( ysnL f7,b6;S Cu.rs,r,1frtcS '.. 244 V. Deretic
80 Lipinska BS, Sharma.s,.Georgopour-o^s c. Sequence anarysis ancr reguration of the t 4. p {tt. J htrA gene of Escherichia coi:'a o32-indepena.nt r".tt'unitr. oi'tr.ut-incllcible ftlu Edq. , ErucL - transcription. Nucleic Acids Res lggg; 16: 1b053_67. {. r+. W;oldld_ue 8l Johnson K, charles.I, zvlr. L6L Dougan G, et ar. The rore of stress-response protein in ) nq6 . Salmotrclla f*A* ^^ ryphitnuriutn virulence. Mol Micrcbiol l99l;5: +Of _i]- w,ie,./ -iun s'-H. &-rlland tt Lourenco RV, et ar. Inflammaiory: r",,.iion and airway 3::::^l?:.*\Id..l_K,rn cystic fibrosis. gg: - .. lrlmage J Lab Clin Med 1976; 423_6. tt3- May TB, shinabarger .D, Maharaj R, et ar. Alginate synthesis by I'seudtsrlorut.s ae.rugittosa.: a key. pathogenic factor in chronii purmonary inr.arons of cystii Chapter Twelve - fibrosis patients, Clin MicrobiolRev L99I;4: l9l_206. 84 Deretic V. Signal transduction ancl environmental stress in control of pseudortutnas aentgitrosa virulence. In: rransductiott .signal and. Bactetial virulence' - " (eds R , fappuoli, V Scarlato,B-Arico), Landes, Austin, 1995, pp a3_ir0. 85 wozniak DJ, ohman DE Transcriptionar anaryiisor irii pieu-io,,ro,ro., aerugitrosa Antibiotics genes.a/gR,.algB, for Pseudomonas and and reveals a hierarchy of alginate g.n.' .*pi.rtion- which is modulatedby -algD ! 'r" - _ algT. J Bacteriol 1994;176: A6Ol_ti. 86 Lam J, chan JR, Lam Related Infections K, cosrerton JW. hoduction of mucoicl microcolonies by within infected rungs in cysti" nuio.ir,-ii,rr"r Lrni,ir Roberr E. W. Hancock and David p. Speert l:21d2,!olo:aerugitrosa1980;28:546-56. Dcpartments of Pediat.ics 87 colledge wH, Abella BS, sourhem, and Microbiology and Immunology, Utiversity of KW, et al. Generation and characterization of a AF508 cystic fibrosis mouse moder. Nature Genet r99s: r0:445-s2. B ritish C olunbia, Vancouver, Canada
INTRODUCTION
The prognosis for patients with cystic fibrosis (cF) has improvcd clriunatically over the pa.st 20 years with the meclian suryival in canacla increasing from 22 to 40 yearsr. This enhanced life expectancy is probably clue to u of factors, bur improved therapy of bactirial-lung in-fections has"o,oplex.ange unaoubtea'iy played a major role. Respirarory tract infeptionJconrinue to be the leadin! cause death pseudornonas of among patients with cF, and aeruginosa is the predominant rcspiratory tract pathogen. The chronicity of p." aeruginasa infections in CF, its high lever intrinsic antimicrobial resistance and its propensity to develop resistance during prolonged antimicrobial therapy have presented all rnajor therapeutic challenges to CF caregivers. To counter these challenges, new antibiotics have been introduced ancinovel approaches have been employed, including inhalationar therapy ancl home aclministration of intravenous antimicrobial therapy. The concepr that anti-Pseudomonas therapy is of little or no benefit in the management of acute pulmonary exacerbations in cF was intr.oducecl by Beaudry and colleagues in 19802. Theycompared an anti-pse udomonas regimen consisting of carbenicillin and gentamicin to cloxacillin and demonstratect-no difference in outcome. The study involved a small number of patients ancl the close of
C)'rrtit' l"ibrosis*Curreul"l'o1tis.;,VolurnaJ. Eclitccl byJ.A. Dulge, D. J. H. Brock ancl J. l{. Wiclcliconrtrc re 1996 John Wilev ,t Sons Lrd. II 246 R. E. W. Hancock and D. P. Speert Antibiotics for Ps eudomonas 247 gentamicin (5 mg/kg/day) may have been too low to result in therapeutic sputum activity have been applied to several core structures. Early pJactams had no concentrations. A similar study was performed by Hyau et a1.3 and reached a activity, but the development of the a-carboxypenicillins, carbenicillin and then diferent conclusion. They compared oxacillin plus sisomicin and carbenicillin to ticarcillin represented a major breakthrough (Table 1). However, the moderate oxacillin alone in the management of acute pulmonary exacerbations, and the activities and high susceptibility of these compounds to p-lactamases severely patients who received the anti-Pseudomotuts therapy responded better than the limited their useze. Newer penems, the acylureido penicillins mezlocillin, placebo group in terms of both clinical and bacteriological outcome criteria. In piperacillin and azlocillin, had improved activity but were still susceptible to B- another study, tobramycin monotherapy appeared marginally superior to placebo{. lactamase hydrolysis. However these B-lactams have found some usage in Recently Gold and eolleagues have rekindled the controversy by suggesting that combination with aminoglycosides and will probably be administered in the antibiotics are not required i4 the management of CF patients with mild to future together with B-lactamase inhibitors. moderately severe pulrnonary exacerbationss. Erch of these srudies employed a The carbapenems, e.g. imipenem, have excellent activity against P. somewhat diferent design, perhaps explaining the conflicting conclusions. aeruginosa but have substantial problems with rapid development of Nonetheless, most clinicians caring for patients with CF believe that antimicrobial resisiance30. Similarly cephalosporins (cephems) have been developed that therapy is useful in ttre management of lung infections and administer specific have excellent anti-pseudomonal activity, starting with the third generation anti-Pseudomonas antimicrobial therapy to CF patientg colonieed with P. cephalosporins cefoperazone, and especially ceftazidime3l. More recently, the aeruginosawho experience moderate to severe pulmonary exacerbationso. fourth generation cephalosporins, cefpirome, cefepime and cefaclidine, with Although there is considerable evidence that properly administered positively charged quaternary amnonium functions in the 3 position have been antimicrobial therapy decreases the density of P. aeruginosa in the sputum of developed since they are better taken up across the outer membrane and are patients with CF and improves pulmonary function of patients who are more effective against mutants with derepressed p-lactamase32. Another class experiencing a pulmonary exacerbation?'8, the optimal means of therapy has of p-lactams, the monobactams, has aztreonam as its sole representative. not been clearly established. A wide range of approaches have been advocated, Although containing an aminothiazole oxime side chain like the above including (i) admission to the hospital at regular intervals for parenteral therapy cephalosporins, it has somewhat inferior activity. irrespective of clinical slatuse, (ii) admission to the hospital for intravenous therapy only when dictated by pulmonary exacerbation'o, (iii) inhalational Mechanism of action antimicrobial therapytt.zo, (iv) parenteral therapy at home2r-27, and (v) continuous oral therapyzs. Whereas each of these approaches has inherent p-lactams act by inhibiting enzymes (penicillin binding proteins-PBPs) advantages, .they have not all been compared in a careful prospective involved in peptidoglycan (cell wall) biosynthesis and/or tdggering enzymes randomized fashion, It is therefore impossible to determine the optimal called autolysins33. All f-lactams are capable of binding to multiple PBPs, but antimicrobial approach, and therapeutic decisions are often made ernpirically. generally speaking bind preferentially3a to one of the seven well-characterized This chapter does not provide simple answer$ to the complex queStions about PBPs, either PBPIa (ampicillin, carbenicillin), PBP2 (imipenem) or PBP3 antimicrobial therapy in CF, but rather air overview of anti-pseudomonal (cefotaxime, ceftazidime, cefpirome, piperacillin and aztreonam). Recent therapy in CF, including: a description of agents currently available, special experiments have indicated that a single PBP is usrially the killing target since, considerations for therapy of patients with CF, a description of various routes for example, overexpression of PBP3 from its cloned gene increases resistance of antibiotic adminisuation, and future prospects, only to PBP3+argeted p-lactams35. In Gram negative bacteria, PBPs are sequestered behind a barrier, the outer membrane, and thus accessibility to these target proteins is limited, especially ANTIBIOTICS WITH ACTIVITY AGAINST in P, aeruginosa which has an outer membrane with 12-100 fold lower P S EA DO MO NAS AE RAGIN O SA permeability to B-lactams than e.g. E. colii6. The reason for its lower permeability is deficiencies in the porin pathway whereby the majority of its B.LACTAMS outer membrane porins contain channels that are too small to permit rapid diffusion of B-lactams36-3e whereas those porins that are large enough (e.g. In vitro activity OprF) demonstrate poor activity, with only a small number of functional P. aerugittosa has been a major tsrget for pharmaceutical companies developing channsls per cell36, Dospite this permeability defect, p-lactams can equilibriate new f-lactarns. Semi synthesis programs aimed at improving anti-pseudomonal across thp outer membrane in as little as 2 to 20 seconds. Thus reduced outer 248 R. E. W. Hancock and D. P. Speert Antibiotics for Ps eudomonas 249 membrane permeability works only by slowing down the entry of f-laetam other hand, it is potentially effective against derepressed mutaflrs since p- molecules into the periplasm (the location of the cell wall and the catalytic lactarnases, being fully expressed, cahnot further influence activity a?.ae. One of sites of the target PBPs), permitting a secondary defence mechanism to the major reasons why imipenem retains substantive activity against such function. Two such secondary defence mechanisms have been suggested, p- derepressed mutants is a combination of its resistance to the hydrolytic activity lactamasesao and active effiuxar. The latter topic is discussed in more detail of p-lactamases combined with its ability to access a speiial pathway oi below; however, it has not yet been convincingly demonstrated that active uptake involving the porin oprp+'st. oprD falls into the class of specific effiux is involved in shuttling B-lactams from the periplasm across the outer pOrins ancl has, as its natural substrate, basic amino acids and small peptides membrane into the extemal medium, and the influence of efrux muunts on d- containing sueh amino acids. Imipenem is taken up through the oprD channel lactamase inducibility, PBP interaction and outer membrane permeability has because it mimics a basic amino acid containing dipeptide5', but the oprD not yet been studied. Therefore, we will only discuss BJactamases here. channel is essentially impermeable to other antibioticsre. unfortunately The inteqplay of outer membrane permeability, p-lactamase activity and resistance to imipenem occurs very commonly in patients with cF complicatecl target PBP interactions is given by a rearrangement4z'43 of the Zimmerman and by P. aerugirrosa infections, due to murational loss of Oprpsr,sr. Rosselet4 equation Mutations resulting in altered PBPs such that these proteins can still fulfil their enzymatic functions, but do not bind specific p-lactams, have been observed$.s3 MIC = Sp(l + VmaxfPA(Sp + Km)) (l) but are not conunon. similarly, oprF-deficient porin mutants have been observecl s where: Sp = the concentration of p-lactam in the periplasm to which the PBPs after quinolone therapy and result in moderate p-lactam resisthnce, but these are are exposed, when the external concentration = MIC; Vmax and Km are the also uncommon. A third class of clinical mutants involves thoss with so.called kinetic constants of p-lactamase; P = the outer membrane perrneability high intrinsic resistance to p-lactams and other antibiotics. It has been proposecl coefficient: and A = the area of the outer membrane. that these are mutants with enhanced antibiotic.6u*ar's5. Thus according to equation 1, increasing maximal hydrolytic activity (Vrnax) incrcasing the binding affinity p-lactam p-lactamase (i.e. decreasing or of to Future prospects Km), will increase the MIC. Two types of enzymes are influential. One type cornprises plasmid-borne class A penicillinases. At least 15 of these have been Three classes of B-lactams show some promise for the future. Fourth generation identified, but generally speaking they are not of major importance for clinical cephalosporins which are, at the time of writing, just being introduced into the resistance4s.. The second type comprises a single chromosomally-encoded marketplac-e.,. are relatively less affected by derepression of chromosornal B- cephalosporinase, the class C enzyme found in all Pseudomanas sbainsat'. This lactamasear'ae. Novel carbapenems with two basic groups appear unaffected 6y enzyme is inducible by B-lactams themselves and although found at a basal level OprD mutations, although they can result in resistant mutants by other in cells not exposed to p-lactams, it may be induced during antibiotic treatment. mechanisrnss6. Catechol p-lactams overcome the outer mernbrane permeability This induction can substantively increase MICs, as revealed by comparison of banier by-binding Fe3* and achieving passage through iron scavenger uptake normally-inducible strains and their non-inducible mutantsa?. pathwayssT. However, such p-lactamJ fiave been reported in the literatuie for years, but have not as yet progressed far through clinical trials. An even more exciting prospect is provided by compounds designed to be Mechanisms of resistance utilized in combination with plactams to overcome potential or actual The most significant and widespread mechanism of resistance studied to date is resistance mechanisms. These include p-lactamase inhibitors, aimed at chromosomal p-lactamases8, due to mutations leading to derepressed production of the chromosomal B- _. and polycationic peptides known as lactamaseas. Such mutations make P. aeruginosa clinically resistant to all p- permeabilizersse, which overcome the outer membrane permeabiliry barrier. lactams with the exception of the carbapenems and fourth generation observed after long-term therapy P. cephalosporins4?'4e. They are commonly of AMINOGLYCOSIDES aeruginosa with pJactams, e.g. in CF patients who have long-term, chronic infections. In vitro activity Imipenem is a potent inducer of chromosomal p-lactamase and results in p- lactamase levels equivalent to those observed in the above derepressed Aminoglycosides remain one of the most valuable tools, usecl by physicians in mutantso?'50. Thus it cannot be used in conjunction with other B-lactams. On the combination with a p-lactam, to overcome serious Gram negarive infections. ) 250 E. 1,V. Hancock and D. P. Speert Antibiotics f,or Pseudomonas 2.
especially. P. a.eruginosam. Ahhough rimited or unpredictable penerrarion can After entering the periplasm, aminoglycosides pass across the cytoplasm be a problemrr,.they can be formulated to pennit inhalation ti"r*;; t;6; membrane by a process that is energized by the protonmotive force (eGctric patients. They have the potential problem of ireversible ototoiiciry ancl potential component) and requires an glectron transport chain componer reversible nephrotoxicity, a concern that relates to dosage and is rnore often proposed to be respiratory quinones6'67. Energized uptake occurs observed in elderly and debilitated patients6r, ln $ p!a!91, EDP(energy dependrn_t phase)I, a slow but accelerating phase, ar of the many known aminoglycocides, only gentamicin, &mikacin ancr EDPII, a rapid uptake phase6'67. The transition from EDpI to noFlf appears tobramycin are commonly used against p. aerugiiosa. However, their peak occur at the same time as the lethal bactericidal event triggered t serum levels (approximately 6 pg/ml) at rhe usual dose (S mg/kg/day)oi *, aminoglycosides6T'68. This lethal event is still controversial, despite decades c similar to their MICs (Table l), and anirnar studies clearly inailatl a disparity research. The usual suggested mechanism, protein synthesis inhibition r between in vivo and in vitro activitiesq2. Therefore aminoglycosides are uiually misreading during translation appea$ to used in combination with p-lactams@. be at most a codeterminant, and u favour inhibition of DNA synthesis initiation as the primary lethal target68,6e.
Mechanism of action Mechanism of resistance Aminoglycoside$ interact directry with the outer mernbranes of Gram negative Most large studies of the clinical outcome of aminoglycosides have demor bacteria to permeabilize them to other molecules of aminoglycosicle in a strated frequencies of gentamicin resistance of between 3 and lzo/070. There ar process termed self'promoted uptake63. At the same time they enirance uptake two major causes of resistance. Acquisition of certain plasmids can lead to th of other molecules, explaining in part their synergy wirh p-lacta-s*. Th* production of enzymes which modify the aminoglycoside by variousl observation^rhat they utilize this non-porin mediatedpathway of uptake in p. acetylating, adenylating or phosphorylating the antibiotic molecule. This resulr aeruginosao'and E. coli65, explains why they have iimilar'efficacies against in reduced uptake and/or reduced efficacy of the modified aminoglyc
"Normal srrainr lxrring rcs.istsnce .t!tt9 $ ran*fer plarrnids, dccprcrsed chmmrxonrar f.loctannsc or The introduction of the fluoroquinolones in recent years has provide{ a major increased intrinsic resishnce duc ro porin alterations. hope for anti-pseudomonal therapy. The most effective and clinically mosr 252 ( % R. E. W. Hancock and D. R. Sp."rt( Antibiotics for Pseudomonas utilized agent has been ciprofloxacin with an MICrn However, even of around 0.25 to snbunit wirh tnis co.poud;"rrp.uiL I ltgrmr. B). In addition the evidence suggested that at least seven mutants hatl disappointing, ,erutt* t lu-J in part. u"*r* Ir Lrir*n"J"' u"en qrit" other mutations. although a.u"r"pr;;rrli' fr"u.rth"r"rr, in cF paiient. tu"toioiog.rT;;."r.. other mutanrs have been identified with complex phenorypes including ment rare ancr ,".istance cell common' rhere t::i:* creverop- e.nvelope changcs (e.g._o-prF loss, ov€rexpres-sion * ir"ir"""r"ri in lung functionrs.fiiat of a s0 iDa protein aia7o, ascribed ro down-resuration tras been lipopolysaccharide (LPS) changes;rr'etr- nr ui*t"n""rl"ror.. combinations often accompaniecl by transport of quinorones deficiencies. Some of these mutations fiTiffJffi are probably effiui mutants which have ::S*l*.Tii1$'i#;;'",",vn*ryist.iJ;,inii,nro,,uno,"ry been better described in the laboratory is resuiting from clerepression of oprM, oprN or oprJ (in conjunction with clerepresiion of inner membrane components Mechanism of action of an effiux systems2). one item of major concern is the tenclency quinolones of to select mutants that are resistant io *ore than one class of Quinolones u"t uo31il1:n.'vry" antibiotics due to either the broad specificity O*.o *lT"_1i Hoylu-._r, of effiux systems?t, or regulatory directry to DNA whether they bincr mutants affecting Lryr:..or to the teniary comprex more than one resistance mechanism simultaneously i;, or the nas nor been of Dil *itrr nrva gyrase possibility - vet definitiverv .r,utiirtia. that quinolones, being DNA-damaging agents, may be rnuiug.ni".' qi,i""r"""I;-" ilctericiaat anti- Resistance development has been modelled in tfe laborarory successive mech an i sm- r by :"L,ffi "Jr,o"'*H.: ]Na repair cr u ri n selection ilfi:'Jt "J. . g of increasingly resistant strains on two-fold the MIc of theiilff major ':" u"riJJirri, damage to DNA u""r??r.ij"i'..,,lll"ttttole ;;d;;;;: ciprofloxacin. Increasing,Mrcs up to eight-fold the MIC of the parental strain were clue to changes in DNA gyrase. quite conrroversiar Further increases in MIC were minored o#i,i::iill'ili :,:.iTl*t:,J#ffiis ancr has been by changes in the cell mem-brane (including eitherporinornon,_oorin6"k.p;;"";,"#iffr"::1, oprF deficiency) ancl correspond- jiil#il:1"":il:,*; ing alterations in susceptibility to other antibiotic classessa. Increased resisiance to other drug classes lut not quinolones could be partly complementecl by the cloned ff iT'J#iJ:ffi f ,#,*'j,nx..i*"'T-'ll"':;ii*',"Niriia"#i'., oprF gene. CIher laboratory mutiresistant mutants involving clerepres- sion of effiux systems have been isolated as single-step mutanrs. Typitaily Ll','fr ilyJ:"iliil.:i'l,i:J these muhnts can be recognized thetrinicurtie;i;;.,,",i"siil*,i::';{,i^":#fi:f"jUl'l#ffi itr-',|fl";f il:v",'rffi by acquisition of a 4g-50 kDa- outer membrane protein (oprM, N or J) which is part of the effiux machinery 8r. binding ancr the ifi existence of a satumuil effiux "%,rJiy#tt:ffi system lwhictr of course a'p"nainf on Future prospects I'T{ffl',;H:lk;*ll "o'*" the .on..ii.i ion or antibioric There are thought to urleast Many fluoroquinolones have been isorated, but to date none has exceecled the g.. three effux systems in p. on rcsistanr mutant studies t" rrtrfr, aerugi,o.ra basecr activity of ciprofloxacin against p. aeruginasa. Furthermore, all known ,rr"r",.y.r.r, have been The most important in-wircr-type crerepressecr"-r. resistance mechanisms result in simultaneous cross-resistance to all known rnexA, r"Jie best stucriecr, is mexB, oprM (formeriy ";i; ttrar basecron rhe quinolones. Thus it is safe to say that it seems unlikely that this class of ..ri.J'rprrl"o""*1r"-urane oper9nf2. Interposons membrane componenr in the inner antibiotics will see many improved compounds in the future. one class of y"*a ;l;; component supersusceptible to ciprofloxacin oprM are compounds that would be of interest would be one that inhibits effiux pumps ar" to J."."used effiux 8:. for use in cornbination with quinolones, thus overcoming an irnportant resistance mechanism. Mechanism of resistance The.mechanism of quinolone resistance in the.clinic has been 13 mutants, investigatecr in SPECIAL CONSIDERATIONS FOR ANTIBIOTIC roonne-ro' the.abirity oi-,r,. ff;Tff:lfiXt#t "r"""0 E. coti THERAPY IN CYSTIC FIBROSIS 1i,ino1-on"';;';;'r.i:itj:n"X,ilJi;",Tf,"'#:::*:'*:1i.il,*:ll; PHARMACOKINETICS complenrenred suggesing thai murant ;; ;;;,; ed. gvrA murations courd be compremented (one other Patients with CF dispose of many drugs more rapidly than do other individuals witrh trr.'Jon.a Jyra g.".'i"rbNO gyrase and require extraordinarily high doses of most antimicrobial acents to achieve 254 R. E. W. Hancock and D. P. Speert Antibiotics for Ps eudomonas 255 therapeutic concentrations in serum or sputumsi'86. Antimicrobial agents of FAILURE TQ ACHIEVE THERAPEUTIC ANTIMICROBIAL ACTIVITY various classes, including aminogrycosides, pe11c{lins and trime-thoprim- IN SPUTUM s.u$hamethoxazole, are cliared at inhancea ruturn-r ana require appropriare dosing adjustments. c91ve1ryly, ciprofloxacin pharmacokinetics appear lo be Infections in patients with CF occur predominantly in the endobronchial space normal in patients wi.th cF and dosing adjustments ar€ not nicessary$. and only invade the parenchyma of the lung late in the course
PREFERRED ANTIMICROBIAL AGENTS AND COMBINATIONS Therapy of pulmonary exacerbations, clue to p. aeruginasa, usually consists INHALATIONAL THERAPY of a combination of a semisynthetic penicillin, such as ticarcillin or piperacil- and lin an aminoglycoside, such as tobramycin. These clrugs hlve been shown As described above, local factors in the endobronchial space interfere with the to be p. synergistic irr virro against aerugirto.sc (see above;. other agents that antibacterial activities of intravenously administerecl antibioticsr0r'r02. have proven-to be effective in treating pulmonary exacerbations in cF inclucle Concentrations of antibiotics many times above the MIC for P. aeruginosa quinolonesr0T-rB and newer B-lactami such ai cefoperazone, cefraziclirne, may be flecessary to achieve afltimicrobial activity. One strategy for circum' aztreonam and imipenem. These agents may be given singly or in combination veriting this problem has been to deliver the antibiotics directly to the site of with an aminoglycoside, but they should be choGn in the ligtrt of results fr.om infection by the aerosol ioute"-2o. Although this approach appears to be in uitro antimicrobial susceptibility resting. some of the newer p-lactams, such attractive theoretically, a number of practical implications must be considered. a.s imipenem, induce p-lactamase activity ancl shoulcl not be given in combina- To deliver the drug to the site of infection in the lower respiratory tract, the tion with other B-lactams. often, a clinical improvement riay be seen even aerosol must be between I and 5 pm in diameter; certain aerosol gener6tors when antimicrobial agenrs are administerecl to *hich the infecting strain of p. appear better suited than others to cleliver appropriate aerosolsrr2. Large doses aeruginosa is resistant in vitrottt . oi ,lrugs are required, but the cost may be offset by the decreased need for 258 R. E. W. Hancock and p, D. $peert Antibiotics for Ps eudomenas 259 hospitar admission for parenrerar rherapy. IIBFa antimicrobial agents parienrs wirh cF rravl incruaeJ- .uid""iriui"; used in S. maltophilic has also been proposed to have low outer rhembrane tobramvcin, ;;;;;*t.inl ."pr,*oridine, coristin, prrv*y*n n # permeability. In addition it expresses two inducible BJactamases, a type C parenreral antibiotics. aik.:r"'rri""-"r'i" iombina rion with Resuris from ctinif* riuru rr*rul." cephalosporinase (named L2) and an inducible type D metallo-B-lacramase (a rhe quarity of the ,i*.0 as has been so-called imipenemase nameci stucy design. e *""*ry reponea Ll;3'. However, relatively little research on over pracebo-controrecr cross_ srudy evatuated the effiiacy or inirir.,ri;il;*;,;1 ju,,.n,, resistance mechanisms has been done on this organism. either 600 mg tobramycin rcceivecl or ruiin"-cuiiy for each oi ti,re"? rhose who received ir,. a*g-huJJ-i;ninr*i;;;";;;"; day periocrs. funcrion and a decre... in purmonary THERAPY l;-".p*rr" irt".rirv of aerugirosa acquisition: .p. without an oi- untiiioti"-r.sisran t isorites Therapy of infections with these'honorary' Pseudomonas species patients ffi: fJHtT, jiiffi or evidence o r in with CF should be guided by the same principle as therapy for P. aeruginosa. Antimicrobial therapy is based upon in vilro susceptibility, and the duration is ,j{gryg.RA$ routinely for two to three weeks. since both B. cepacia and s. maltophilia ue rHERApy gf, highly resistant to many antibiotics, the regimen yJqqqpoMoNADs, : B. of ticarcillin and tobramycin CEPAcIA AND S. u,q,LrbPfriiii,^, (which is often effective for P. aeruginosa) is usually not appropriate. Antimicrobial WHY agents with in vitro activity against either or both of these two THESE BACTERIA ARE DIFFERENT FROM P, AERIJGINOSA species include ceftazidime, ticarcillin-clavulanare, trimethoprim/sul- For years B' cepacia and s..m\lton-h,ia phamethoxazole and ciprofl oxacin. borethe fam'y name pseudomonQs. taxonomic ffJ,il?lli' rriffifff ii{1i;;"f:l{" srucries incru
29 ttO). Microbiat Resistance Pryun LE to Qrugs. Springer Verlag, Berlin, 19g9. stable partially derepressed producing strains. 30 Quinn JP, Dudeck EJ, vincenzo B-lactamase J. Antimicrol Di CA,"er ;1. d"rrgrilL of resisrance of C hemother 1990; 26 : 247 imipenem d*hq- therapy for Pseudomones -59. aeruginosaTnfections. J lfect Dis 49 Nikaido H, Liu W, Rosenberg EY. Outer permeability 1986; 154 : 289-94. membrane and B-lactamas( stability of dipolar ionic cephalosporins containing methoxymino substituents. 3l Rolinson GN.f-ractam antibiotics. J Antimicrob chemother 19g6; 17: 5-36. Antimicroh Agents Chemother 1990;34: 337 32 Hancock REW, Beilido F. Facrors -42. invotved in ttrg inhun"J'#ru"y against 50 Bellido F, veuthey Blaser J, et al. Novel Gram-negadve bacreria c, resistance to imipenem associater of fourth generation *pr,.i"ip"ii,i, .-'i Antimicrob with an aftered PBP4 Pseudomonas Chemother t992;29,Suppl in a aeruginosa clinical isolate. J Antinticrol ^^ A: l-6. Chenwther 1990; 33 Noguchi MH, Matslhaitii 25: 5l -68. u, Matsuhashi s, comparabre studies of penicirtin_ 5l Trias J, Nikaido H. Protein D2 channel in of the Pseudortonas aeruginosa outer !1$nq^n^rotgins Pseudomonas aeruginosa and Eschericlria coli. Eur J Bioclrcm membrane 1979; 100:41-9. hai a binding site for basic amino acids and peptides. J Biol chen 1990;265: 15680-4. 34 Bryan LE, Godfrey, AJ. B-ractam andbiotics: Mode of action and bacterial 52 Krilov LR, Blumer JL, stern RC, et al. Imipenem/cilastatin resistance. ln: Antibiotics in Laboraton 'i"i in acure pulmonarl uedtcini, 3od-roiii* v Lorian), exacerbations of cystic fibrosis. Rev Infect Dis 1985; 7, Suppl 3: 5482-9. Academic Press, Orlando, 1991, pp 599156'e,. __ - , 53 Godfrey Bryan LE, Rabin HR. resisrance Piiudotnonas aerugittosa 35 Liao X, Hancock REW. Manuscrift in preparation. {f., B-lactam 36 woodruffwA, parr.TR, with modified penicillin-binding proteins emerging during cystic filrosis Hancock RE*, Jiur. 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Sem Resp lifect t992; i, ZtO_7i'.'- l12- weber A, smith A, williams-wanen J, al. N"burizer aeriueiy'or tobramycin-- to M. Alfaham and M. C. Goodchild* the lower respiratory Eacn pediatr pulmonol"t -' 1994; 17: fJi_S-.-' Cystic Fibrosis Unil, University Hospital of Wales, Cardif , UK and ll3 Palleroni Nj, Kuiisawa R, co;;;ffir"; R, Duodoroff Nucteic pseudomonai. M. acid *Department of Health, Llandough Hospital, Cardiff UK in the,genus Int .r sysi pquiii[istii-]s, Child , l14. . . Burdgelom.otogu*el :::-s. DR, Noble,MA, Campbell et al. Xanthomonas mattophilia misidentified pseudom.onas .ME, as ceiicia in cuitur"s of sputum from patients with a^diagnostic pitfari gl:ti. !^b*:it_; with major crinicar ir"irii"rii""r, ciin l6ect Di.r 1995;20:45-8. The term Aspergillus, which encompasses about 150 species, was coined by l15 Moore RA, Hancock REW, Involvement of the outer membrane of pseudomorws Micheli, a botanist and priest, in 1729t. The name itself is derived from the cepacia in aminoglycoside and porymyxin resistance . iiiirirrou egr,;i Latin asperge meaning to scatter2. Chemother 1986: 30: 923-6. 116 Jensen T, Pedersen Aspergillus species are ubiquitous and thrive over a wide temperature range, SS, Garne S, et al. colistin inhatation rherapy in cystic fibro.sis patients with chronic pseudomonas from 12"C to 53oC3'4. Thus they are abundant in damp, decaying vegetation aeruginosa lung infection. ^r Antinticrolt Chentother Lg87 ; lg : 831 *8. heated by bacterial fermentation, but they are also present in the air, in newly l17 Hancock REW, Farmer s. Mechanism of uptake of ctegrucoteichopranin cut grass and in a variety of moist situations. In houses they are found derivatives amicre across the membranes of Eicherichia- A.eudonrcrrts especially in basements, bedding and house dust. Some Aspergillus species aerugirtosa. Antimicrob Agents Chenrcther 1993; 37: 453_4."7i'--il" 116. . ^ also grow as a commensal in the human respiratory tract, with the potential to Barghouihi s' sp€eft Dp. Dextrans interfere with adhesion of pseudonrcrws aeruginosa to spread to other organs and body cavities5. -epithelial cells. Eighth Annual North American cystic Fibrosis Conference. 1994. no, S5.5, t tn l;t:I*{:l::""rP* W, Hodges RS. Cross-reactive and strain-specific antipeptide HUMAN ASPERGILLOSIS anuDoores to rEeudomonas aeruginosa pAK and pAo pili. Iifect Inmui igg}; 58:2727 -33. This was first described in 1847 by Sluyter6. Despite the high number of Aspergillw species, only a few affect humans, with Aspergillus fumigans (AF) accounting for more than 90Vo of infections or allergic responsesa. Other species implicated we A. niger, A.flavus, A. terreus, A. clavatus, A. glaucus, A. nidulans, A. oryzae and A. nivensT'8. A. fumigatus is the most widely distributed of all microorganisms and a troublesome contaminant in microbiology laboratoriese'r0. It liberates its spores Cy"rtrc'Fibrosrr*CurrentTopic's,Valune J. Edited by J.A, Dodge, D. J. H. Brock and J. H. widdicombe O 1996 John Wiley & Sons Ltd.