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The new oral cephalosporins in community-acquired infections
The new oral cephalosporins in community- acquired infections D. E. Low Mount Sinai Hospital, The Toronto HospitaJ, Toronto Medical Laboratories, University of T o ronto, Ontario, Canada
ClitJ Microbiol fllject 2000: 6 (Supplement 3): 64-69
Oral cephalosporins have been used primarily for the treatment of community-acquired infections such as community-acquired
infections seen in general medica.l practice, accounting for a significant number of physician office visits per year. Although
pneumonia, pharyngitis, otitis media, bronchitis, skin, and skin
patients recover clinically without antibiotic therapy, treatment is
strucrure infections and wlcomplicated urinary traCt infections. The goal in the development of the first oral cepll,,]osporins was to
fever and to reduce the incidence of locally invasive infecti on.
unprove their phannacokinetic profiJe. Having accomplished that, the nel\.1: was to enhance their antibacterial activity. The newer oral
'gold standard' treatll1ent for streptococcal pharyngitis [1], and
recommended to hasten clinical resolution, to prevent rheumatic Since its introduction in the 1940s, penicillin has been the
cephalosporins demonstrate an increased ill vitro antibacterial activity and enhanced [3-laCtan1ase stability and phanmcokinetic properties (Table 1). They not on.ly provide an a.ltemative for the treatment of
for many years it effected consistent microbiologic eradication ra tes of over 90"10 [2]. However, in more recent years, the incidence of bacteriologic failure \vith oral penicillin therapy 11,15
infections in the COnIDlllnity due to pathogens resistant to other antimicrobia.l agents, but their improved phanl1acokinetics increase
increased to as much as 10"/0-30% [3,4]. Alternatively [3-lactarnasest.1ble oral cepha.losporins have been shown to be highly effective
compliance. [n addition they may be used in the hospital setting for switclung from parenteral to oral therapy, thereby decreasing costs and alJO\ving earlier patient discharge. The new oral cephalosporins can be divided into those absorbed as the parent compound
in the treatlJlenr of streptococcal pharyngitis [3,41. In addition, triaJs of expanded-and broad-spectrum oral cepha.losporins in Europe [51 and more recendy m North America [6] suggest d13t a 5- to 7-day duration of therapy is as effective as or even more effective than dle classica.l I D-day regimen of penicillin .
(cefdimr, cefi:ibuten, cefixime and cetprozil) and those absorbed in the fonn of ester prodrug; (cefi.lroxime axetil, cetpodoxi11le proxetil
The phenomenon of higher S. pyogclles eradication rates for
and cefetamet pivoxiJ). In this paper, because of space limitations,
cephalosporins has been previously noted. Pichichero and
we will review the role of these new oral cepha.losporins in a
Margolis have reviewed a number of studies comparing
selected number of important clinical indications.
cephalosporin with penicillin for the treatment of streptococcal pharyngitis [7) . Based on their meta-a nalysis, they concluded that the cep halosporins are genera lly more efficacio us,
PHARYNGITIS AND TDNSILLlTIS
presumably due to their resistance to degradation by ~
Pharyngitis due to SfreptococCIIs pyogelles (group A ~-hemo lytic
lactamases. This may be especially true for patients with recurrent streptococcal pharyngitis w ho have been treated with penicillin within the previous 3 months [8]. This o pinion is not shared universally, howeve r. Shulman and co Ll eagues have also reviewed the snldles included in the Pichi chero meta-analysis, and concluded that the availab le literatu re do cs not show that cephalosporins are superio r to penicill in for
streptococci [GABHS]) is one of the most conIDlon bacterial Corresponding author and reprint requests: Dr Donald E. Low, Dcpamnent of Microbiology, Mount Sinai Hospital , 600 University Avenue, R.oom 1487, Toronto. Ontario M5G I X5. anada Tel.: +1 416 5R6 4435 Fax. : + I 4165868746
Table 1 Pharmacokinetics of oral cephalosporins after single dose Antimicrobial
Dose (mg)
400 500 400 400 500 500 300
Ceflxlme Cefuroxlme -axetil Cef1lbuten Cefpodoxlme-proxetil Cefprozll Cefetamet - PIVOXII Cefdlnlr Adapted from
In
healthy volunteers
Frequency
COl"" (mg / l)
AUC o., (mg h / l)
00
3.6 4.9
26 19 79 27 30 25 6.5
BID
00 00 BID BID BID
17
4.5 10 4.1 1.6
T 1/2
(h)
3.1 2 2.3 2.4 1.3 2.3 1.4
Urinary elimination (% )
32 24 70 22 18
(17) .
r
2000 Copyrrght by the European Society of Clinical Microbiology and InfectiOUs Diseases, eMf. 6 (Suppl. 3). 64- 69
Low New oral cephalosporins
treatment of streptococcal pharyngitis (9). The Food and Drug Administration in the USA has approved the use of a 5-day co urse of cefdinir for the treatment of streptococcal pharyngitis and had previously approved cefpodoxi me proxetil for 5-day therapy as well. All of the newer ora l cep halospori ns have excellent ac ti vity aga inst the GAB H S with MI C", < I mg/ L.
OTITIS MEDIA Acute otitis media contin ues to be an important public health problem around the world. The most commo n bacterial pathogen, StreptocoCCli s pllelllllollille, has been implicated as part of the current antibiotic resistance crisis. The first cases of penicillin- resistant S. P"Cllloliac were reported in Australia and New Guinea in the ea rly 1970s. In less than a decade, highly resistant strains that exhibited resistance to multiple antibiotics we re isolated from patients with invasive infections, as well as trom carriers, in South Africa. The prevalence of penicillin-resistant pneumococcal infections has escalated steadi ly. The increasing use of day- care facili ti es provides a vector for transmission of resistant pneumococci [10] . lntemational spread of resistant isolates has been documented [I 1- 13], so that penicillin-resistant pneumococcal infections have become a global problem r14, 15]. The optimal management of ac ute otitis media is widely debated for many reasons [1 6], beginning at th e most basic level of medica.l management, because there is no conse nsus rega rdin g diagnostic criteri a. The selection of antibi oti c therapy is usually empiric because of the difficulty of obtaining cultures. Although authorities usually agree that S. p"clilllOlliai' and un typeable HaclI10phillis illjlll clizae are the most conUllon bacterial pathogens, the prevalence of resistance is not as well documented . With the exception of ceftibuten, which is less ac ti ve against Moraxel/a ((/tarrlw lis and S. p"rill/Wiliac, the new oral cep halosporins are generally more potent irthibitors of co nulluni ty- acquired respiratoly pathogens than the older oral cep halosporim [1 7]. Eradication of pat hogens fi'om midd le ea r fluid an d clini cal outcome have been reported to be less favorab le if pathogens with reduced antimicrobia l susceptibility are present [1 8]. J acobs et al. [1 91 condu cted a large, internatio nal study of infants and children with acute otitis media to identify pathogens and susceptib ili ty patterns. During the winter of 1994-95, middl e ear fluid sa mpl es were collected from 9 17 patients with acute otitis media in Bulgaria, the Czec h Republic, Hun gary, Romania, Slovakia, Israel, and the USA. Pathogens were isolated from 62% of the patients. For . JJIIClllll olliar (30% of the patients), untypcable H . il~f1111'lIzac ( 17%) and M. ((/fan·lta/is (4%), there was significant variation among geographic regions (P < 0.00 I).
65
~ -I actamase was produced by 31 % and 100% of the isolates of H. itif/ll e" zae and M. catarrltalis respectively. The prevalence of resista nt S. PIiCII//IOHiae was highest 111 patients less than 12 months of age. Several studies have now reported the outcome of treating acu te o r persistent otitis media due to pneumococci that are nonsusceptible to penicillin. As is generally the case, oto~copic eval uation of the tympanic membrane and clinical condition define the outcome measures. Thus, the results are somewhat subj ective, especially 111 nonrandomized, investigatorunblinded studies. All the studies 1I1c1uded an iniual tympa noce ntesis for culture of middle ear fluid . Cefuroxime and cefprozil, were found to be efficacious in most of the children evalu ated in these studies; cefaclor and cefLxime have not been as effective as some of these other agents. Although only a small number of children were treated in one tudy, cefpodoxime did not appear to be particularly effecuve despite having reasonable 111 vitro activity against S. p"euII/oniac isolates that were nonsusceptible to penicillin (20). This lack of effectiveness might possibly be related to the relatively low concentrations achieved in the middle ear. [n a second study of cefPodoxime for otitis media, the outcome in all four children with penicillin-nonsusceptible strains (mainly intermediate) was satisfactory (21). In the treatment of infections due to S. JJllelII/lOIl/(/C \V1th the oral cep halospOlins, the rates of resistance for the region or co untly must be taken into account. [n Europe there is a marked variation in the rates of pemcillin-resistant S. P"Cllllolliae varyi ng frOl11 0%-3% in The Netherlands and Italy to 30%-52% in Hungary and Spa1l1 [22). The length of therapy of acute otins medla has been debated. Kozyrskyj et al. [23] conducted a meta- analysis of ra nd om ized controlled trials of antibiotic treatment of acute oti tis media in children to detemline whether outcomes were compa rable in children treated with antibiotics for less than 7 days or 7 days or more. Their results suggested that 5 days of sholt-acting antibiotic use IS effective treatment for uncom pli cated aC llte otitis media in children . Cohen et a1. [2~), in a prospective, comparative, double-blind, randomized, multlcenter trial, compared amoxicillinl clavulanate in three divided doses for 10 days with an Identical 5-day regimen , followed by a 5-day placebo period. Multivanate analysis showed that the IO-day course was statlStically ~upenor (86.8% vs. 70.8%; P= O.OOS) .
COMMUNITY-ACQUIRED PN EUMONIA When considering the relevance of antll1ucrobial resistance of th e bacterial pathogens that are the etiolOgiC agents of coml11 uni ty- acquired pneumonia (CAP), it IS important to take into co nsideration whether or not the agent cau~es a
( 2000 Copyright by the European Society of Clin(cal Microbio logy and InfectiOUS Diseases, eMI, 6 (Suppl. 3). 64- 69
66
Clinical Microbiology and Infection, Volume 6, Suppl ement 3, 2000
concomitant bacteremia and the level of resistance of the organism to the antimicrobial. Although H. i'!f7Hellzae is often cited as one of the most frequent causes of CAP, it is infrequently isolated from the blood [25]. In studies carried Ollt prior to the introduction of the H. h!f7Hellz ae type b vaccine, approximately one-third to one-half of the blood culture documented cases of H. i,if/lleuzae pneumonia were due to type b [26,27] . To date in Canada, due to the Wldespread use of the type b vaccinc, the rate of colonization and invasive disease, such as pneumonia and bacteremia, is significantly less 111 all age groups [28]. S. pllel/molliac is clearly the most important bacterial pathogen causing CAP. Approximately 30% of all cases of CAP due to pneumococci are bacteremic, and therefore potentially able to cause secondary infections at extrapulmonary sites. p-Lactam resistance in H. i,.if/llellzae is due almost exclusively to the acquisition and expression of the TEM and ROB p-lactamase genes. Currently the rates of plactamase positive H. hif/uel1zae are> 30% [19]. The relevance of this increase in resistance to the impact of the treatment of CAP is questionable. [n addition, the new oral cephalosporins have retained excellent activity against the p-Iactamase positive strams with MIC<)I, ~ 4 mg/L (Table 2) [17]. The use of the oral p-Iactams for the treatment of penicillinresistant nonmeningeal lIlvasive pneumococcal infections is controversial [29-32] . Where clinical data are lacking, pharmacokinetics and pharmacodynamics may provide insight as to the expected efficacy of a p-lactam [33-35]. Animal studle~ with variolls penicillins and cepha lo ponns against penicillin-susceptible and -resistant pneumococci have shown that the duration of time that serum levels are above the M [C IS the key parameter in detemlining efficacy. Mortality was virtua.lly 100% if serum levels were above the M IC for ~ 20% of the dosing interval . In contrast, when the time above the MIC was ~ 40% for penicillins and ~ 30% for cephalosporins the mortality rate was < 10% [34].
The general consensus is that nonmeningea l invasive pneumococcal infections due to strains that are intermediately resistant to penicillin can be treated with penicillin or amoxicillin . There is little clinica.l evidence for their failure when treating penicillin-resistant pneumococci, even high ly resistant strains. This is most likely the resu lt of the high concentrations achieved in the serum and at the site of infection [33]. Although there again is little evidence for clinical failures when intermediately and highly penicillin resistant nonmeningeal invasive pneumococcal infections are treated with an oral cephalosporin, they should be used with caution, especially for the treatment of high ly penicillin resistant strains. There is a uniform increase of four- to 16-fold in the M[Cs of the oral cephalosporins for those strains of pneumococci that are intermediately resistant as compared with those that are susceptible, and another two- to eightfold increase for strains that are highl y penicillin resistant as compared with those intermediately resistant [33,36]. Craig (34] determined the time above the MIC for several oral p-lactams (amoxicillin-c1avu!ana te, cefaclor, cefuroxime, cefprozil, loraca rbcf, cefpodoximc, cefixime) and found that only amoxicillin/clavulanate was above the MIC for > 40% of the dosing interval for penicillin-resistant strains of pneumococci. Cefuroxime and cefprozil were above the M IC for 35% and 32%, respectively, of the dosing interval, but on ly for susceptible and intermediately resistant pneumococci.
UNCOMPLICATED SKIN AND SOFT TISSUE INFECTIONS Cellulitis is one of the mo t important diseases of ski n and soft tissue. Cellu litis is a common disease, w hic h is rare ly life threatening and can usually be managed witho ut hospita l admission. It is most commonly due to GABHS and Staphylococcus mueus. As noted previously the new ora l cephalosporins have uniformly excellent activity against Ta bl e 2 The in vitro activity of the new ora l cephalosporins against H. influenzae
MI C (mg / L) ~- I actamase
Ceflxlme Cefuroxime Ceftibuten Cefpodoxlme Cefprozil Cefetamet Cefd,"" Cefaclor
negat ive
~- I act amase
posit ive
50%
90%
50%
90%
0.12 1 0.06 0.06 2 0.12 0.12
0.12 2 0.06 0.125 16 0.25 0.25 16
0.03 1 0.06 0.06 16 0.25 0.12
0.12 4 0.06 0.125 > 16 0.5 0.25 32
4
4
Adapted from (17] .
( 2000 Copyright by the European Society of Clinical MIcrobiology and Infectious Diseases. eMI. 6 (Suppl . 3). 64- 69
Low New oral cephalosporins
GABHS. Wise [371 studi ed th e pharmacokinetics of SOllie of the new cephalosporins (cefpodoxi ll1e proxetil, cefm oxim e axeti l, cefixi me, cefprozil and ceftibut en) and found th e penetration into IIlflammato ry exudate to be 132% of the se rum conce:ntration for cefixime, 113% for ceftibuten, 104% for cefpodoxime, 92% for cefuroxime and 79% for cefprozil. There was a relati onship between the serulll elimination half-llfe of these:: agents and the degree of ti ss ue penetration, those: agents with longer half-li ves penetrating to a gre:ater extent. H owever, there is marked variabi lity in the activity of these new agents to S. IIl1rCIIS (Table 3). Cefixillle, ceftibuten and cefetamet all ha ve MI C'!fI ~ 32 mg/ L, making them un acct!ptab le for the tn:atment of documented S. IIl1rCIIS infections.
SEXUAllY TRANSMITTED DISEASES The cephalosporins have mainly been recommended for the treatment of gonorrhea. Their value for this indication is especially important with the eme rgence of penicillinaseproducing Neisserill J!Ollorr//(Jclle, spectin omyc in- resistant straim, and the escalating rates of fluoroquinolone-resistance [3R,391. With the exception of cefprozil , the new o ral cephalospo rins provide excellent activ ity aga inst N. gOllorr/welle (Table 4). Ceful"oxime is less active against chrom oso mally resistant isolates than agai nst susceptible ones. These agents have not on.ly provided an alternative treatment for ll1ultidrug-resistant gonorrhea, but with a one dose regimen they have ensured compliance:.
SWITCH THERAPY Switch therapy, the switch from a parental to an oral antimicrobial agent, has been used successfully in the trea tment of many se ri ous II1fections. Several studies have found that sign ifi cant cost savll1 gs can be achieved by switch th erapy. Mo reover, it has the further advantages of shorteni ng hospital
stay and reducing intravenous line-related nosocon1131 bacterenua. The new oral cephalosporins are excellent agents for switch therapy because of their pharlllacok.ll1etic properties and expanded in vitro activity, especially agall1st Gramnegative bacteria. Ceftibuten, cefixime and cefetalllet even exhibit activity against isolates reSIStant to cefotaxime and ceftazidime. Cefixime is a primary candldate for sWitch therapy. Prelinu nary studies have shown excellent chmcal outcomes with switch therapy to cefixune after 2-3 days for a variety of senous infecoon.s (40]. Ranurez et al. (41] srurued switch therapy in 120 patients with a new roentgenographic pulmonary infiltrate and at least two symptoms (cough, fever o r leukocytosis) who were arunitted to hospital and treated with intravenous ceftizoxime sodium (I g every 12 h) or ceftri axone sodi um ( I g every 24 h). Paoents were sWitched to oral cefixi me (400 mg every 24 h) as soon as they met the following cliteria: (1) resolution of fever; (2) improvement of cough and respiratory dlstress; (3) l.I11provement of leukocytosis; and (4) presence of nornlal gastr01l1testinal tract absorption. Of the 120 patients enrolled 75 (62%) had clmical data evaluated. Long- teml follow- up showed that 74 panents (99%) were cured; one patient required readn1lSsion for further intrave nous therapy. Mean duration of hospital Stay was 4 days. This study indicates that switch therapy was effective treatment and reduced hospital coStS by over 100 000.
CONCLUSION The new oral cephalosporin.s have not only provided an alternati ve trea tm ent for emerging lllultidrug reoistant pathogens in the community, nurs1I1g home and hospital setting, but because of improved pharnlacokIneocs they also increase compliance and convenience with once or tWlce a day dosing. In addition th ey have provided an alternative to parenteral therapy, allowing th e patient to be switched to an o ral agent that results in more co t-effective therapy and ea rli er discharge . Ta bl e 3 The in vitro activity of Ihe new oral cephalosponns against 5 aureus
M IC (mg / L) ~- Iactamase
50% Cefixim e Cefuroxlme Cehibulen Cefpodoxlme Cefprozil Cefetamet Cefdlnlr
16
> 64 2 0.5 > 64 0.5
67
positive
~- I ac t amase negative
90%
50%
90%
32 2 > 64 4 05 > 64 0.5
16 2 > 64 4
32 2 > 64 4 4 > 64 0.5
> 64 0.5
Adapled from [42.43]
( 2000 Copynghl by the European SOciely of Clinical Microbiology and InfectiOUs Diseases. eMI. 6 (Suppl. 3) . 64-89
68
Clinical Microbiology and Infection, Volume 6, Supplement 3, 2000
Table 4 The in vitro actIvity of Ihe new oral cephalosporins against N. gonorrhoeae
MIC (mg/L) ~-Iactamase
negative
50% Cef,x,me
90%
0.008 0.06 0.06
Cefuroxime Cehlbuten Cefpodoxlme Cefprozil
p-Iactamase positive 50%
0.03 0.125 0.25
0.008 8.0 0.01
Cefetamet Cefdlntr
0.008
0.03 32 0.06 0.03
Cefaclor
8.0
32
90%
0.03 0.25 0.1
0 .06 1.0 0.5 0.06
0.03 16 0.03 0.01 > 16
>64 0.06 0.06 >64
Adapted from [17).
13. Stcpht!n~on J lcelandlc researche~ are showing che way to bring down rates
REFERENCES
of antlb,otlc-re,;"ant bacteria. }AMA 1996; 275 : 175. DaJam A, Taubert K. Ferrien p. Perer G. Shulman S. Treatment of
14 . Appdbaum PC. Antlmicroblal
\[J.tement for heAlth Endocardlri~. DI~ase In
prort.~c;sonal\.
Jnd Kawas.akl
Comml[[ce on Rhc..'ul11.ltlC rever,
J)i~l"a~c
of the COUllu\ 011 CardlOvalicu!ar ~ lean
the Young. che Amcncan
As url.lUon. Pet/iatrits 1995;
96 751164
2. Feldman
'>.
Bl
pelllClI"n G
111
cd. A,,'ItItiml!,,'af 71u.'mpy
group A «reptococc.1 ph.lryng"''' reev.,lu.lrion.} Peri,""
to
eradIcate group A meptocorCl dUring an outbreak of
LIJ/w 19HII; ii : 49tl-502,
5. I'ortler If . ('hJvJnet p. W.ldller-Comhernollx A et al riw vcrsU\ ten day, (r~a(men{ of ~trep(o(occaJ ph:tryngollHl\lllltl\ ...1 randolnl1cd controlled trial
romp.lnng ,dj>odoxllne proxet" alld phenoxymethyl l'"mClIi,n . Scnllli
J
Ualrimorc. M.lryl,md : Uarri ere
to or,ll cephalo'i'ponns III acute oc::itl~ media cau\ed by pneul1lococci with
19. Jacob, MR. Dagan
to
pemClI"n. I'<'lllIItr iJifi,,(1 Dis} 199/\; 15: 980-5.
R. Appelb.lUlIl PC. Burch
DJ.
Prevalence of
1111ddle ear thud: mulnn,lt1onal \tudy
In
of 917 children With acute otlti, media. /1111;"111",/1 A.~('tII5 CI'rllwllier 1998 ; 42: 5l!9 ·95. 20. V.l n D yk JC . Tere'pol,ky A, Meyer
S. vall N,ekcrk C II . Klugman KP.
Pcnctr.mon of (t..·fPodoxlille U1(O 1111ddll' C.1r OuuJ 111 pc..·"iI.ltric parJel1b with
II/(ra /)JS 1994; 26: 59·.(>6.
6. Plchichero ME. Gooch WM. Rodnguez W et .1. Eflhtlvc , horl-cou""
A bctJ-hcmol)'Clc \rrepto(occal coll'iilloph.uyngi-
m. Tell d,IY' ofpelllCllian V v, 5 day. or 10 day, lIfccfpodo"""c therapy '" rhildren. Arr" P('d",,, Adolm Aleri 1994; 148 : I05J· 1,0. 7. (',ell/thero ME, M.rgoli, PA. A comp.lrJson of ,ep halo'p0rIJ" a"d rhe (rcannellt' of group A bet.l-hcmolytK srrcptoc:occ.11
acute orlm medl'. I',dintr Iliff(1 Di,) I Y97; 16: 79-l! I. 21. Geh.nno p. Barry B. Bob," S. Safran C. TwlCc dAIly "'~'odox ,,"c proxenl compJrcd with thrke d:llly 31110XI(;i1hn/clavublllc ,Idd for rrca nncm of
.Kute otlm IIIcd,.1
chIldren Sr,,,,,'} 111/,'"
III
DII
11)94; 26; ,77· H4.
22. RIChard MI'. AgU.ldo AG. Mattina R. Marre R. Senm,vllY to 'parfloxacin .1nd
other .lnnblotlc'i,
of Streproc.:o(,'cus
PIlc..'lIl1lonJ.le.
Il.lt.·rnopllllm
phJrynglu\: a meta-;lI1aIY\I\ \UPportlllg the concept of mKroblill (opacho·
wllucnzJc ,md Moraxcll,l cJLlrrh.lh, ,rr.lIm l'\oJ.ned from ilclult paw.'m'i
gerullry Prl""rr I,,(ret /),,) 1991 , 10 275H I
With cOllll11unJty-acqlllrl"d lower respiratory rrJct
H. I fohn S. f lenntng C. (,rahn E.
c(
al. h pCI1I(ilhll thl' JPpropriacc
rrCJCl1lcm
for rccurrcm [Onsilioph'lrynglCl~? Re,ulr~ from .1 ro rnp;U';ttIVI.: r.mdomizl.'d
hlmd \{udy of cefuroxllne axt"ol .1I1J phcnoxymctilylpcllI, a)ltn 111 duldrcn. The ~wedl h ~,u<.ly Group.'i
I '(I({/m's,
DJ!:Jn R. Abranmln O. I.elbovltz E Ct al. Imp.,ired b,lC[eriolog,r response
,1111'IUllrroblal-re\l\t3nc pathogcm
group A 'treptococ,,1 pharyngitis. 1" 'llta" III(ea /), .• 1986; 5: (\4')··54.
rre;H111~m of .lcute group
I~ .
IIltcrmediate re'hlallce
~ 4 . ~tlllenl1all M Companson of oral reph.lo'porlll' with PClliClillll rherapy for
pelllCllhn~ III
/l1Il1
Will'Jm, and WIlke",. 19'JH: 70J-48.
3 Gas~111.1duy AS. KaplJIl EL. Il uwe IJB. McKay C. W.llIl.l1nakcr LW. pharyn~''''.
rrcptococcus pncul11oniae: an
15. Appelbaum PC, Anribloric-n:)lstJnt pnelll1lococci fact' .lIld ficnon . ) C/J('JJtol/Jer 1994; 6 (Supp!. 4): 7· 15. 16, Par,ldl'ic Jl. Treaclllem guidehne\ for O[lrJ:-, media: the I1cc..'d for breadth and flexlhllary. Perii"tr III(erl Dis} 1995: 14: 429 -35. 17. 1J.,·,kler A. Uelfiglao SR. Cephal"'l'on",: Oral III: Yu VL. Mongan Te.
I'JR7. 110' 7KJ-7. Fadure of peJllciillll
re~i~caJlce III
overview. Clill iJ!{iw Dis 1992; 15: 77-83.
acute \rrcptococcal pharyngitis and prevention of rheumatic fever: a
pharyng.tls: the case for penlCilllIl 'herapy. I'rd'dtr III(e(1 Oil} 1994; 13: 1-7.
111. RelChler MR. Allrilln AA. I:lrellll.lJl RF ct al. The 'pre.d of llIultiply d.IY cMe centc..'r
III
OhiO.) !tift'(f DiJ
SPAR
Study
Group.
rc:"huncc 111 pneumococci 111 fccland
/ .lIIIU"
1992; 339, 160(,· 7,
12. MUIlOl R. Cof!oy TJ. DanIel, M ct .,1. l/ltercolltlllen~ll 'prcad of a o(~rotype
23r Srrept()lo((U\
pnCUI1WIlIJC.
J bU"11 DB
IIlfection~ : ,1 European
Sur\'l.'11I,1I1('t~
Programme of
Alltlb,otlc It,...",allce} ,-IIIIII"irrol> ChelJl",Itl" I~~H ; 41 ' 207- 14.
23 K()/y"lYJ AL. H,ld,... -R'p;telll Gr.. LOllg-ot.,ffc J
'>E et al.
Tr
\horte llcd (OUriC of ,1I1ubIOtin: J lll~t;l -Jna ly\l'L Jtl,~ fA
I99R; 279 171642. 24. Cohen It. Levy C, Boueherat M . LangueJ. de LJ Rocque F. A /lIlIlelCe",er. r.lJldoIl1l7ed. dOllble-bhnd tnal of 5 vel''''' III day' of anllb,otic t herapy for .1CUte o"m med,a '" young ch,IUren.) 1" 't/i,II' IlJ9H; 133 : 634 ·9. 25. Lang CD. rille M. Orloff J ct .,1. New
1'192; 166 1346·53. II. Kn~C1n~~n KG. IIJdlm.lI'~dotUr MAt SrclIlg:nl11 ..\Un () Incn:.I\lng pt.·llll ll1ll1
mulurec.hcanc clone 11)')1; 1M JIl2-6.
study.
ontl' Ilwdl.1 with
Shullll.lll ST. Gerber MA. T.n7 RR. MarkowJt7 M . StJ'cpto('()cc.,1
rt..··mt.lOc 5trcp(()cocCLl~ pncumomae ,1C a
111 11 Itu.:entre
.111"
elllcrW"l! etiologIC, for
c.:omI111l1l1t)' ·,lCqu lred pncurnom.1 With Ill1pIK.IfIUI1\ for dH:r;lpy. A prO\pcl' tI\'C
IlIl1ltl
26. W.ll1"ce
RJJ.
IIltt'nlOI1\ 111
C.I'....
.I/('.I,ril/(· (13.1/111""") 1990. 69' 307· 16.
Mu,hcr OM. Sepramu,
adult\:
PJ
et .1. 11 .!Cllloph ,lu, ",tlueIl1J"
char.tCtcn7Jt10n of rr.lIm
by
\crotype~. bu')typc\, .1Ild
bct.ll.,ct.l/l1,,,e production} II/(rll DIS 19HI. 144 ' 101 6.
I
2000 COPYright by Ihe European SocIety of Cltntcal MIcrobiology and InfectIOUs Diseases. eMI. 6 (S uppl. 3). 64-69
Low New oral ce ph alosporins 69
27
J)t:'l1lolt~lI
F, Nan JM . Bella
r
cc .11. Pro\pc(tI\'!t cpldl'I1l1ologICai 'fl1dy of
1IlVal,J\'l' JI.ICIllOphlhh Illtlucnzal' dl~t..'a.~1!
l1l
35 , Drusano GL. Craig WA. Rdt.'vancl" of phamlJcoklllcnn and phJ.n1l.Jco-
.1duJt" Em J elm ,\ licm/"t.1 II/Ji-'ct
dynamIC' 111 d,C ,dectlon of al'ltIblOClc'i for rC'ipir.uory tract inlc-ction\.
2H. PL'ero!' EO. 1,0\\ 1)[, C,IllJdl.lIl B.lCteri.11 ~ur\'cll1:lI1n,' N"tworJ... ,'r
Serotypc ch;lr.l('[l'nl.uloll of I (d('l//(tl'hi/'H d l\CJ'L' III C.IIUd.l
.1otll
WJ,hlll~"[()J1. 1)(:
29. Anol1ymou\.
or t Ir h
('f' Ami///;(rt,blr,1
A ,\!f'lItS
,'.1«(l I1t.'"
,md
.4/"tfdffS
I!(
36, Appdh.llllll PC. NL'W prospN'b for annb.lctL'nal .1gCllr' J~lII"[ muludrugrc~i\r.l11{ pnClII1l0CO(Cl . ,\I;rrlli, f)mg Rrsi.H 1995; 1 4J ·H 37, Wi\c R. T he p h;lrm3Cokll1L'tl
I llft'(OOU\
cvalu.Hlon of cl'fubmcn 39. Kni.lpp
pnOllIllO(Oen . On'.~.' 1996; 52 (Supp\. 2): 42-(,.
or rL'JIIt,, ?
I W. G.lf,lll
J
JJ C.old~rClll
Sf.\
/...""(1'1 1Y<)7; 350: 233
due to pt·nh: ilhn - n.'~I\c.lIl[ Strt'pll'((I((/lS IHlt'I""olliae . S(llIld
J
lI1(raVl'110l!\
',!(r(/Ol.< 19<)(\: 25 ' 213-7.
gonorrhocJt.' rf\ts[Jn[ to nprutloxJC1I1 and oilnxacin.
J.
CCfiXlnlC for '\\1,eh ,hcr.lpv CIII'n,,,,II"QPr I WK. 44
r.
Ahkee S. !luang A. Raif MJ . Early ,wHeh from
ro oral t.'cphalmporuh
III
rhe rrl'.lt1nCm of ho,pnailzt'tl
I UrCCtlOm
r,!{t'(l
p.:anenh
42. B.lIemfell1d A. J"n!,,,,"rdl R. Anab.crenal Jca",)' of cetpodoXllllc
of {he future . Di"~i!11 ,\ IIt-mll",1
U1
cOl11pan\OIl with cdhunc. l'dainir. cefetamec. cefnburcn, lorar,ubc:t: (ctpronl
Dl.o;
HAY 3522, cCnlrOXJI11c.!, cdaclor and ccfadrmal. IS'Ul',
CllO,c.1
gonorrhea. A pilot ,mdy 111 Hong Knng . .s~:.\'
with L'OlTll1l11J1lry-.lcqu lred pncl1 l11onia. Arcl, Imr", .\Ied 199:;; I SS ' 1'273--6.
1997: 29' 255-7 34 Cr.lig WA, Antllnicrobl:ti r(''''.. t.lnce
11)
0" 19
41. n...mora J A. Srl/wh StrI'I""((}((1/,\
,\I/cmbi,,/ 1995; 43 : 237··8Cholft.' of an oral ber.l-l.1cr.ll1l antlblotll: for
J
(SlIPP\. I): 24-7 .
J t\l('d
rw ,
J . Nt'i\\eria
Tr,,,,,,,,,
40. I-bnnl,on-Mdlcr
3() yc:af\ of pcninll in rl'~hr3nr S pm' II/WIII;,II': 1nych
32 Srr.ll'h.lIl ~A, Fnl·dl.lIld IR . Therapy (or pCI1I1.: dhn-rl',,,,r:ll1r IIIU'/ll1wI/idt'.
rene\\'.
Tra".'''' Oi, 199H; 25 : 464-7.
I)I 'C:1\t.'\
19l}'. 99' 2HIJ-'i')
Gold\(l'lll
',I
38. Chong LV . Chellng WM . Leung CS. Vu CWo Ch.n LV
chlldrl'll wlth II1\'a,IVc pnculllococcal IIlfl'c[Jom.
J{) Klug-m.1I1 KP, Epldt'J1110Iogy, comroi and In..'JCmelH of l11ulrirc\I\[.lllt
J I.
o( cht:' oral cephalo'ponm-
A"Ii/"im" CIII'I""I/'f( I <)l)O; 26 (SlIPPI. E): 13 ·20 .
CIU'/l/I,t"a(I!')',
Amcn ca n SOClcty for Mll"roblolo1-.'Y. 191.)0.
ThL·r.lp)' t()f
AIllL"rIl'.lJl Acadt..'Ill)' of Pl.'d l.ltnn C011111l1ttL'C on
red""",.,
.11.
I/Jlll/fII~'/1' I,OJ.ltC' (;llI\ l ll~ IIlV,l'IVC
following thl.' II1rrodul.:rion
C(l/!{I'rl'II(f
rWnwiClkf
J
CII,·",,,,/,,·, 19\17; 9 (StiPP\. 3): 3H 44.
/)" 1')\)4; 13 ; ().H-H.
43
l"/~'frmtl
1991 : 19: 353-62.
Feimingh'lII D. Robb"1\ MJ. Gha,h G et al. AJl on "ltro characrotiution of cefJttofcll,.l nc\\ oral cephalo(jporm. Dm.~j £\'P elm Rt') 1994,20: 127-47.
" 2000 COPYrigh t by the European Society of Clinica l Microbi ology and Infect'ous Diseases. eMI. 6 (Suppl 3). 64-69
ClitJ Microbiol fllject 2000: 6 (Supplement 3): 64-69
Oral cephalosporins have been used primarily for the treatment of community-acquired infections such as community-acquired
infections seen in general medica.l practice, accounting for a significant number of physician office visits per year. Although
pneumonia, pharyngitis, otitis media, bronchitis, skin, and skin
patients recover clinically without antibiotic therapy, treatment is
strucrure infections and wlcomplicated urinary traCt infections. The goal in the development of the first oral cepll,,]osporins was to
fever and to reduce the incidence of locally invasive infecti on.
unprove their phannacokinetic profiJe. Having accomplished that, the nel\.1: was to enhance their antibacterial activity. The newer oral
'gold standard' treatll1ent for streptococcal pharyngitis [1], and
recommended to hasten clinical resolution, to prevent rheumatic Since its introduction in the 1940s, penicillin has been the
cephalosporins demonstrate an increased ill vitro antibacterial activity and enhanced [3-laCtan1ase stability and phanmcokinetic properties (Table 1). They not on.ly provide an a.ltemative for the treatment of
for many years it effected consistent microbiologic eradication ra tes of over 90"10 [2]. However, in more recent years, the incidence of bacteriologic failure \vith oral penicillin therapy 11,15
infections in the COnIDlllnity due to pathogens resistant to other antimicrobia.l agents, but their improved phanl1acokinetics increase
increased to as much as 10"/0-30% [3,4]. Alternatively [3-lactarnasest.1ble oral cepha.losporins have been shown to be highly effective
compliance. [n addition they may be used in the hospital setting for switclung from parenteral to oral therapy, thereby decreasing costs and alJO\ving earlier patient discharge. The new oral cephalosporins can be divided into those absorbed as the parent compound
in the treatlJlenr of streptococcal pharyngitis [3,41. In addition, triaJs of expanded-and broad-spectrum oral cepha.losporins in Europe [51 and more recendy m North America [6] suggest d13t a 5- to 7-day duration of therapy is as effective as or even more effective than dle classica.l I D-day regimen of penicillin .
(cefdimr, cefi:ibuten, cefixime and cetprozil) and those absorbed in the fonn of ester prodrug; (cefi.lroxime axetil, cetpodoxi11le proxetil
The phenomenon of higher S. pyogclles eradication rates for
and cefetamet pivoxiJ). In this paper, because of space limitations,
cephalosporins has been previously noted. Pichichero and
we will review the role of these new oral cepha.losporins in a
Margolis have reviewed a number of studies comparing
selected number of important clinical indications.
cephalosporin with penicillin for the treatment of streptococcal pharyngitis [7) . Based on their meta-a nalysis, they concluded that the cep halosporins are genera lly more efficacio us,
PHARYNGITIS AND TDNSILLlTIS
presumably due to their resistance to degradation by ~
Pharyngitis due to SfreptococCIIs pyogelles (group A ~-hemo lytic
lactamases. This may be especially true for patients with recurrent streptococcal pharyngitis w ho have been treated with penicillin within the previous 3 months [8]. This o pinion is not shared universally, howeve r. Shulman and co Ll eagues have also reviewed the snldles included in the Pichi chero meta-analysis, and concluded that the availab le literatu re do cs not show that cephalosporins are superio r to penicill in for
streptococci [GABHS]) is one of the most conIDlon bacterial Corresponding author and reprint requests: Dr Donald E. Low, Dcpamnent of Microbiology, Mount Sinai Hospital , 600 University Avenue, R.oom 1487, Toronto. Ontario M5G I X5. anada Tel.: +1 416 5R6 4435 Fax. : + I 4165868746
Table 1 Pharmacokinetics of oral cephalosporins after single dose Antimicrobial
Dose (mg)
400 500 400 400 500 500 300
Ceflxlme Cefuroxlme -axetil Cef1lbuten Cefpodoxlme-proxetil Cefprozll Cefetamet - PIVOXII Cefdlnlr Adapted from
In
healthy volunteers
Frequency
COl"" (mg / l)
AUC o., (mg h / l)
00
3.6 4.9
26 19 79 27 30 25 6.5
BID
00 00 BID BID BID
17
4.5 10 4.1 1.6
T 1/2
(h)
3.1 2 2.3 2.4 1.3 2.3 1.4
Urinary elimination (% )
32 24 70 22 18
(17) .
r
2000 Copyrrght by the European Society of Clinical Microbiology and InfectiOUs Diseases, eMf. 6 (Suppl. 3). 64- 69
Low New oral cephalosporins
treatment of streptococcal pharyngitis (9). The Food and Drug Administration in the USA has approved the use of a 5-day co urse of cefdinir for the treatment of streptococcal pharyngitis and had previously approved cefpodoxi me proxetil for 5-day therapy as well. All of the newer ora l cep halospori ns have excellent ac ti vity aga inst the GAB H S with MI C", < I mg/ L.
OTITIS MEDIA Acute otitis media contin ues to be an important public health problem around the world. The most commo n bacterial pathogen, StreptocoCCli s pllelllllollille, has been implicated as part of the current antibiotic resistance crisis. The first cases of penicillin- resistant S. P"Cllloliac were reported in Australia and New Guinea in the ea rly 1970s. In less than a decade, highly resistant strains that exhibited resistance to multiple antibiotics we re isolated from patients with invasive infections, as well as trom carriers, in South Africa. The prevalence of penicillin-resistant pneumococcal infections has escalated steadi ly. The increasing use of day- care facili ti es provides a vector for transmission of resistant pneumococci [10] . lntemational spread of resistant isolates has been documented [I 1- 13], so that penicillin-resistant pneumococcal infections have become a global problem r14, 15]. The optimal management of ac ute otitis media is widely debated for many reasons [1 6], beginning at th e most basic level of medica.l management, because there is no conse nsus rega rdin g diagnostic criteri a. The selection of antibi oti c therapy is usually empiric because of the difficulty of obtaining cultures. Although authorities usually agree that S. p"clilllOlliai' and un typeable HaclI10phillis illjlll clizae are the most conUllon bacterial pathogens, the prevalence of resistance is not as well documented . With the exception of ceftibuten, which is less ac ti ve against Moraxel/a ((/tarrlw lis and S. p"rill/Wiliac, the new oral cep halosporins are generally more potent irthibitors of co nulluni ty- acquired respiratoly pathogens than the older oral cep halosporim [1 7]. Eradication of pat hogens fi'om midd le ea r fluid an d clini cal outcome have been reported to be less favorab le if pathogens with reduced antimicrobia l susceptibility are present [1 8]. J acobs et al. [1 91 condu cted a large, internatio nal study of infants and children with acute otitis media to identify pathogens and susceptib ili ty patterns. During the winter of 1994-95, middl e ear fluid sa mpl es were collected from 9 17 patients with acute otitis media in Bulgaria, the Czec h Republic, Hun gary, Romania, Slovakia, Israel, and the USA. Pathogens were isolated from 62% of the patients. For . JJIIClllll olliar (30% of the patients), untypcable H . il~f1111'lIzac ( 17%) and M. ((/fan·lta/is (4%), there was significant variation among geographic regions (P < 0.00 I).
65
~ -I actamase was produced by 31 % and 100% of the isolates of H. itif/ll e" zae and M. catarrltalis respectively. The prevalence of resista nt S. PIiCII//IOHiae was highest 111 patients less than 12 months of age. Several studies have now reported the outcome of treating acu te o r persistent otitis media due to pneumococci that are nonsusceptible to penicillin. As is generally the case, oto~copic eval uation of the tympanic membrane and clinical condition define the outcome measures. Thus, the results are somewhat subj ective, especially 111 nonrandomized, investigatorunblinded studies. All the studies 1I1c1uded an iniual tympa noce ntesis for culture of middle ear fluid . Cefuroxime and cefprozil, were found to be efficacious in most of the children evalu ated in these studies; cefaclor and cefLxime have not been as effective as some of these other agents. Although only a small number of children were treated in one tudy, cefpodoxime did not appear to be particularly effecuve despite having reasonable 111 vitro activity against S. p"euII/oniac isolates that were nonsusceptible to penicillin (20). This lack of effectiveness might possibly be related to the relatively low concentrations achieved in the middle ear. [n a second study of cefPodoxime for otitis media, the outcome in all four children with penicillin-nonsusceptible strains (mainly intermediate) was satisfactory (21). In the treatment of infections due to S. JJllelII/lOIl/(/C \V1th the oral cep halospOlins, the rates of resistance for the region or co untly must be taken into account. [n Europe there is a marked variation in the rates of pemcillin-resistant S. P"Cllllolliae varyi ng frOl11 0%-3% in The Netherlands and Italy to 30%-52% in Hungary and Spa1l1 [22). The length of therapy of acute otins medla has been debated. Kozyrskyj et al. [23] conducted a meta- analysis of ra nd om ized controlled trials of antibiotic treatment of acute oti tis media in children to detemline whether outcomes were compa rable in children treated with antibiotics for less than 7 days or 7 days or more. Their results suggested that 5 days of sholt-acting antibiotic use IS effective treatment for uncom pli cated aC llte otitis media in children . Cohen et a1. [2~), in a prospective, comparative, double-blind, randomized, multlcenter trial, compared amoxicillinl clavulanate in three divided doses for 10 days with an Identical 5-day regimen , followed by a 5-day placebo period. Multivanate analysis showed that the IO-day course was statlStically ~upenor (86.8% vs. 70.8%; P= O.OOS) .
COMMUNITY-ACQUIRED PN EUMONIA When considering the relevance of antll1ucrobial resistance of th e bacterial pathogens that are the etiolOgiC agents of coml11 uni ty- acquired pneumonia (CAP), it IS important to take into co nsideration whether or not the agent cau~es a
( 2000 Copyright by the European Society of Clin(cal Microbio logy and InfectiOUS Diseases, eMI, 6 (Suppl. 3). 64- 69
66
Clinical Microbiology and Infection, Volume 6, Suppl ement 3, 2000
concomitant bacteremia and the level of resistance of the organism to the antimicrobial. Although H. i'!f7Hellzae is often cited as one of the most frequent causes of CAP, it is infrequently isolated from the blood [25]. In studies carried Ollt prior to the introduction of the H. h!f7Hellz ae type b vaccine, approximately one-third to one-half of the blood culture documented cases of H. i,if/lleuzae pneumonia were due to type b [26,27] . To date in Canada, due to the Wldespread use of the type b vaccinc, the rate of colonization and invasive disease, such as pneumonia and bacteremia, is significantly less 111 all age groups [28]. S. pllel/molliac is clearly the most important bacterial pathogen causing CAP. Approximately 30% of all cases of CAP due to pneumococci are bacteremic, and therefore potentially able to cause secondary infections at extrapulmonary sites. p-Lactam resistance in H. i,.if/llellzae is due almost exclusively to the acquisition and expression of the TEM and ROB p-lactamase genes. Currently the rates of plactamase positive H. hif/uel1zae are> 30% [19]. The relevance of this increase in resistance to the impact of the treatment of CAP is questionable. [n addition, the new oral cephalosporins have retained excellent activity against the p-Iactamase positive strams with MIC<)I, ~ 4 mg/L (Table 2) [17]. The use of the oral p-Iactams for the treatment of penicillinresistant nonmeningeal lIlvasive pneumococcal infections is controversial [29-32] . Where clinical data are lacking, pharmacokinetics and pharmacodynamics may provide insight as to the expected efficacy of a p-lactam [33-35]. Animal studle~ with variolls penicillins and cepha lo ponns against penicillin-susceptible and -resistant pneumococci have shown that the duration of time that serum levels are above the M [C IS the key parameter in detemlining efficacy. Mortality was virtua.lly 100% if serum levels were above the M IC for ~ 20% of the dosing interval . In contrast, when the time above the MIC was ~ 40% for penicillins and ~ 30% for cephalosporins the mortality rate was < 10% [34].
The general consensus is that nonmeningea l invasive pneumococcal infections due to strains that are intermediately resistant to penicillin can be treated with penicillin or amoxicillin . There is little clinica.l evidence for their failure when treating penicillin-resistant pneumococci, even high ly resistant strains. This is most likely the resu lt of the high concentrations achieved in the serum and at the site of infection [33]. Although there again is little evidence for clinical failures when intermediately and highly penicillin resistant nonmeningeal invasive pneumococcal infections are treated with an oral cephalosporin, they should be used with caution, especially for the treatment of high ly penicillin resistant strains. There is a uniform increase of four- to 16-fold in the M[Cs of the oral cephalosporins for those strains of pneumococci that are intermediately resistant as compared with those that are susceptible, and another two- to eightfold increase for strains that are highl y penicillin resistant as compared with those intermediately resistant [33,36]. Craig (34] determined the time above the MIC for several oral p-lactams (amoxicillin-c1avu!ana te, cefaclor, cefuroxime, cefprozil, loraca rbcf, cefpodoximc, cefixime) and found that only amoxicillin/clavulanate was above the MIC for > 40% of the dosing interval for penicillin-resistant strains of pneumococci. Cefuroxime and cefprozil were above the M IC for 35% and 32%, respectively, of the dosing interval, but on ly for susceptible and intermediately resistant pneumococci.
UNCOMPLICATED SKIN AND SOFT TISSUE INFECTIONS Cellulitis is one of the mo t important diseases of ski n and soft tissue. Cellu litis is a common disease, w hic h is rare ly life threatening and can usually be managed witho ut hospita l admission. It is most commonly due to GABHS and Staphylococcus mueus. As noted previously the new ora l cephalosporins have uniformly excellent activity against Ta bl e 2 The in vitro activity of the new ora l cephalosporins against H. influenzae
MI C (mg / L) ~- I actamase
Ceflxlme Cefuroxime Ceftibuten Cefpodoxlme Cefprozil Cefetamet Cefd,"" Cefaclor
negat ive
~- I act amase
posit ive
50%
90%
50%
90%
0.12 1 0.06 0.06 2 0.12 0.12
0.12 2 0.06 0.125 16 0.25 0.25 16
0.03 1 0.06 0.06 16 0.25 0.12
0.12 4 0.06 0.125 > 16 0.5 0.25 32
4
4
Adapted from (17] .
( 2000 Copyright by the European Society of Clinical MIcrobiology and Infectious Diseases. eMI. 6 (Suppl . 3). 64- 69
Low New oral cephalosporins
GABHS. Wise [371 studi ed th e pharmacokinetics of SOllie of the new cephalosporins (cefpodoxi ll1e proxetil, cefm oxim e axeti l, cefixi me, cefprozil and ceftibut en) and found th e penetration into IIlflammato ry exudate to be 132% of the se rum conce:ntration for cefixime, 113% for ceftibuten, 104% for cefpodoxime, 92% for cefuroxime and 79% for cefprozil. There was a relati onship between the serulll elimination half-llfe of these:: agents and the degree of ti ss ue penetration, those: agents with longer half-li ves penetrating to a gre:ater extent. H owever, there is marked variabi lity in the activity of these new agents to S. IIl1rCIIS (Table 3). Cefixillle, ceftibuten and cefetamet all ha ve MI C'!fI ~ 32 mg/ L, making them un acct!ptab le for the tn:atment of documented S. IIl1rCIIS infections.
SEXUAllY TRANSMITTED DISEASES The cephalosporins have mainly been recommended for the treatment of gonorrhea. Their value for this indication is especially important with the eme rgence of penicillinaseproducing Neisserill J!Ollorr//(Jclle, spectin omyc in- resistant straim, and the escalating rates of fluoroquinolone-resistance [3R,391. With the exception of cefprozil , the new o ral cephalospo rins provide excellent activ ity aga inst N. gOllorr/welle (Table 4). Ceful"oxime is less active against chrom oso mally resistant isolates than agai nst susceptible ones. These agents have not on.ly provided an alternative treatment for ll1ultidrug-resistant gonorrhea, but with a one dose regimen they have ensured compliance:.
SWITCH THERAPY Switch therapy, the switch from a parental to an oral antimicrobial agent, has been used successfully in the trea tment of many se ri ous II1fections. Several studies have found that sign ifi cant cost savll1 gs can be achieved by switch th erapy. Mo reover, it has the further advantages of shorteni ng hospital
stay and reducing intravenous line-related nosocon1131 bacterenua. The new oral cephalosporins are excellent agents for switch therapy because of their pharlllacok.ll1etic properties and expanded in vitro activity, especially agall1st Gramnegative bacteria. Ceftibuten, cefixime and cefetalllet even exhibit activity against isolates reSIStant to cefotaxime and ceftazidime. Cefixime is a primary candldate for sWitch therapy. Prelinu nary studies have shown excellent chmcal outcomes with switch therapy to cefixune after 2-3 days for a variety of senous infecoon.s (40]. Ranurez et al. (41] srurued switch therapy in 120 patients with a new roentgenographic pulmonary infiltrate and at least two symptoms (cough, fever o r leukocytosis) who were arunitted to hospital and treated with intravenous ceftizoxime sodium (I g every 12 h) or ceftri axone sodi um ( I g every 24 h). Paoents were sWitched to oral cefixi me (400 mg every 24 h) as soon as they met the following cliteria: (1) resolution of fever; (2) improvement of cough and respiratory dlstress; (3) l.I11provement of leukocytosis; and (4) presence of nornlal gastr01l1testinal tract absorption. Of the 120 patients enrolled 75 (62%) had clmical data evaluated. Long- teml follow- up showed that 74 panents (99%) were cured; one patient required readn1lSsion for further intrave nous therapy. Mean duration of hospital Stay was 4 days. This study indicates that switch therapy was effective treatment and reduced hospital coStS by over 100 000.
CONCLUSION The new oral cephalosporin.s have not only provided an alternati ve trea tm ent for emerging lllultidrug reoistant pathogens in the community, nurs1I1g home and hospital setting, but because of improved pharnlacokIneocs they also increase compliance and convenience with once or tWlce a day dosing. In addition th ey have provided an alternative to parenteral therapy, allowing th e patient to be switched to an o ral agent that results in more co t-effective therapy and ea rli er discharge . Ta bl e 3 The in vitro activity of Ihe new oral cephalosponns against 5 aureus
M IC (mg / L) ~- Iactamase
50% Cefixim e Cefuroxlme Cehibulen Cefpodoxlme Cefprozil Cefetamet Cefdlnlr
16
> 64 2 0.5 > 64 0.5
67
positive
~- I ac t amase negative
90%
50%
90%
32 2 > 64 4 05 > 64 0.5
16 2 > 64 4
32 2 > 64 4 4 > 64 0.5
> 64 0.5
Adapled from [42.43]
( 2000 Copynghl by the European SOciely of Clinical Microbiology and InfectiOUs Diseases. eMI. 6 (Suppl. 3) . 64-89
68
Clinical Microbiology and Infection, Volume 6, Supplement 3, 2000
Table 4 The in vitro actIvity of Ihe new oral cephalosporins against N. gonorrhoeae
MIC (mg/L) ~-Iactamase
negative
50% Cef,x,me
90%
0.008 0.06 0.06
Cefuroxime Cehlbuten Cefpodoxlme Cefprozil
p-Iactamase positive 50%
0.03 0.125 0.25
0.008 8.0 0.01
Cefetamet Cefdlntr
0.008
0.03 32 0.06 0.03
Cefaclor
8.0
32
90%
0.03 0.25 0.1
0 .06 1.0 0.5 0.06
0.03 16 0.03 0.01 > 16
>64 0.06 0.06 >64
Adapted from [17).
13. Stcpht!n~on J lcelandlc researche~ are showing che way to bring down rates
REFERENCES
of antlb,otlc-re,;"ant bacteria. }AMA 1996; 275 : 175. DaJam A, Taubert K. Ferrien p. Perer G. Shulman S. Treatment of
14 . Appdbaum PC. Antlmicroblal
\[J.tement for heAlth Endocardlri~. DI~ase In
prort.~c;sonal\.
Jnd Kawas.akl
Comml[[ce on Rhc..'ul11.ltlC rever,
J)i~l"a~c
of the COUllu\ 011 CardlOvalicu!ar ~ lean
the Young. che Amcncan
As url.lUon. Pet/iatrits 1995;
96 751164
2. Feldman
'>.
Bl
pelllClI"n G
111
cd. A,,'ItItiml!,,'af 71u.'mpy
group A «reptococc.1 ph.lryng"''' reev.,lu.lrion.} Peri,""
to
eradIcate group A meptocorCl dUring an outbreak of
LIJ/w 19HII; ii : 49tl-502,
5. I'ortler If . ('hJvJnet p. W.ldller-Comhernollx A et al riw vcrsU\ ten day, (r~a(men{ of ~trep(o(occaJ ph:tryngollHl\lllltl\ ...1 randolnl1cd controlled trial
romp.lnng ,dj>odoxllne proxet" alld phenoxymethyl l'"mClIi,n . Scnllli
J
Ualrimorc. M.lryl,md : Uarri ere
to or,ll cephalo'i'ponns III acute oc::itl~ media cau\ed by pneul1lococci with
19. Jacob, MR. Dagan
to
pemClI"n. I'<'lllIItr iJifi,,(1 Dis} 199/\; 15: 980-5.
R. Appelb.lUlIl PC. Burch
DJ.
Prevalence of
1111ddle ear thud: mulnn,lt1onal \tudy
In
of 917 children With acute otlti, media. /1111;"111",/1 A.~('tII5 CI'rllwllier 1998 ; 42: 5l!9 ·95. 20. V.l n D yk JC . Tere'pol,ky A, Meyer
S. vall N,ekcrk C II . Klugman KP.
Pcnctr.mon of (t..·fPodoxlille U1(O 1111ddll' C.1r OuuJ 111 pc..·"iI.ltric parJel1b with
II/(ra /)JS 1994; 26: 59·.(>6.
6. Plchichero ME. Gooch WM. Rodnguez W et .1. Eflhtlvc , horl-cou""
A bctJ-hcmol)'Clc \rrepto(occal coll'iilloph.uyngi-
m. Tell d,IY' ofpelllCllian V v, 5 day. or 10 day, lIfccfpodo"""c therapy '" rhildren. Arr" P('d",,, Adolm Aleri 1994; 148 : I05J· 1,0. 7. (',ell/thero ME, M.rgoli, PA. A comp.lrJson of ,ep halo'p0rIJ" a"d rhe (rcannellt' of group A bet.l-hcmolytK srrcptoc:occ.11
acute orlm medl'. I',dintr Iliff(1 Di,) I Y97; 16: 79-l! I. 21. Geh.nno p. Barry B. Bob," S. Safran C. TwlCc dAIly "'~'odox ,,"c proxenl compJrcd with thrke d:llly 31110XI(;i1hn/clavublllc ,Idd for rrca nncm of
.Kute otlm IIIcd,.1
chIldren Sr,,,,,'} 111/,'"
III
DII
11)94; 26; ,77· H4.
22. RIChard MI'. AgU.ldo AG. Mattina R. Marre R. Senm,vllY to 'parfloxacin .1nd
other .lnnblotlc'i,
of Streproc.:o(,'cus
PIlc..'lIl1lonJ.le.
Il.lt.·rnopllllm
phJrynglu\: a meta-;lI1aIY\I\ \UPportlllg the concept of mKroblill (opacho·
wllucnzJc ,md Moraxcll,l cJLlrrh.lh, ,rr.lIm l'\oJ.ned from ilclult paw.'m'i
gerullry Prl""rr I,,(ret /),,) 1991 , 10 275H I
With cOllll11unJty-acqlllrl"d lower respiratory rrJct
H. I fohn S. f lenntng C. (,rahn E.
c(
al. h pCI1I(ilhll thl' JPpropriacc
rrCJCl1lcm
for rccurrcm [Onsilioph'lrynglCl~? Re,ulr~ from .1 ro rnp;U';ttIVI.: r.mdomizl.'d
hlmd \{udy of cefuroxllne axt"ol .1I1J phcnoxymctilylpcllI, a)ltn 111 duldrcn. The ~wedl h ~,u<.ly Group.'i
I '(I({/m's,
DJ!:Jn R. Abranmln O. I.elbovltz E Ct al. Imp.,ired b,lC[eriolog,r response
,1111'IUllrroblal-re\l\t3nc pathogcm
group A 'treptococ,,1 pharyngitis. 1" 'llta" III(ea /), .• 1986; 5: (\4')··54.
rre;H111~m of .lcute group
I~ .
IIltcrmediate re'hlallce
~ 4 . ~tlllenl1all M Companson of oral reph.lo'porlll' with PClliClillll rherapy for
pelllCllhn~ III
/l1Il1
Will'Jm, and WIlke",. 19'JH: 70J-48.
3 Gas~111.1duy AS. KaplJIl EL. Il uwe IJB. McKay C. W.llIl.l1nakcr LW. pharyn~''''.
rrcptococcus pncul11oniae: an
15. Appelbaum PC, Anribloric-n:)lstJnt pnelll1lococci fact' .lIld ficnon . ) C/J('JJtol/Jer 1994; 6 (Supp!. 4): 7· 15. 16, Par,ldl'ic Jl. Treaclllem guidehne\ for O[lrJ:-, media: the I1cc..'d for breadth and flexlhllary. Perii"tr III(erl Dis} 1995: 14: 429 -35. 17. 1J.,·,kler A. Uelfiglao SR. Cephal"'l'on",: Oral III: Yu VL. Mongan Te.
I'JR7. 110' 7KJ-7. Fadure of peJllciillll
re~i~caJlce III
overview. Clill iJ!{iw Dis 1992; 15: 77-83.
acute \rrcptococcal pharyngitis and prevention of rheumatic fever: a
pharyng.tls: the case for penlCilllIl 'herapy. I'rd'dtr III(e(1 Oil} 1994; 13: 1-7.
111. RelChler MR. Allrilln AA. I:lrellll.lJl RF ct al. The 'pre.d of llIultiply d.IY cMe centc..'r
III
OhiO.) !tift'(f DiJ
SPAR
Study
Group.
rc:"huncc 111 pneumococci 111 fccland
/ .lIIIU"
1992; 339, 160(,· 7,
12. MUIlOl R. Cof!oy TJ. DanIel, M ct .,1. l/ltercolltlllen~ll 'prcad of a o(~rotype
23r Srrept()lo((U\
pnCUI1WIlIJC.
J bU"11 DB
IIlfection~ : ,1 European
Sur\'l.'11I,1I1('t~
Programme of
Alltlb,otlc It,...",allce} ,-IIIIII"irrol> ChelJl",Itl" I~~H ; 41 ' 207- 14.
23 K()/y"lYJ AL. H,ld,... -R'p;telll Gr.. LOllg-ot.,ffc J
'>E et al.
Tr
\horte llcd (OUriC of ,1I1ubIOtin: J lll~t;l -Jna ly\l'L Jtl,~ fA
I99R; 279 171642. 24. Cohen It. Levy C, Boueherat M . LangueJ. de LJ Rocque F. A /lIlIlelCe",er. r.lJldoIl1l7ed. dOllble-bhnd tnal of 5 vel''''' III day' of anllb,otic t herapy for .1CUte o"m med,a '" young ch,IUren.) 1" 't/i,II' IlJ9H; 133 : 634 ·9. 25. Lang CD. rille M. Orloff J ct .,1. New
1'192; 166 1346·53. II. Kn~C1n~~n KG. IIJdlm.lI'~dotUr MAt SrclIlg:nl11 ..\Un () Incn:.I\lng pt.·llll ll1ll1
mulurec.hcanc clone 11)')1; 1M JIl2-6.
study.
ontl' Ilwdl.1 with
Shullll.lll ST. Gerber MA. T.n7 RR. MarkowJt7 M . StJ'cpto('()cc.,1
rt..··mt.lOc 5trcp(()cocCLl~ pncumomae ,1C a
111 11 Itu.:entre
.111"
elllcrW"l! etiologIC, for
c.:omI111l1l1t)' ·,lCqu lred pncurnom.1 With Ill1pIK.IfIUI1\ for dH:r;lpy. A prO\pcl' tI\'C
IlIl1ltl
26. W.ll1"ce
RJJ.
IIltt'nlOI1\ 111
C.I'....
.I/('.I,ril/(· (13.1/111""") 1990. 69' 307· 16.
Mu,hcr OM. Sepramu,
adult\:
PJ
et .1. 11 .!Cllloph ,lu, ",tlueIl1J"
char.tCtcn7Jt10n of rr.lIm
by
\crotype~. bu')typc\, .1Ild
bct.ll.,ct.l/l1,,,e production} II/(rll DIS 19HI. 144 ' 101 6.
I
2000 COPYright by Ihe European SocIety of Cltntcal MIcrobiology and InfectIOUs Diseases. eMI. 6 (S uppl. 3). 64-69
Low New oral ce ph alosporins 69
27
J)t:'l1lolt~lI
F, Nan JM . Bella
r
cc .11. Pro\pc(tI\'!t cpldl'I1l1ologICai 'fl1dy of
1IlVal,J\'l' JI.ICIllOphlhh Illtlucnzal' dl~t..'a.~1!
l1l
35 , Drusano GL. Craig WA. Rdt.'vancl" of phamlJcoklllcnn and phJ.n1l.Jco-
.1duJt" Em J elm ,\ licm/"t.1 II/Ji-'ct
dynamIC' 111 d,C ,dectlon of al'ltIblOClc'i for rC'ipir.uory tract inlc-ction\.
2H. PL'ero!' EO. 1,0\\ 1)[, C,IllJdl.lIl B.lCteri.11 ~ur\'cll1:lI1n,' N"tworJ... ,'r
Serotypc ch;lr.l('[l'nl.uloll of I (d('l//(tl'hi/'H d l\CJ'L' III C.IIUd.l
.1otll
WJ,hlll~"[()J1. 1)(:
29. Anol1ymou\.
or t Ir h
('f' Ami///;(rt,blr,1
A ,\!f'lItS
,'.1«(l I1t.'"
,md
.4/"tfdffS
I!(
36, Appdh.llllll PC. NL'W prospN'b for annb.lctL'nal .1gCllr' J~lII"[ muludrugrc~i\r.l11{ pnClII1l0CO(Cl . ,\I;rrlli, f)mg Rrsi.H 1995; 1 4J ·H 37, Wi\c R. T he p h;lrm3Cokll1L'tl
I llft'(OOU\
cvalu.Hlon of cl'fubmcn 39. Kni.lpp
pnOllIllO(Oen . On'.~.' 1996; 52 (Supp\. 2): 42-(,.
or rL'JIIt,, ?
I W. G.lf,lll
J
JJ C.old~rClll
Sf.\
/...""(1'1 1Y<)7; 350: 233
due to pt·nh: ilhn - n.'~I\c.lIl[ Strt'pll'((I((/lS IHlt'I""olliae . S(llIld
J
lI1(raVl'110l!\
',!(r(/Ol.< 19<)(\: 25 ' 213-7.
gonorrhocJt.' rf\ts[Jn[ to nprutloxJC1I1 and oilnxacin.
J.
CCfiXlnlC for '\\1,eh ,hcr.lpv CIII'n,,,,II"QPr I WK. 44
r.
Ahkee S. !luang A. Raif MJ . Early ,wHeh from
ro oral t.'cphalmporuh
III
rhe rrl'.lt1nCm of ho,pnailzt'tl
I UrCCtlOm
r,!{t'(l
p.:anenh
42. B.lIemfell1d A. J"n!,,,,"rdl R. Anab.crenal Jca",)' of cetpodoXllllc
of {he future . Di"~i!11 ,\ IIt-mll",1
U1
cOl11pan\OIl with cdhunc. l'dainir. cefetamec. cefnburcn, lorar,ubc:t: (ctpronl
Dl.o;
HAY 3522, cCnlrOXJI11c.!, cdaclor and ccfadrmal. IS'Ul',
CllO,c.1
gonorrhea. A pilot ,mdy 111 Hong Knng . .s~:.\'
with L'OlTll1l11J1lry-.lcqu lred pncl1 l11onia. Arcl, Imr", .\Ied 199:;; I SS ' 1'273--6.
1997: 29' 255-7 34 Cr.lig WA, Antllnicrobl:ti r(''''.. t.lnce
11)
0" 19
41. n...mora J A. Srl/wh StrI'I""((}((1/,\
,\I/cmbi,,/ 1995; 43 : 237··8Cholft.' of an oral ber.l-l.1cr.ll1l antlblotll: for
J
(SlIPP\. I): 24-7 .
J t\l('d
rw ,
J . Nt'i\\eria
Tr,,,,,,,,,
40. I-bnnl,on-Mdlcr
3() yc:af\ of pcninll in rl'~hr3nr S pm' II/WIII;,II': 1nych
32 Srr.ll'h.lIl ~A, Fnl·dl.lIld IR . Therapy (or pCI1I1.: dhn-rl',,,,r:ll1r IIIU'/ll1wI/idt'.
rene\\'.
Tra".'''' Oi, 199H; 25 : 464-7.
I)I 'C:1\t.'\
19l}'. 99' 2HIJ-'i')
Gold\(l'lll
',I
38. Chong LV . Chellng WM . Leung CS. Vu CWo Ch.n LV
chlldrl'll wlth II1\'a,IVc pnculllococcal IIlfl'c[Jom.
J{) Klug-m.1I1 KP, Epldt'J1110Iogy, comroi and In..'JCmelH of l11ulrirc\I\[.lllt
J I.
o( cht:' oral cephalo'ponm-
A"Ii/"im" CIII'I""I/'f( I <)l)O; 26 (SlIPPI. E): 13 ·20 .
CIU'/l/I,t"a(I!')',
Amcn ca n SOClcty for Mll"roblolo1-.'Y. 191.)0.
ThL·r.lp)' t()f
AIllL"rIl'.lJl Acadt..'Ill)' of Pl.'d l.ltnn C011111l1ttL'C on
red""",.,
.11.
I/Jlll/fII~'/1' I,OJ.ltC' (;llI\ l ll~ IIlV,l'IVC
following thl.' II1rrodul.:rion
C(l/!{I'rl'II(f
rWnwiClkf
J
CII,·",,,,/,,·, 19\17; 9 (StiPP\. 3): 3H 44.
/)" 1')\)4; 13 ; ().H-H.
43
l"/~'frmtl
1991 : 19: 353-62.
Feimingh'lII D. Robb"1\ MJ. Gha,h G et al. AJl on "ltro characrotiution of cefJttofcll,.l nc\\ oral cephalo(jporm. Dm.~j £\'P elm Rt') 1994,20: 127-47.
" 2000 COPYrigh t by the European Society of Clinica l Microbi ology and Infect'ous Diseases. eMI. 6 (Suppl 3). 64-69