a higher plasma con-unrelated to any agent presently marketed that arecentration profile for a given dose than eperezolid.active orally or intravenously against multidrug-

resistant Gram-positive bacteria. In patients with Additional advances have recently been made in


Table 4 In vitro activities of oxazolidinones against staphylococci and streptococci. Adapted from Zurenko et al.128

Organism Drug Weighted average

MIC50 (�g/ml) MIC90 (�g/ml)

S. aureus methicillin-sensitive Eperezolid 1.7 2.9Linezolid 2.9 2.9Vancomycin 0.6 0.8

S. aureus methicillin-resistant Eperezolid 2.3 2.3Linezolid 2.3 3.5Vancomycin 0.9 1.3

S. pneumoniae penicillin-sensitive Eperezolid 0.5 0.5Linezolid 0.5 1Vancomycin 0.13 0.25

S. pneumoniae penicillin-intermediate Eperezolid 0.3 0.3Linezolid 0.5 1Vancomycin 0.25 0.5

S. pneumoniae penicillin-resistant Eperezolid 0.38 0.5Linezolid 0.74 0.74Vancomycin 0.25 0.4

the oxazolidinone agents. The oxazolidones PNU- influenzae. The most characteristic aspect of this classof drugs is that there is no cross-resistance with107922, PNU-140457, PNU-172576 and PNU-176798

have been evaluated for their activity against Gram- macrolides or lincosamides, although these anti-microbials also inhibit protein synthesis at the ri-positive bacteria including MRSA and PRSP, H. in-

fluenzae and M. catarrhalis as well as for their aqueous bosomal level. Quinupristin/dalfopristin consists oftwo structurally unrelated compounds, group A (dal-solubility.65–67 Further modification of the ox-

azolidinone nucleus may yield agents with even greater fopristin) and group B (quinupristin). They inhibitbacterial growth by disrupting the translation ofpotency and with novel spectra of activity.mRNA into protein. In particular, attachment ofdalfopristin to the peptidyl transferase domain of 23S

StreptograminsrRNA in the bacterial 50S ribosomal subunit resultsin a conformational change which increases the ri-Streptogramin antibiotics have been developed for

the treatment of multi-drug-resistant Gram-positive bosome’s affinity for quinupristin.70 MICs of qui-nupristin/dalfopristin range from 0.20 to 1 �g/ml forbacterial infections and consist of two molecules which

are group A streptogramins (macrolactones) and S. pneumoniae and from 0.25 to 2 �g/ml for S. aureus,two of the principal target organisms of this drug.group B streptogramins (cyclic hexadepsipeptides).

The natural streptogramins are produced as mixtures Quinupristin/dalfopristin is also active against my-coplasmas, H. influenzae, Legionella species and M.of the group A and B compounds, the combination

of which is a more potent antibacterial agent than catarrhalis. It offers potentially promising activityagainst MRSA.either type of compound alone. Whereas the type A

or type B compound alone has, in vitro and in animalmodels of infection, a moderate bacteriostatic activity,

Glycylcyclinesthe combination of the two has strong bacteriostaticactivity and often bactericidal activity. The strep- A new class of tetracyclines, named glycylcyclines,

has been the subject of numerous reports.71 The gly-togramins are a class of antibiotics remarkable fortheir antibacterial activity and their unique mechanism cylcyclines are currently the only derivatives that ex-

hibit antibacterial activity comparable to that of theof action.68,69 These antibiotics are produced naturallyby Streptomyces species, but the therapeutic use of early tetracyclines when they were first introduced.

These compounds show potent activity against athe natural compounds is limited because they do notdissolve in water and parenteral forms have not been broad spectrum of Gram-positive and Gram-negative

bacteria, including strains that carry the two majoravailable. New semisynthetic derivatives, in particularthe injectable streptogramin quinupristin/dalfopristin, tetracycline-resistance determinants, efflux and ri-

bosomal protection. The spectrum of activity of thewhich are water-soluble derivatives, offer promise fortreating the rising number of infections that is caused N,N-dimethylglycylamido derivative of minocycline

(DGM-MINO) and 6-demethyl-6-deoxytetracyclineby multiple resistant bacteria. They act synergisticallyagainst not only multi-drug-resistant Gram-positive (DGM-DMDOT), two of the glycylcycline de-

rivatives, includes organisms with resistance to anti-strains but also other respiratory pathogens, includingM. catarrhalis, S. pneumoniae, S. pyogenes, and L. biotics other than tetracyclines, e.g. MRSA and PRSP.

They are not, however, active against species inherentpneumophila, and are somewhat less active against H.


resistance to tetracyclines such as Pseudomonas spe- Cephalosporins and carbacephalosporinscies. Using isogenic panels of bacteria carrying various

Cephalosporins and carbacephalosporins bearingtetracycline-resistance determinants, a series of morevarious thiazolylthio moieties at C-3 have been syn-than 300 analogues was tested for antibacterial ac-thesized which show both in vitro antibacterial activitytivity, which allowed for structure-activity re-against MRSA and high affinity for PBP-2′.76 RO-lationships to be determined. Results indicated that639141 and ME1209 (CP-6679), are the most prom-certain substituents at the 9 position of the tetracyclineising agents but they are still at the stage of pre-molecule restored activity against bacteria harbouringclinical evaluation and much more research is requiredgenes encoding either or both efflux and ribosomalbefore they might be used in the clinic. RO-639141, aprotection. A single chemical modification overcamepyrrolidinone-3-ylidenemethyl cephalosporin, inducesthe two molecularly distinct forms of resistance whilea potent inhibition of PBP-2′, which gives rise tomaintaining activity against susceptible Gram-posi-methicillin resistance in staphylococci, and penicillin-tive, Gram-negative, aerobic, and anaerobic bacteria.72

resistant pneumococci, through a high rate of acyl-The 9-t-butylglycylamido derivative of minocyclineation, a high affinity, and lower rate of deacylation,(GAR-936) exhibited similar activity against MRSAthus reversing all the factors that normally render thisand PRSP, with little or no resistance arising in targetprotein resistant to �-lactams.77 ME1209 (CP-6679), abacteria, and activity against a wide diversity of Gram-3′-quaternary ammonium cephem with a fluoromethylnegative aerobic and anaerobic bacteria, most ofresidue on the oxime group and an imidazothiazoliumwhich were less susceptible to tetracycline and mi-moiety at C-3 on the cephem nucleus, shows broad-nocycline.73 It shows better tolerability and activityspectrum activity that includes strains of MRSA andthan DMG-MINO and DMG-DMDOT.74 AlthoughP. aeruginosa.78,79

resistance to GAR-936 has not been seen in clinicalActually, a number of novel oral cephalosporinsisolate, GAR-936-resistant strains containing a muta-

have either been just launched or are in the late stagestion in tetA(B) (efflux-mediated resistance) were gen-of development. Orally active cephalosporins continueerated in the laboratory. However, the difficulty into be sought, with a few candidate compounds havingcreating the mutants which had only a slight reductionadvantages over the marketed third-generation oralin sensitivity, indicate that resistance may be slow tocephalosporins because of their broader antibacterialdevelop.75 The preliminary observation that GAR-936spectrum. FK041 currently in phase I trials, cefdinir,was active in vivo against lung infection due to P.cefprozil, cefcapene pivoxil, cefcanel daloxate hydro-aeruginosa (despite only modest in vitro activitychloride, currently in phase II trials, S-1090, currentlyagainst this pathogen) deserves further investigation,in phase III trials, closely resembling the group ofas it may offer a therapeutic option for patients withparenteral third-generation cephalosporins remain un-cystic fibrosis or infected with resistant strains of thisaffected by the normally occurring enzymes, althoughspecies.75

their antimicrobial activity is exactly identical.80 In anycase, these compounds show only slight improvementover existing therapies.

INHIBITORS OF PEPTIDOGLYCANSYNTHESIS Carbapenems

Carbapenems bearing various thiazolylthio moietiesDuring the past 50 years the development of agentsat C-2 also show potent in vitro and in vivo anti-that inhibit peptidoglycan synthesis has given rise to

a large number of valuable chemotherapeutic drugs MRSA activity and good affinity for PBP-2′, dem-that include the �-lactams, glycopeptides, fosfomycin onstrating that the thiazolylthio moiety has an im-and cycloserine. Research on this class of inhibitors portant role in improving the affinity for PBPO-2′continues and is currently focused on the �-lactams and consequently the anti-MRSA activity of theseand glycopeptides. Selected examples are discussed drugs.81 These agents may be useful in treatment ofbelow. infections caused by these two nosocomial pathogens.

On the basis of the available information, J-111,225 and S-4661 are the most promising parenteralcarbapenems for the treatment of respiratory tract

�-lactams infections. J-111,225 is a novel carbapenem activeagainst MRSA as well as Gram-positive and Gram-There are few �-lactams with the potential to overcomenegative organisms including MRSA and P. aeru-the recent issues associated with the development ofginosa81,82 (Table 6). Studies on the pharmacokineticbacterial resistance (Table 5) and consequently, useful

for the treatment of pulmonary infections. profile in rhesus monkeys showed better plasma levels,


Table 5 New �-lactams for respiratory tract infections.

Cephalosporins and carbacephalosporinsRO-639141 (active against MRSA and PRSP)ME1209 (CP-6679) (broad-spectrum activity, including strains of MRSA and P. aeruginosa)

CarbapenemsJ-111,225 (parenteral) (active against MRSA as well as Gram-positive and Gram-negative organisms including MRSA and

P. aeruginosa)S-4661 (parenteral) (broad-spectrum activity, including Gram-positive and -negative bacteria, including PRSP and drug-resistantP. aeruginosa)L-084 (oral) (extreme activity against pneumococci in vivo)

Trinem antibioticsSanfetrinem (broad spectrum of activity, including activity against PRSP)

Table 6 In vitro anti-MRSA activities of J-111225 in was well tolerated with no severe adverse effects ob-comparison to imipenem and vancomycin. Adapted from Di

served in healthy male volunteers.91 Also OCA-983Medugno and Felici.76

has good oral bioavailability and in vivo efficacyAntibacterial agent MIC90 (�g/ml) against Gram-positive and Gram-negative strains.

This compound is effective against a wide range ofJ-111225 4Imipenem 128 bacterial strains, including PRSP and �-lactamaseVancomycin 1 producing K. pneumoniae, but does not cover in-

fections caused by P. aeruginosa.91

combined with good activity against community- Trinem antibioticsacquired respiratory tract pathogens and a greater

Sanfetrinem is the first member of a new class ofstability to human dehydropeptidase (DHP)-1 com-tricyclic �-lactam compounds (trinems) to be de-pared to imipenem, indicating the potential of thisveloped. This compound and its orally bioavailablecompound for use as a single agent in the treatmentprodrug ester sanfetrinem cilexetil are currently inof respiratory bacterial infections in man.83 S-4661 isPhase II clinical trials.92 Sanfetrinem, that inhibits theanother attractive new 1�-methylcarbapenem for theactivity of PBP1a and PBP2b by 50% in PRSP,93

treatment of respiratory infections caused by Gram-exhibits stability to commonly encountered �-lac-positive and -negative bacteria, including PRSP andtamases and has a broad spectrum of antibacterialdrug-resistant P. aeruginosa.84 However, there areactivity, including activity against penicillin-resistantsome concerns due to the reportedly elevated levelsstrains of S. pneumoniae that do not produce �-of hepatic transaminases which were observed duringlactamase.93,94 Unlike many penems and carbapenemsphase II trials.85

(also members of the �-lactam class), sanfetrinem isFour new orally active carbapenems – L-084, whichstable to human dehydropeptidases.95 These propertiesis a pivalolyloxymethyl ester of the parenteral car-make it a promising agent for treating community-bapenem LJC 11,036 [L-036],86 OCA-983, a peptidoylacquired respiratory tract infections. The synthesis ofprodrug derivative of CL-191121,87 CS-834, the orallytwo new series of trinems has been reported. The firstactive prodrug of R-95867, and KR-21056, which isone is characterized by the presence of an exo-doublea (isopropyloxycarbonyloxy)ethyl ester of KR-bound at the C-4 position of the trinem ring system,21 01288 – are attractive new drugs (Table 7). L-substituted with an aromatic moiety. The second one084, in particular, exhibits extreme activity againstconsists of a pentacyclic �-lactam derivative. Bothpneumococci in vivo.86 Its active metabolite, LJCclasses are characterised by excellent in vitro anti-11 036, has showed high binding affinities for PBP1A,MRSA activities, as well as good stability to DHP-1.-1B, -2A/2X, -2B, and -3 of PRSP and for PBP1B,Moreover, their affinities for the altered PBP2 were-2, -3A, and -3B of H. influenzae.89 The MICs90s of LJCgood, i.e. 40- to 50-fold better than imipenem.91

11 036 against methicillin-susceptible staphylococci, S.pneumoniae including penicillin-resistant organisms,E. coli, K. pneumoniae, H. influenzae including am- Glycopeptidespicillin-resistant organisms, L. pneumophila, and M.

The emergence of high-level resistance to vancomycincatarrhalis are equal to or less than 1 �g/ml. In murinein the enterococci and the potential transfer of thisrespiratory infection models of penicillin-susceptibleresistance to other pathogenic Gram-positive cocciand -resistant S. pneumoniae and H. influenzae, therepresent threats to the chemotherapeutic applicationefficacies of L-084 were better than those of reference

drugs.90 A phase I clinical trial, showed that L-084 of this antibiotic.96 Two proteins (Van A and Van H)


Table 7 Characteristics of oral carbapenems currently under development. Adapted from Andreotti and Biondi.91

OCA-983 L-084 CS-834

Spectrum of activity Gram-positive and Gram- Gram-positive and Gram- Gram-positive and Gram-negativenegative organisms, including negative organisms, including organisms, including PRSP andPRSP, anaerobes and ESBL PRSP, anaerobes and ESBL ESBL producers. Poorly activeproducers. No anti- producers. No anti- against anaerobes Gram-negativePseudomonas or MRSA Pseudomonas or MRSA rods. No anti-Pseudomonas oractivity of clinical relevance activity of clinical relevance MRSA activity of clinical

relevance

Bioavailability No data are available 38% in rats No data are available

Clinical phase Preclinical Phase I Phase II

Side effects No data are available No severe adverse events Well tolerated. Reduction ofreported plasma carnitine levels due to the

trimethylacetyl moiety

Toxicity No data are available No data are available No renal toxicity in animalmodels

Potential dose No data are available 100–200 mg tid 150 mg tid

Indication Treatment of RTI and UTI Treatment of RTI and UTI Treatment of RTI and UTI

that are responsible for changing the pathway of in peptidoglycan biosynthesis. LY191145 has pooraffinity for binding D-Ala-D-Lac residues, but thepeptidoglycan synthesis to produce a modified pep-

tidoglycan structure in which the UDP-muramyl pen- combination of strong dimerization and membraneanchoring may be sufficient to facilitate intra-mo-tapeptide terminates with D-alanyl-D-lactate (D-Ala-

D-Lac) rather than the D-alanyl-D-alanine (D-Ala-D- lecular effects and effectively increase the bindingaffinities for peptidoglycan intermediates at the targetAla) unit found in vancomycin-susceptible strains.95,96

This substitution prevents binding of vancomycin to site in bacteria resistant to vancomycin.99

A new glycopeptide antibiotic, oritavancincell wall components, thereby allowing peptidoglycanpolymerisation to continue in the presence of the (LY333328), a semisynthetic N-alkyl derivative of

LY264826, a naturally occurring structural analogantibiotic.The therapeutic challenges posed by high-level van- of vancomycin, has improved in vitro activity over

vancomycin and teicoplanin against a range of Gram-comycin resistance have resulted in new glycopeptidedrug discovery programmes.95 The most rational ap- positive organisms, including MRSA.100 However, it

is not yet clear whether VISA strains are also hitproach to the chemical transformation of gly-copeptides involves the modification of the internal effectively or better by this new derivative, as com-

pared to vancomycin. BI 397 (derivative of A-40926)101‘binding pocket’ and the peripheral regions of themolecule that participate in the stabilization of the is in Phase I evaluation, while derivatives of te-

icoplanin and LY264826 (A82846B) are in pre-clinicalantibiotic-target complex. Novel semisynthetic drugsof this group with enhanced antibacterial activities are evaluation.now available. These new derivatives are particularlyinteresting because they do not appear to bind to theusual vancomycin target. Thus, they may have a AGENTS INTERFERING WITH MEMBRANE

FUNCTIONunique mechanism of action. The enhanced anti-bacterial activities of N-substituted derivatives of van-comycin derive from the nature of the hydrophobic Cationic peptidesside chain, which can have a marked effect on dimer-ization and membrane binding.97 It has been dem- Many species of life contain cationic antimicrobial

peptides as components of their immune systems.onstrated that vancomycin analogs containingmodified carbohydrates are effective against resistant The antimicrobial activity of these peptides has been

studied extensively, and many peptides have a broadbacteria because they interact directly with bacterialproteins involved in the transglycosylation step of cell spectrum of activity not only against Gram-negative

and Gram-positive bacteria but also against antibiotic-wall biosynthesis.98 The mechanism of action of theprototype compound LY191145 has been investigated. resistant bacteria, fungi, viruses, and parasites. Such

cationic antimicrobial peptides can also act in synergyLY191145 and other N-alkylated derivatives ofLY264826 interact with small D-Ala-D-Ala and D- with host molecules, such as other cationic peptides

and proteins, lysozyme, and also conventional anti-Ala-D-Lac containing residues of peptidoglycan in-termediates leading to inhibition of transglycosylation biotics, to kill microbes. It has been found that certain


peptides are produced in large quantities at sites of like defensins and magainins, but is structurally dis-tinct.108 A recombinant fragment of the cationic pro-infection/inflammation, and their expression can betein BPI (found in human neutrophils), rBPI21 hasinduced by bacterial products such as endotoxic lipo-completed a phase II clinical trial. It is effective inpolysaccharide (LPS) and proinflammatory cytokines,vitro against C. pneumoniae.109 In addition, rBPI21such as tumour necrosis factor-� (TNF-�). Thesedisplays high anti-endotoxic activity. Protegrins andpeptides often have a high affinity for bacterial prod-their derivatives are a new class of peptide antibioticsucts, such as LPS, allowing them to modulate thebased on mammalian antimicrobial peptides. Theirhost response and reduce the inflammatory responsepharmacological properties include an unusuallyin sepsis. More recently, they have been found tobroad spectrum of antimicrobial activity againstinteract directly with host cells to modulate the in-Gram-positive and Gram-negative bacteria, fungi andflammatory process and innate defences.102

some enveloped viruses. The protegrin IB-367 hasCurrently there is great interest in peptide anti-entered a phase I/II clinical trial as an aerosol for-biotics, especially the cationic peptides, some of whichmulation for respiratory infections in cystic fibrosisare derived from endogenous antimicrobial peptidespatients.109

of animals.103 Thousands of such molecules have beensynthesized and just a few are now entering clinicaltrials. One prominent class of cationic antibacterial Lipopeptidespeptides comprises the �-helical class, which is un-

Daptomycin, a unique cyclic lipopeptide antibiotic, isstructured in free solution but folds into an am-an antimicrobial agent with bactericidal activityphipathic �-helix upon insertion into the membranesagainst all clinically important Gram-positive bac-of target cells. Magainins, cecropins, and dermaseptinsteria, including resistant pathogens.110–113 It kills bac-are representatives of the amphipathic �-helical anti-teria by disrupting multiple aspects of bacterial plasmamicrobial peptides. A synthetic derivative of magainin,membrane function, including inhibition of pep-pexiganan acetate (MSI-78) has shown broad spec-tidoglycan synthesis, inhibition of lipoteichoic acidtrum activity.104

synthesis and dissipation of bacterial membrane po-Although the exact mechanism by which they killtential, while not penetrating into the cytoplasm.114,115

bacteria is not clearly understood, it has been shownThe MIC value for daptomycin against susceptiblethat peptide-lipid interactions leading to membranestrains is typically 4 times less than that of van-permeation play a role in their activity. In particular,comycin.110 Antibacterial activity against resistantcationic antibacterial peptides appear to form chan-strains is comparable to that against susceptible

nels in the bacterial cytoplasmic membrane; this leadsstrains.112 Daptomycin exhibits rapid, concentration-

to collapse of the transmembrane proton gradient,dependent bactericidal activity in vitro against Gram-

thereby affecting energy generation and transport pro- positive organisms.110 Development of resistance iscesses.105 It has been suggested that the major target unlikely when therapeutic serum levels of daptomycinfor the cationic peptides could be the cytoplasmic are maintained. This lipopeptide antibiotic exhibitsmembrane if the propensity to disrupt the membrane linear pharmacokinetics, minimal accumulation withis very high, but that for many peptides the lethal once daily dosing, and low plasma clearance andaction would occur in the bacterial cytoplasm.106 Se- volume of distribution.110 It is in Phase III studies forlectivity for bacterial cells compared to host cells the treatment of MRSA infections.appears to result from a variety of factors includingthe absence of cholesterol in bacterial membranes, thehigh content of anionic lipids at the surface of the OTHER AGENTSbacterial cytoplasmic membrane and differences inelectrochemical gradients across bacterial and mam- Attempts are currently under way to find novelmalian cell membranes. That these peptides vary with inhibitors of Class C serine �-lactamases or metallo-regard to their length, amino acid composition, and �-lactamases, to discover specific inhibitors of te-next positive charge, but act via a common mech- tracycline efflux systems, and to develop compoundsanism, may imply that other linear antimicrobial pep- that thwart the function of efflux pumps that leadtides that share the same properties also operated by to multiple resistance in organisms such as P.the same mechanism.107 aeruginosa and other bacteria.

Granulysin is a novel lytic molecule produced by A good approach to countering bacterial �-human cytolytic T-lymphocytes (CTLs) and natural lactamases is the delivery of a �-lactam antibiotickiller (NK) cells. It is active against a broad range in combination with a �-lactamase inhibitor. Severalof microbes, including Gram-positive and -negative such combinations are currently available, containingbacteria, parasites and Mycobacterium tuberculosis. It the inhibitors: clavulanic acid, sulbactam, and ta-

zobactam. However, these inhibitors are not activeis functionally related to other antibacterial peptides,


against Class C �-lactamases that are hyperproduced CONCLUSIONby some enterobacteria and Pseudomonas after

The emergence of antibiotic resistance has made theexposition to third and fourth generation ce-use of antimicrobials more complex. Probably thephalosporins. Moreover, genes for these enzymessingle most important approach for controlling thishave begun to escape to plasmids. Also the recentproblem is judicious use of chemotherapeutic agents.emergence of bacterial strains producing inhibitor-Physicians must recognize situations in which anti-resistant TEM (IRT) enzymes that could be relatedbiotics are not necessary. Only when therapy withto the frequent use of clavulanic acid, sulbactamthese agents becomes necessary should the physicianand tazobactam in hospitals and in general practicechoose the most appropriate drug and use the optimalis an important gap disadvantage.116 Consequently,dose and shortest appropriate duration of therapy.126there is a growing need for new broad-spectrum �-Careful use of the extended-spectrum agents in tar-lactamase inhibitors.geted patient populations should permit their long-Effective inhibition of Class C cephalosporinasesterm usefulness. However, although the rational useare to be found among the penems and mono-of antibiotics can limit the development of resistance,bactams, but none of these has yet proved suitableit is not sufficient to abate the resistant bacteria.for pharmaceutical development.117 BRL 42715, aTherefore, new drugs are designed with emergingnovel penem inhibitor, enhances the activity ofneeds in mind: specific resistant and hard-to-treatthe �-lactams against both Class C and Class Aorganisms. But the difficulty to find new drugs is aproducers.118 The penicillanic acid sulfone Ro 48-major problem.1271220 shows good activity against both Class A and

New antibiotic development has been plagued withClass C producing organisms at lower concentrationsdifficulties, including changing methods of clinicalthan tazobactam.119 Syn2190, a monobactam de-study and current demands for extensive pre-clinicalrivative containing 1,5-dihydroxy-4-pyridone as theand clinical documentation, excessive costs involvedC-3 side chain, is a potent inhibitor of Class Cin the development of a new chemical entity, poorenzymes, but generally poor inhibitor of Class Aperception of clinical studies, negative influences ofor D �-lactamases. The concentrations of inhibitorhealth insurance programs, deficient government pub-needed to reduce the initial rate of hydrolysis oflic policies regarding new drug approval, and thesubstrate by 50% for Syn2190 against Class Cineffective policies of pharmaceutical companies.127

enzymes were in the range of 0.002 to 0.01 mM.Therefore, it is probable that in the future we willThese values were 220- to 850-fold lower than thosehave only a few new drugs. While there is a needof tazobactam.120 Metallo-�-lactamases hydrolysefor continued development of novel antibiotics, thealmost all commercially available �-lactams. Severalgrowth of managed healthcare in the Western worldinhibitors of carbapenem-hydrolysing metallo-�-lac-is likely to have a significant impact on research andtamases such as LL-10G568�, J-111,225, some tri-development activities. This is especially the case forfluoromethyl alcohol and ketone derivatives of L-compounds showing slight improvement over existingand D-alanine, biphenyltetrazokes, and mer-therapies.captoacetic acid thiol esters, are under preclinical

Regarding the agents described here that are alreadystudy.76 A series of thioester derivatives has beenin the research and development pipeline, only theshown to competitively inhibit purified IMP-1oxazolidinones, the cationic peptides and the li-metallo-�-lactamase.121 As substrates for IMP-1, thepopeptide antibiotics can be truly considered as struc-thioesters yielded thiol hydrolysis products whichturally novel drugs because the other agents arethemselves were reversible competitive inhibitors.analogues of existing compounds that have been inRo 07-3149 inhibits the tetracycline efflux pumpuse for many years. However, only the clinical use ofwithout affecting the energy state, and exhibits verythese drugs will establish their real innovative role inlow antibacterial activity but shows weak synergythe treatment of respiratory infections.with tetracycline.122 The development of compounds

that thwart the function of efflux pumps that leadto multiple resistance in P. aeruginosa is a very

REFERENCESdifficult task because a tripartite efflux pump isnecessary for the efflux of all substrate antibiotics.123

1. Jacobs MR. Emergence of antibiotic resistance in upper andMoreover, the intrinsic resistance of P. aeruginosa lower respiratory tract infections. Am J Manag Care 1999;

5 (11 Suppl): S651–S661.to most of the �-lactams is due to the interplay of2. Emori TG, Gaynes RP. An overview to nosocomialboth chromosomal �-lactamase and the MexAB- infections, including the role of the microbiology

OprM efflux system.124 Bacterial efflux pump in- laboratory. Clin Microbiol Rev 1993; 6: 428–442.3. Hiramatsu K, Hanaki H, Ino T, Yabuta K, Oguri T,hibitors have been discovered, but their properties

Tenover FC. Methicillin-resistant Staphylococcus aureusas revealed to date are not sufficiently attractive to clinical strain with reduced vancomycin susceptibility. J

Antimicrob Chemother 1997; 40: 135–136.warrant development.125


4. Centers for Disease Control and Prevention. Reduced role of antimicrobials in the emergence of multiply resistantstrains. J Infect Dis 1994; 170: 377–383.susceptibility of Staphylococcus aureus to vancomycin –

Japan, 1996. Morbid Mortal Weekly Rep 1997; 46: 22. Towner KJ. Clinical importance and antibiotic resistance ofAcinetobacter spp. J Med Microbiol 1997; 46: 721–746.624–635.

5. Thornsberry C, Ogilvie P, Kahn J, Mauriz Y. Surveillance 23. Flaherty JP, Weinstein RA. Nosocomial infection caused byantibiotic-resistant organisms in the intensive-care unit.of antimicrobial resistance in Streptococcus pneumoniae,

Haemophilus influenzae, and Moraxella catarrhalis in the Infect Control Hosp Epidemiol 1996; 17: 236–248.24. Chopra I, Hodgson J, Metcalf B, Poste G. The search forUnited States in the 1996–1997 respiratory season. The

Laboratory Investigator Group. Diagn Microbiol Infect Dis antimicrobial agents effective against bacteria resistant tomultiple antibiotics. Antimicrob Agents Chemother 1997;1997; 29: 249–257.

6. Thornsberry C, Ogilvie PT, Holley HP Jr, Sahm DF. Survey 41: 497–503.25. Knowles DJC. New strategies for antibacterial drug design.of susceptibilities of Streptococcus pneumoniae, Haemophilus

influenzae, and Moraxella catarrhalis isolates to 26 Trends Microbiol 1997; 5: 379–383.26. Lee VJ, Miller GH, Yagisawa M. What’s new in theantimicrobial agents: a prospective US study. Antimicrob

Agents Chemother 1999; 43: 2612–2623. antibiotic pipeline. Curr Opin Microbiol 1999; 2: 475–482.27. Moellering RC Jr. Antibiotic resistance: lessons for the7. Schito GC. The European experience with antibiotic

resistance in respiratory pathogens. Infect Med 1999; 16: future. Clin Infect Dis 1998; 27 (Suppl 1): S135–S140.28. Chopra I. Research and development of antibacterial42–47.

8. Appelbaum PC. Emergence of resistance to antimicrobial agents. Curr Opin Microbiol 1998; 1: 495–501.29. Mitsuyama J. Structures of existing and new quinolonesagents in gram-positive bacteria – pneumococci. Drugs

1996; 51 (Suppl. 1): 1–5. and relationship to bactericidal activity againstStreptococcus pneumoniae. J Antimicrob Chemother 1999;9. Koornhof HJ, Wasas A, Klugman K. Antimicrobial

resistance in Streptococcus pneumoniae: a South African 44: 201–207.30. Alovero F, Pan X-S, Morris JE, Manzo RH, Fisher LM.perspective. Clin Infect Dis 1992; 15: 84–94.

10. Kam KM, Luey KY, Fung SM, Yiu PP, Harden TJ, Engineering the specificity of antibacterial fluoroquinolones:benzenesulfonamide modifications at C-7 of ciprofloxacinCheung MM. Emergence of multiple antibiotic-resistant

Streptococcus pneumoniae in Hong Kong. Antimicrob change its primary target in Streptococcus pneumoniae fromtopoisometase IV to gyrase. Antimicrob Agents ChemotherAgents Chemother 1995; 39: 2667–2670.

11. Geslin P, Buu-Hoi A, Fremaux A, Acar JF. Antimicrobial 2000; 44: 320–325.31. Schmitz FJ, Hofmann B, Hansen B, Scheuring S, Luckefahrresistance in Streptococcus pneumoniae: an epidemiological

survey in France, 1970–1990. Clin Infect Dis 1992; 15: M, Klootwijk M, Verhoef J, Fluit A, Heinz HP, Kohrer K,Jones ME. Relationship between ciprofloxacin, ofloxacin,95–98.

12. Song JH, Yang JW, Peck KR, Kim S, Lee NY, Jacobs MR, levofloxacin, sparfloxacin and moxifloxacin (BAY 12-8039)MICs and mutations in grlA, grlB, gyrA and gyrB in 116Appelbaum PC, Pai CH. Spread of multidrug-resistant

Streptococcus pneumoniae in South Korea. Clin Infect Dis unrelated clinical isolates of Staphylococcus aureus. JAntimicrob Chemother 1998; 41: 481–484.1997; 25: 747–749.

13. Doern GV, Pfaller MA, Kugler K, Freeman J, Jones RN. 32. Souli M, Wennersten CB, Eliopoulos GM. In vitro activityof BAY 12-8039, a new fluoroquinolone, against speciesPrevalence of antimicrobial resistance among respiratory

tract isolates of Streptococcus pneumoniae in North representative of respiratory tract pathogens. Int JAntimicrob Agents 1998; 10: 23–30.America: 1997 results from the SENTRY antimicrobial

surveillance program. Clin Infect Dis 1998; 27: 764–770. 33. Kayser FH, Santanam P, Huf E. In vitro activity ofmoxifloxacin against invasive pneumococcal strains14. Clavo-Sanchez AJ, Giron-Gonzalez JA, Lopez-Prieto D,

Canueto-Quintero J, Sanchez-Porto A, Vergara-Campos A, compared with other antimicrobials. In: Adam D, Finch R,eds. Moxifloxacin in practice. Vol 1. Oxford: MaximMarin-Casanova P, Cordoba-Dona JA. Multivariate

analysis of risk factors for infection due to penicillin- Medical, 1999, 39–47.34. Kohler T, Pechere JC. Bacterial resistance to quinolones.resistant and multidrug-resistant Streptococcus pneumoniae

a multicenter study. Clin Infect Dis 1997; 24: 1052–1059. Mechanisms and clinical implications. In: Andriole VT, ed.The quinolones. 2nd ed. San Diego: Academic Press, 1998,15. De Galan BE, van Tilburg PM, Sluijter M, Mol SJ, de

Groot R, Hermans PW, Jansz AR. Hospital-related 117–142.35. Dalhoff A. Pharmacodynamics of fluoroquinolones. Joutbreak of infection with multidrug-resistant Streptococcus

pneumoniae in the Netherlands. J Hosp Infect 1999; 42: Antimicrob Chemother 1999; 43 (Suppl B): 51–59.36. Kim OK, Barrett JF, Ohemeng K. Advances in DNA185–192.

16. Paradisi F, Corti G. Is Streptococcus pneumoniae a gyrase inhibitors. Exp Opin Invest Drugs 2001; 10:199–212.nosocomially acquired pathogen? Infect Control Hosp

Epidemiol 1998; 19: 578–580. 37. Blondeau JM. Expanded activity and utility of the newfluoroquinolones: a review. Clin Ther 1999; 21: 3–40.17. Doern GV, Brueggemann AB, Pierce G, Holley HP, Rauch

A. Antibiotic resistance among clinical isolates of 38. Bauernfeind A. Comparison of the antibacterial activities ofthe quinolones Bay 12-8039, gatifloxacin (AM 1155),Haemophilus influenzae in the United States in 1994 and

1995 and detection of �-lactamase-positive strains resistant trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin.J Antimicrob Chemother 1997; 40: 639–651.to amoxicillin-clavulanate: results of a national multicenter

surveillance study. Antimicrob Agents Chemother 1997; 41: 39. Jevons GM, Andrews JM, Wise R. The tentative BSACbreakpoint of gemifloxacin, a novel fluoroquinolone. J292–297.

18. Gold HS, Moellering RC. Antimicrobial-drug resistance. N Antimicrob Chemother 1999; 44 (Suppl A): 141.40. Grimm H, Grimm K, Machka K. In vitro activity ofEngl J Med 1996; 335: 1445–1443.

19. Livermore DM, Yuan M. Antibiotic resistance and gemifloxacin in comparison to ciprofloxacin, moxifloxacin,ofloxacin and trovafloxacin against Gram-positive andproduction of extended-spectrum �-lactamases amongst

Klebsiella species from intensive care units in Europe. J Gram-negative pathogens with reduced suscptibility againstciprofloxacin. Rev Esp Quimioterap 2000; 13 (Suppl 2): 10.Antimicrob Chemother 1996; 38: 409–424.

20. De Gheldre Y, Maes N, Rost F, De Ryck R, Clevenbergh P, 41. Felmingham D, Robbins MJ, Dencer C, Salman H,Mathias I, Rudgway GL. In vitro activity of gemifloxacinVincent JL, Struelens MJ. Molecular epidemiology of an

outbreak of multidrug-resistant Enterobacter aerogenes against S. pneumoniae, H. influenzae, M. catarrhalis, L.pneumophila and Chlamydia spp. J Antimicrob Chemotherinfections and in vivo emergence of imipenem resistance. J

Clin Microbiol 1997; 35: 152–160. 1999; 44 (Suppl A): 131.42. Milatovic D, Fluit A, Schmitz F-J, Verhoef J. In vitro21. Richard P, Le Floch R, Chamoux C, Pannier M, Espaze E,

Richet H. Pseudomonas aeruginosa outbreak in a burn unit: activity of sitafloxacin (DU-6859A) and six other


fluoroquinolones. Part I: Gram-negative aerobic bacteria. J 60. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL. TheAntimicrob Chemother 1999; 44 (Suppl A): 171. oxazolidinone linezolid inhibits initiation of protein

43. Milatovic D, Fluit A, Schmitz F-J, Verhoef J. In vitro synthesis in bacteria. Antimicrob Agents Chemother 1998;activity of sitafloxacin (DU-6859A) and six other 42: 3251–3255.fluoroquinolones. Part II: Gram-positive cocci. J 61. Dresser LD, Rybak MJ. The pharmacologic andAntimicrob Chemother 1999; 44 (Suppl A): 171. bacteriologic properties of oxazolidinones, a new class of

44. Turnidge J. Pharmacokinetic and pharmacodynamic profiles synthetic antimicrobials. Pharmacotherapy 1998; 18:of the new quinolones. J Antimicrob Chemother 1999; 44 456–462.(Suppl A): 27. 62. Fines M, Leclercq R. Activity of linezolid against Gram-

45. Johnson AP. Pazufloxacin. Curr Opin Invest Drugs 2000; 1: positive cocci possessing genes conferring resistance to52–57. protein synthesis inhibitors. J Antimicrob Chemother 2000;

46. Bonnefoy A, Girard AM, Agouridas C, Chantot JF. 45: 797–802.Ketolides lack inducibility properties of MLSB resistance 63. Jansz AR, Mouton JW. Multi-center in vitro evaluation ofphenotype. J Antimicrob Chemother 1997; 40: 85–90. linezolid compared with other antibiotics in The

47. Agouridas C, Denis A, Auger JM, Benedetti Y, Bonnefoy Netherlands. Clin Microbiol Infect 2000; 6 (Suppl 1): 86.A, Bretin F, Chantot JF, Dussarat A, Fromentin C, 64. Pawsey SD, Daley-Yates PT, Wajszczuk CP, et al. U-100766D’Ambrieres SG, Lachaud S, Laurin P, Le Martret O, safety, toleration and pharmacokinetics after oral andLoyau V, Tessot N. Synthesis and antibacterial activity of intravenous administration. In: Program and abstracts ofketolides (6-O-methyl-3-oxoerythromycin derivatives): a the 1st European Congress of Chemotherapy 1996; F151.new class of antibacterials highly potent against macrolide- 65. Hutchinson DK, Barbachyn MR, Hester JB, et al. Synthesisresistant and -susceptible respiratory pathogens. J Med and antibacterial activity of azolylphenyloxazolidinonesChem 1998; 41: 4080–4100. having nitrogen-bound five-membered heterocyclic rings. In:

48. Reinert RR, Bryskier A, Lutticken R. In vitro activities of Abstracts of the 38th Intersci Conf Antimicrob Agentsthe new ketolide antibiotics HMR 3004 and HMR 3647 Chemother 1998; F-137.against Streptococcus pneumoniae in Germany. Antimicrob 66. Glenn MJ, Allwine DA, Hutchinson DK, et al. SubstituentAgents Chemother 1998; 42: 1509–1511. effects on antibacterial activity of novel highly potent

49. Barry AL, Fuchs PC, Brown SD. Antipneumococcal nitrogen-bound azolylphenyl oxazolidiones. In: Abstracts ofactivities of a ketolide (HMR 3647), a streptogramin the 38th Intersci Conf Antimicrob Agents Chemother 1998;quinupristin-dalfopristin), a macrolide (erythromycin) and a F-138.lincosamide (clindamycin). Antimicrob Agents Chemother 67. Gadwood RC, Walker EA, Thomasco LM, et al. Synthesis1998; 42: 945–946. and antibacterial activity of azolylphenyl oxazolidinones

50. Davies TA, Dewasse BE, Jacobs MR, Appelbaum PC. In having carbon-bound 1,3-thiazolyl rings. In: Abstracts ofvitro development of resistance to telithromycin (HMR the 38th Intersci Conf Antimicrob Agents Chemother 1998;3647), four macrolides, clindamycin and pristinamycin in F-139.Streptococcus pneumoniae. Antimicrob Agents Chemother 68. Rubinstein E, Keller N. Future prospects and therapeutic2000; 44: 414–417. potential of streptogramins. Drugs 1996; 51 (Suppl 1):

51. Yassin HM, Dever LL. Telithromycin: a new ketolide 38–42.antimicrobial for treatment of respiratory tract infection. 69. Barriere JC, Berthaud N, Beyer D, Dutka-Malen S, ParisExp Opin Invest Drugs 2001; 10: 353–367. JM, Desnottes JF. Recent developments in streptogramin

52. Capobiano JO, Cao Z, Shortridge VD, Ma Z, Flamm RK, research. Curr Pharm Des 1998; 4: 155–180.Zheng P. Studies of the novel ketolide ABT-773. Transport, 70. Cocito C, Di Giambattista M, Nyssen E, Vannuffel P.binding to ribosomes and inhibition of protein synthesis of Inhibition of protein synthesis by streptogramins andStreptococcus pneumoniae. Antimicrob Agents Chemother related antibiotics. J Antimicrob Chemother 1997; 392000; 44: 1562–1567. (Suppl A): 7–13.

53. Nilius AM, Bui M, Almer L, et al. Comparison of the in 71. Sum PE, Sum FW, Projan SJ. Recent developments invitro activity of ABT-773, a novel antibacterial ketolide, tetracycline antibiotics. Curr Pharm Des 1998; 4: 119–132.with erythromycin and ciprofloxacin against respiratory72. Projan SJ. Preclinical pharmacology of GAR-936, a novelpathogens. J Antimicrob Chemother 1999; 44 (Suppl A):

glycylcycline antibacterial agent. Pharmacotherapy 2000;76.20: 219S–223S.54. Jorgensen JH, Crawford SA, McElmeel ML, Whitney CG.

73. Petersen PJ, Jacobus NV, Weiss WJ, Sum PE, Testa RT. InActivity of the ketolide ABT-773 against recent Northvitro and in vivo antibacterial activities of a novelAmerican isolates of Streptococcus pneumoniae. Clinglycylcycline, the 9-t-butylglycylamido derivative ofMicrobiol Infect 2000; 6 (Suppl 1): 85.minocycline (GAR-936). Antimicrob Agents Chemother55. Ma Z, Or YS, Clark R, et al. Synthesis and antibacterial1999; 43: 738–744.activity of 6-O-substituted ketolides. In: Abstracts of the

74. Sum PE, Petersen P. Synthesis and structure-activity38th Intersci Conf Antimicrob Agents Chemother 1998; F-relationship of novel glycylcycline derivatives leading to the126.discovery of GAR-936. Bioorg Med Chem Lett 1999; 9:56. Phan LT, Or YS, Chen Y, et al. 2-Substituted tricyclic1459–1462.ketolides: new antibacterial macrolides – synthesis and

75. Johnson AJ. GAR-936. Curr Opin Anti-infect Invest Drugsbiological activity. In: Abstracts of the 38th Intersci Conf2000; 2: 164–170.Antimicrob Agents Chemother 1998; F-127.

76. Di Modugno E, Felici A. The renewed challege of �-57. Slee AM, Wuonola MA, McRipley RJ, Zajac I, Zawadalactams to overcome bacterial resistance. Curr Opin Anti-MJ, Bartholomew PT, Gregory WA, Forbes M.Infect Investig Drugs 1999; 1: 26–39.Oxazolidinones, a new class of synthetic antibacterial

77. Page M, Bur D, Hebeisen P, et al. Inhibition of theagents: in vitro and in vivo activities of DuP 105 and DuPpenicillin-binding proteins of methicillin-resistant721. Antimicrob Agents Chemother 1987; 31: 1791–1797.Staphylococci by pyrrolidinone-3-ylidenemethyl cephems.58. Rubinstein E, Cammarata SK, Oliphant TH, WunderinkIn: Abstracts of the 38th Intersci Conf Antimicrob AgentsRG. Linezolid (PNU-100766) versus vancomycin in theChemother 1998; F-22.treatment of hospitalized patients with nosocomial

78. Ida T, Kurazono M, Yoshida T, et al. ME1209 (CP6679), apneumonia: a randomized, double-blind, multicenter study.new parenteral cephalosporin I. In vitro and in vivo activityClin Infect Dis 2001; 32: 402–412.against MRSA. In: Abstracts of the 38th Intersci Conf59. Shinabarger DL, Marotti KR, Murray RW, Lin AH,Antimicrob Agents Chemother 1998; F-12.Melchior EP, Swaney SM, Dunyak DS, Demyan WF,

79. Yoshida T, Ida I, Kurazono M, et al. ME1209 (CP6679), aBuysse JM. Mechanism of action of oxazolidinones: effectsnew parenteral cephalosporin II. In vitro and in vivoof linezolid and eperezolid on translation reactions.

Antimicrob Agents Chemother 1997; 41: 2132–2136. activity against Pseudomonas aeruginosa. In: Abstracts of


the 38th Intersci Conf Antimicrob Agents Chemother 1998; D-alanyl-D-alanine and D-alanyl-D-lactate residues.Antimicrob Agents Chemother 1997; 41: 66–71.F-11.

80. Cazzola M. Novel oral cephalosporins. Exp Opin Invest 100. Harland S, Tebbs SE, Elliott TS. Evaluation of the in-vitroactivity of the glycopeptide antibiotic LY333328 inDrugs 2000; 9; 237–243.

81. Adachi Y, Nagano R, Shibata K, Kato Y, Hashizume T, comparison with vancomycin and teicoplanin. J AntimicrobChemother 1998; 41: 273–276.Morishima H. In vitro activities if J-111,225, J-114,870, J-

114,871, novel carbapenems having potent activities against 101. Krivoy N. BI-937. Curr Opin Anti Infect Invest Drugs1999; 1: 120–124.MRSA and Pseudomonas aeruginosa. In: Abstracts of the

38th Intersci Conf Antimicrob Agents Chemother 1998; F- 102. Scott MG, Hancock RE. Cationic antimicrobial peptidesand their multifunctional role in the immune system. Crit54.

82. Andes D. J-111,225. Curr Opin Antiinfect Invest Drugs Rev Immunol 2000; 20: 407–431.103. Hancock RE, Chapple DS. Peptide antibiotics. Antimicrob1999; 1: 111–113.

83. Shibata K, Nagano R, Nagami K, et al. Studies on Agents Chemother 1999; 43: 1317–1323.104. Ge Y, MacDonald DL, Holroyd KJ, Thornsberry C, Wexlerpharmacokinetics and basic toxicity of novel trans-3,5-

disubstituted pyrrolidinylthio-1�-methylcarbapenem. In: H, Zasloff M. In vitro antibacterial properties of pexiganan,an analog of magainin. Antimicrob Agents ChemotherAbstracts of the 38th Intersci Conf Antimicrob Agents

Chemother 1998; F-53. 1999; 43: 782–788.105. Johansen C, Verheul A, Gram L, Gill T, Abee T.84. Tsuji M, Ishii Y, Ohno A, Miyazaki S, Yamaguchi K. In

vitro and in vivo antibacterial activities of S-4661, a new Protamine-induced permeabilization of cell envelopes ofGram-positive and Gram-negative bacteria. Appl Environcarbapenem. Antimicrob Agents Chemother 1998; 42:

94–99. Microbiol 1997; 63: 1155–1159.106. Hancock REW, Nair P. Cationic antimicrobial peptide85. Saito A, Inamatsu T, Shimada J. Clinical studies of S-4661,

new parenteral carbapenem antibiotic, in chronic antibiotics. Curr Opin Anti-infect Invest Drugs 2000; 2:140–144.respiratory tract infections. In: Abstracts of the 37th

Intersci Conf Antimicrob Agents Chemother 1997; F-219. 107. Oren Z, Shai Y. Mode of action of linear amphipathic ?-helical antimicrobial peptides. Biopolymers 1998; 47:86. Andes D. L-084. Curr Opin AntiInfect Invest Drugs 1999;

1: 101–103. 451–463.108. Krensky AM, Okada S, Clayberger C, Kumar J.87. Weiss WJ, Mikels SM, Petersen PJ, Jacobus NV, Bitha P,

Lin YI, Testa RT. In vivo activities of peptidic prodrugs of Granulysin: a novel antimicrobial. Exp Opin Investig Drugs2001; 10: 321–329.novel aminomethyl tetrahydrofuranyl-1�-

methylcarbapenems. Antimicrob Agents Chemother 1999; 109. Hancock REW, Nair P. Cationic antimicrobial peptideantibiotics. Curr Opin AntiInfect Invest Drugs 2000; 2:43: 460–464.

88. Morrissey I. KR-21,056. Curr Opin Anti-infect Invest 140–144.110. Tally FP, Zeckel M, Wasilewski MM, et al. Daptomycin: aDrugs 1999; 1: 108–110.

89. Hikida M, Itahashi K, Igarashi A, Shiba T, Kitamura M. novel agent for Gram-positive infections. Exp Opin InvestDrugs 1999; 8: 1223–1238.In vitro antibacterial activity of LJC 11,036, an active

metabolite of L-084, a new oral carbapenem antibiotic with 111. Jacobus NV, McDermott L, Lonks JR, Boyce JM,Snydman DR. In vitro activity of daptomycin againstpotent antipneumococcal activity. Antimicrob Agents

Chemother 1999; 43: 2010–2016. resistant Gram-positive pathogens. In: Abstracts of the 38thIntersci Conf Antimicrob Agents Chemother 1998; F-112.90. Miyazaki S, Hosoyama T, Furuya N, Ishii Y, Matsumoto

T, Ohno A, Tateda K, Yamaguchi K. In vitro and In vivo 112. Rybak MJ, Hershberger E, Moldovan T. Comparative invitro activity of daptomycin versus vancomycin, linezolid,antibacterial activities of L-084, a novel oral carbapenem,

against causative organisms of respiratory tract infections. and synercid against methicillin-resistant and susceptiblestaphylococci, vancomycin-intermediate susceptibleAntimicrob Agents Chemother 2001; 45: 203–207.

91. Andreotti D, Biondi S. Overview of recent developments in Staphylococcus aureus (VISA) and vancomycin-susceptibleStaphylococcus aureus. In: Abstracts of the 38th Interscicarbapenem and trinem antibiotics. Curr Opin Anti-infect

Invest Drugs 2000; 2: 133–139. Conf Antimicrob Agents Chemother 1998; C-146.113. Oliver N, Andrew T, Silverman JA, Tally FP. In vitro92. Niccolai D, Tarsi L, Thomas RJ. The renewed challenge of

antibacterial chemotherapy. Chem Comm 1997; 2: studies on resistance to lipopeptide antibiotic daptomycin.In: Abstracts of the 38th Intersci Conf Antimicrob Agents2333–2342.

93. Sifaoui F, Varon E, Kitzis MD, Gutmann L. In vitro Chemother 1998; F-117.114. Canepari P, Boaretti M, Del Mae Lleo M, Satta G.activity of sanfetrinem and affinity for the penicillin-binding

proteins of Streptococcus pneumoniae. Antimicrob Agents Lipoteichoic acid as a new target for activity of antibiotics:mode of action of daptomycin (LY146032). AntimicrobChemother 1998; 42: 173–175.

94. Di Modugno E, Erbetti I, Ferrari L, Galassi G, Hammond Agents Chemother 1990; 34: 1220–1226.115. Alborn WE Jr, Allen NE, Treston DA. DaptomycinSM, Xerri L. In vitro activity of the tribactam GV104326

against Gram-positive, Gram-negative, and anaerobic disrupts membrane potential in growing Staphylococcusaureus. Antimicrob Agents Chemother 1991; 35: 2639–2642.bacteria. Antimicrob Agents Chemother 1994; 38:

2362–2368. 116. Chaibi EB, Sirot D, Paul G, Labia R. Inhibitor-resistantTEM �-lactamases: phenotypic, genetic and biochemical95. Nicas TI, Zeckel ML, Braun DK. Beyond vancomycin: new

therapies to meet the challenge of glycopeptide resistance. characteristics. J Antimicrob Chemother 1999; 43: 447–458.117. Maiti SN, Phillips OA, Micetich RG, Livermore DM. �-Trends Microbiol 1997; 5: 240–249.

96. Arthur M, Courvalin P. Genetics and mechanisms of Lactamase inhibitors: agents to overcome bacterialresistance. Curr Med Chem 1998; 5: 441–456.glycopeptide resistance in enterococci. Antimicrob Agents

Chemother 1993; 37; 1563–1571. 118. Qadri SM, Ueno Y, Cunha BA. Susceptibility of clinicalisolates to expanded-spectrum ß-lactams alone and in the97. Allen NE, LeTourneau DL, Hobbs JN, Jr. The role of

hydrophobic side chains as determinants of antibacterial presence of �-lactamase inhibitors. Chemotherapy 1996; 42;334–342.activity of semisynthetic glycopeptide antibiotics. J Antibiot

(Tokyo) 1997; 50: 677–684. 119. Tzouvelekis LS, Gazouli M, Prinarakis EE, Tzelepi E,Legakis NJ. Comparative evaluation of the inhibitory98. Ge M, Chen Z, Onishi HR, Kohler J, Silver LL, Kerns R,

Fukuzawa S, Thompson C, Kahne D. Vancomycin activities of the novel penicillanic acid sulfone Ro 48-1220against �-lactamases that belong to groups 1, 2b, and 2be.derivatives that inhibit peptidoglycan biosynthesis without

binding D-Ala-D-Ala. Science 1999; 284: 507–511. Antimicrob Agents Chemother 1997; 41: 475–477.120. Nishida K, Kunugita C, Uji T, Higashitani F, Hyodo A,99. Allen NE, Le Tourney DL, Hobbs JN. Molecular

interactions of a semisynthetic glycopeptide antibiotic with Unemi N, et al. In vitro and in vivo activities of Syn2190, a


novel �-lactamase inhibitor. Antimicrob Agents Chemother 125. Coleman K, Athalye M, Clancey A, Davison M, Payne DJ,Perry CR, et al. Bacterial resistance mechanisms as1999; 43: 1895–1900.therapeutic targets. J Antimicrob Chemother 1994; 33:121. Hammond GG, Huber JL, Greenlee ML, Laub JB, Young1091–1116.K, Silver LL, Balkovec JM, Pryor KD, Wu JK, Leiting B,

126. Cazzola M, Matera MG, Donner CF. PharmacokineticsPompliano DL, Toney JH. Inhibition of IMP-1 metallo-ß -and pharmacodynamics of newer oral cephalosporins:lactamase and sensitization of IMP-1-producing bacteria byimplication for treatment of community-acquired lowerthioester derivatives (dagger). FEMS Microbiol Lett 1999;respiratory tract infections. Clin Drug Invest 1998; 16:179: 289–296.335–346.122. Hirata T, Wakatabe R, Nielsen J, Satoh T, Nihira S,

127. Cazzola M. Problems and prospectives in the antibioticYamaguchi A. Screening of an inhibitor of the tetracyclinetreatment of lower respiratory tract infections. Pulmefflux pump in a tetracycline-resistant clinical-isolate ofPharmacol 1994; 7: 139–152.Staphylococcus aureus 743. Biol Pharm Bull 1998; 21:

128. Zurenko GE, Ford CW, Hutchinson DK, et al.678–681.Oxazolidinone antibacterial agents: development of the123. Srikumar R, Kon T, Gotoh N, Poole K. Expression ofclinical candidates eperezolid and linezolid. Expert OpinPseudomonas aeruginosa multidrug efflux pumps MexA-Invest Drugs 1997; 6: 151–158.MexB-OprM and MexC-MexD-OprJ in a multidrug-

129. White P. Antibiotics, market review and developmentsensitive Escherichia coli strain. Antimicrob Agentstrends. Financial Times Business Ltd, 1999.Chemother 1998; 42: 65–71.

124. Masuda N, Gotoh N, Ishii C, Sakagawa E, Ohya S,Nishino T. Interplay between chromosomal �-lactamaseand the MexAB-OprM efflux system in intrinsic resistanceto �-lactams in Pseudomonas aeruginosa. Antimicrob Date received: 5 March 2001.

Date accepted: 13 March 2001.Agents Chemother 1999; 43: 400–402.

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Advances in the Research and Development of Chemotherapeutic Agents for Respiratory Tract Bacterial Infections