Pe

VS: BP 168/89 mm Hg, P 88 bpm, RR 19 breaths per minute, T 38.5°C (101.3°F) CV: Slight tachycardia, positive murmur

Abd: Obese, soft, nontender, nondistended; (+) bowel sounds

Labs: Within normal limits, except WBC = 16.4 x 10 /mm (16.4 x 109/L)

Four sets of blood cultures were drawn. Two sets were drawn on admission and two sets were drawn about 12 hours later when the patient spiked a fever. Results are pending.

Diagnostic Tests

A transthoracic echocardiogram (TTE) has been ordered. Results are pending.

Given this additional information, what is your assessment of the patient's condition? Identify your empirical treatment recommendations for this patient. What other information would be beneficial to obtain?

As penicillin MICs increase (greater than 0.12 mcg/mL but less than or equal to 0.5 mcg/mL) for viridans group streptococci, treatment doses are increased, and 4 weeks of treatment is suggested. In addition, combination therapy with gentamicin is recommended during the first 2 weeks. In patients who are allergic or intolerant to either of the P-lactams, vancomycin is an alternative treatment option. Additionally, in patients with resistant strains of viridans group streptococci (MIC greater than 0.5 mcg/mL), treatment should employ antimicrobial agents for enterococcal IE (precise agents determined by the susceptibility report).

Patient Encounter, Part 3: Additional Laboratory and Diagnostic Tests Blood Cultures: All cultures are positive for viridans group streptococci. Labs: Within normal limits Echo: 3-mm vegetation on the tricuspid valve

Given this additional information, are there any changes in your assessment of the patient?

How would you tailor your treatment based on these new data? What would be your treatment goals, including length of treatment?

What other information would be beneficial to have?

Patients with PVE caused by penicillin-susceptible strains of viridans streptococci require treatment for 6 weeks with penicillin G or ceftriaxone with or without gentamicin during the initial 2 weeks of therapy. However, if the organism demonstrates less susceptibility to penicillin (MIC greater than 0.12 mcg/mL), a combination therapy with penicillin G or ceftriaxone plus gentamicin should be given for the entire 6 weeks. Vancomycin remains the primary alternative if the patient is allergic to P-lactams (e.g., penicillins, cephalosporins, etc.).

Staphylococci

It is important to determine (a) whether the isolate is methicillin-susceptible or methicillin-resistant and (b) whether the patient has a prosthetic valve. For patients with no prosthetic material, methicillin-susceptible staphylococci treatment should consist of a penicillinase-resistant penicillin (e.g., nafcillin or oxacillin) with or without gentamicin, and for methicillin-resistant strains, therapy should consist of vancomycin (see Table 74-4). Combination therapy with aminoglycosides, when used in these patients, typically is given only during the first 3 to 5 days of therapy. In the absence of prosthetic material, some treatment guidelines do not recommend combination therapy against MRSA. However, many clinicians may combine either gentamicin or rifampin with vancomycin if the patient is unresponsive to monother-apy.

Increasing resistance of staphylococci necessitates the expanded use of alternative therapies. A recent clinical study demonstrated similar activity for daptomycin compared to standard therapy (i.e., penicillinase-resistant penicillin for methicillin-sensit-ive S. aureus (MSSA) or vancomycin for MRSA) in staphylococcal IE.41 The FDA, based on this study, has approved an indication of daptomycin for the treatment of right-sided IE or bacteremia caused by S. aureus. Recommended dosing for these indications are 6 mg/kg/day (unless renal adjustments are necessary).41 This study along with another retrospective study reported daptomycin safe and well tolerated.41,42 Additionally, other antibiotics, such as linezolid and quinupristin/dalfopristin, have been used in patients who were unresponsive to standard therapy, although they have had variable response rates.43-45 These therapies often are reserved for patients who have been unresponsive to traditional therapy (e.g., ^-lactams or van-comycin) or for organisms that remain susceptible to these agents when resistant to traditional therapy.

Table 74-3 Therapy of Native-Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and S. bovis

Rrgitfen

Duiayt und Hiuti

Duration IwL'cki)

Strtngtb nf

REiùinitttrtditlift'

Aqueous ciyslalline penicillin G sodium Oft cefiíiíKo™? ícdiom

Aqueous crystalline pwikfcffiiödluim Off cefuianrane plus íjenrainiíin wi^.iic"

Vanooniycin hyAöChkjrkM

12-14 mil en unte/24 hours LTV eflher continuously cr in 4 or 6 equally divided

2Q/-Z4 hours IV/IIW in 1 i»<e Pediatric dose': penicillin

200000 unirsrtu per 2* ho^s

N In i-tfciually divided doses, ipflrtHOie 100 mq/kjg po 74 hnjs IV/IM in 1 due

1?. limiHcr units/24 Ivjurs w either osnilnuoosty c* in 6

equally divided doses 7g/24 hours IWIM in 1 dose

/w0u1 fine. o-tiicilliii ¿oojqoq urtiti/ky per 24 hour J IVirt 4-6 c-qually divided doses, ((ft-iaowtli 100 rugrtg pt'i 2* houri (MM in I dose: gsntamkin 3 mg'kg [xt 24 IwuislV/iw in t Joseo 3 equally divided doses'

30nig'kg per 24 hours IV In

2 cguslly divided (teles no! lo WRd houis unless toncernriiiorii <n strum ¿«e Inappropriately Ic* jVtA'drf.ir dosi: W rng/kg pel homs IV m 2-3 equally drvvjeiidosis Mlt'. less than or equal to 0LI2 mcg/Vnl

Preferred in most patients 6i years oFage or older d poUentswith nllp,lTnii*nr i:i iVjllth Lr.snhll rifirvi function or ferial luncton

Î Vietk regimen not intended fof pjii-Tils with cardtKor esCiacj"d«i. absces-sor for tlvisewlth creatinine tkarJftWûf less Hun 20 mL/lri«V inrg>sre<J etflhsh cranial nerve function, or Abiotropivo, Qarxikcateita, ■Or GrtfruMftS«:* klfcCfcHV JÉrtaoSiSñ dowge should re ^c^t-wl to achieve poakseium concentration of 3-4 nscg/íwvL DSij-3^ mittiûVI) iftd trcurjh ■siírunri cçiventratisn of less lhan F meg/ml. (2.1 pnral/l) when 3 divkk'd doses aie iLSfd; nornograiti ti-sftd for wigledaily dosing'

Vanoon^cin therapy recommended only for mricntiurvjWc to totaiLe nenkllkor cehrlmonfli vancomycin ■dosjcit should tu.- .nj.jsrt.-d (uufciUift peak (I hour after infasicrt completed! seium conoenlrilon -of 30-35 íüO^/rtiL u I -24 prriol/u drkJ ¿ trough wncentTätfonraogeof irj-is mcg/mL (&.Í-10 (jmoVU

IV. mHavencHJsly: IM. inlraniusculiiil^ WIC, miMwn inhibitory concentiation. Ojwge iLtomfnendod ju.lIui patents-with noimal renal iunctkm

TA. tpndiriun with fv»3érvc vtf/or GWtflil a^MIWflt Hut i prOMdtM Oí treatment r UwMllid tffMtiVifc bluit «ldüll Fie.ifiií>iíUJk' randomiínd clinical lriats; IH, corvdmon with evirtence- and/tw genei al agrefYiient thar a procedure or trearnwnt is useful and effeciive-taseiJ on data from a single randomned trial or nonrmdomrred studies.

Pediatric dose should not exceed that dl a normal adull.

Othei potentially nephrotoxk drugs (ejg, notvstetoklal anti-innammatoiy Augs) should be used with caution in patients receiving genlamein ttiaijjy,

See Nicrfou DP. Fjccmsn CD. E" r^eau PP.et tnl. E^Jerientít with 0 once-daily oimrioglycoskk' prorir.imodmini'-Dercd to 2164 adult patents. Aniimlcrob Agenis Cheiroiiwr IW6;

'fiara for once--d*i|y dosing ff ammoglycwidei for children p*Ih, hit no data for ireamnenr <?f IE exist.

-Vancomycin dosages stiould be infused duung coune of ar leasi 1 hour to reduce risk of histamine lelfase 'red nun' synhm£ From Fief.

Table 74^4 Therapy for Endocarditis Caused by Staphylococci in the Absence of Prosthetic Materials

Rcyimtn

Dcugr'

an d Hbuto

DuritiOil Lwrcks |

ilicnglh of

Rrcnmmrndalion"

Contmcnts

OjtadlMn-SulCCpUbl* ¡luí ni

Wafallln a (p^Én1 12 qflA hours IV in t-6 equa lly divrfed dos«

optional a<Jrtiriori of gentamiciri sulfile:

Tor [vriir illin .illi'j<jir (rcnawphybctcld type) parents, cefiriilin

J nVj/ki:j|H*t JJHOMI-S IY/IM in lot iequally divided-doses

Ptftili«: (tow nafclllin Li omcilm I'lK) nig.' kg pef iA ftuiW In A & ■Ltitully Jii-iHL'd ■Jos«; gentamori 3 ipgAq put 24 hours IV/ IMin S equally Uivki-d hours IVin i equaBy divided da^-*.

optional adiltren of IV/W in J a J equally gentankin sulfile divkteddoaes flcTÍVUrt ¡h'r'. cdjííjlin ICO mtylirj p¿í íil Iwuri IV in 3 ectJflljy divided doaesi rjcnljiiíicri í rmVkq per 2+ houn IWM in i oqualty divkkiJ doici

Oiidllln-II«iitin4 Slriim

Vancomycin hyuJicthkjride'

JW^diUeddnG flcrÍLjrticdoSi'.'^CI nyj/ kig pe 24 hours h in 2 3 ixjjijiy divided doses

Tor oorrplhialed right sided IE □■vJ for left ikied IE,-6 wet* [mui nvrm; foi uncomplicated right sided IE, 2-v/eek treatrnunl ClirliCJtl <>

aminoglycosides has nor teen HOblislTed

ConsiiJe« skin tiling for u*jc illin-susceptible staphylococci ard questionable history of imnyi li.>l< "(ypi hypci m i ¡ulivily

[o penicillin; cephalospot ms shoub be avoided in patents with .nvi|ihyi.KKiy i>i:a7 hypersensitivity to ¡HdLiarre, vancomycin should be-used in ihiiiifiWf

Clival bWtfa fiK amiiuglycosides ras nor Iwn eslablishrf

Adjust vancomycin (tosagsno «hieve I hujur (peak) serum concemianon of 3Ü-.tS nrisg/ mL 01 "41 íJrrolvU and trough iCm^iHiirion &Í 10-1J mog/ mL (¿9-1 th tirnm) (see ten foe vancomycin alternatives)

MIC pnini.inum mhijitory concentration,

■tiotijjtt rtjcümrnwvjed ¿¡t IMIÍÍIKS with nern-ui lenji ftjnakm

TA. ccndiunn with evüence and/oí general a^eement lhat a procedure ot (reatmem >s useful and effective, based cm dala from mulnjle randomized tfirfcal bail;; l^ corrftioii with Evidence and/« general agreement rhaT a procedure or ueaimem is uselul and efecth^ based on dala from a single ra^domired ti»al or nonrandomized studies.

'FMfcillln G2A million uniLi/2<l Ixk*s IV in 4 Lo Í oqujlly divided do«s mty De uíéd in of njHullir»(w onjt illin ir slrjin is ponkilli«-lUKewite ¡MiC lew (h»n of «qwi to Oil mqgftttL) «nd <Joesi not prortKe ¡S-lstiwiBie,

'(jjnijíriÍLin iluuld be adnHnlmeied In (low nefnpafal prgrfrfilty tovsmzornjclry minii ^ eg ouai: ilfin doslngi

'PttliiCiiC (tee ilKmkJ Ikiti:»;««! rlvi ci a nurnwl edLII,

Tea ipfiific dmirv) K^eirrient Wid ¡«ueiOüncerninqvarVdiinycin, w BtHe .'4■■ i fekirnnri'i Hrcrri Ref. J.

Table 74-5 Therapy for PVE Caused by Staphylococci

Begin and Kuuit

Dgr^lim Intal

Strarglh üf

Uftüimnltrid-allun-' Comment!

Omillln jiiirfDtllgll Slraint

NafcWncr gtudki plus riairsta plus nrntflrnirin sulfate1

12 ¿)TH iKHJil ft in equity t) iviitoi doset l)0Ü riyi (lir Ji Hvf l'r^ür.! v in 3 e^u*'■>■ divided dos«

J mg/hgpCT lifu^ IV/IM hltti

O-^UJ >■ divided dtiie-j, Pefiiai'K (tow: naiiill.n or OKJCillin ¿COiiK;/ki( pfl hours IV if» 4 F> >■ divided dosier i (farrpin

20 ina/iirj 24 Ficui rv/ct^i rioi«; in 3 «lüially (Iwlded dosei; rjwirjruki J nifj/Vif pci 24 huuis in i «quilly divided dOS«

Oxacillin Rfiiiljnl Sliiini

VjrKOrryiifl

IfckuljgiUe plus ■tfampirt pig genmrtdh

UjIfaW

6 weeks or itMioif ft wei+S fir Iti^Of

KJ jnykrj fyr 24 hours IV in 7 equity divided doses

'XXi nui/ii Ivnjr^ IWu^il in 3 equJ)1 divided doses

equafly divided dosi?4 PediQMc irtase: varcomyc in 4Ü mg/ |ig pti 24 hflwu IVin It« 3 rtjttflly divided dew!; riiijiirpiin X> nnQ/lnj ¡4 liourt IV/ofül hi l«]ijjlly divided (i^p to Miuir daw); Gentamicin 1 mg.'lg per houn WIM <n 3 rquaty dividuddosei f> Or ItrtQir i vwiks or

Per. tillin G 2* million t. rnlVAt hours IV IrH to (> «njilly divided d™.i mjylje used in-pia« ol rufcillin or ourillin iisiiiil is periiiillin-susceptfcile (MIC less than c <.t|uoI (f 0.1 mcg/iiK.) and riosi noi pioduce ^lactamase: vancomycin shouU la* used in (Uriels Willi immediaie-type hyptucnsilivily reactions antJbtotlCi (see Taljle 7*1-i f» doimg [pjhdeliM'ik l ef.l.ui:: I nui be substituted fen naf-cillln V ™cill:ri in pJllWK wiih nonimiVhrfiaoiiype hypersensitivity reactions to pcnlcllllrv

Adjoii v^ifonvin achieve h hour (peak) »u m concentration oi 3D-J5 nxaTftL (U-Jl t.iwJ/l) and trough cofKoniation pi 10-15 ilifig/inl (t.9-1 □ tiimcl/l i

l^iito."! riiflr^fflWdid tft fijirii'iir- .y.I -i n: ii I: ■ il ri'ii.il S ■ l - - Ikmi

16i lonjitiuri MUltvitolMt^l qoritTiil jqrwux'rit Hvit J piytpjorcoi tWihnirtl ii IfVL'iul and landomizctJ m.il or nonrandomized studies.

(.eriTarinlrln ihciuld l>e «inmriitenid in ck>W pfiniiTiity1ijvsf>ronn^"in, rDiciltai, oi o>»i;illifidfisini5. f iedlaifii: düie- shcoVJ rut exceed thai oi a nama'l aduli. liep<rKlnce<i vinh p« irtisioa frnni flef. S.

For staphylococcal PVE, treatment length increases significantly, typically requiring a minimum of 6 weeks (see Table 74-5). For MSSA, a penicillinase-resistant penicillin is still employed, as well as vancomycin for MRSA. However, with either regimen, the addition of both gentamicin for first 2 weeks and rifampin for the entire length of treatment is recommended.

Table 74-6 Therapy for Native-Valve or Prosthetic-Valve Enterococcal Endocarditis Caused by Strains Susceptible to Penicillin, Gentamicin, and Vancomycin

Vancomycin hytfrothlcHidc pJus (junlaiTiHiiri siÄrte

30 mg/kg pel 24 hoots hi in 1 equally divided (JUML'Ï

3 mq/kg per 24 hours IWlM in A equally dh'fcled don's ftdiftrür dMft varKOrmyi in 4Q per

24 IV in ïiir J t^iiall/divided (Joses; gWHmkJn 3 ing/Kg pt'i 24 hours ÎV/IM nîeqwllydlvkteddOKi

Vancomycin therapy i<-tr.*iirrn;ndcd only-for pailems unable to Lolerale penicillin or Afïipk ' in

6 weeks of vancomycin Itrerapy rccommcpded because of dw: it1««! actively against

UowtiiS wonniiiendeil are-for psriifiT? with i/jinvJ refial function.

"lA-t'OftilitiCrftwilh i<vidente .iryfui QrtlGial j^miIiHAI MliL .1 procedure lm vil I ■ KT~il r mwk;ljirn.l i-ffatrive, bjii-d C4td.ll.» Iruniduuilir randomized clinical trials condition vwih evidence and/or geneial agreement that a procedure or treatment ts useful anil effectkt; based on data from a sing I? randcimiraj tr si or ncniandomired siudies.

LXiSiiieof ijeiiuniiuin shuukJ bCMfuSted UfJchieve peak SCaiffl<nnOirwatoft(/310 4 iftQ/lmL f6,3 84 unooVLI JrHf d truughCcmtirilrJlkift of lew ihjh I norti/'iT-' (2,1 iimoCU. Patients wrh a awmnine clearance cf lew than 50 mL/iriln should he (reawtl In wnwfcatJw wirh an iniectious diseases specialist.

Pediatric dose should not ewceed that oia normal adult. 'See Table 74 -3 for dpproprkttii dosaye of vancomycin. From Ref. 5.

Enterococci

For enterococci, it is imperative to determine species and antibiotic susceptibilities. If the organism is susceptible to penicillin and vancomycin, treatment may consist of highdose penicillin G, ampicillin, or vancomycin plus gentamicin (see Table 74-6).

Treatment length is usually 4 to 6 weeks, with the aminoglycoside used over the entire course. As resistance develops to penicillin, ampicillin and vancomycin remain treatment options. Once the isolate becomes resistant to ampicillin, vancomycin is considered the treatment of choice.

If the isolate is determined to be vancomycin-resistant, it is most important to know the exact species because some of the treatment options, such as quinupristin/ dalfopristin, are not active against E. faecalis. Currently, the treatment options for vancomycin-resistant enterococci (VRE) are not well established by clinical studies or patient experience. The treatment recommendations for vancomycin-resistant E. faecium include linezolid or quinupristin/dalfopristin for a minimum of 8 weeks. However, newer agents, such as daptomycin, may provide another option for treatment for either enterococci species (E. faecium and E. faecalis). Additionally, guidelines suggest the use of imipenem-cilistatin plus ampicillin or ceftriaxone plus ampicillin for the treatment of E. faecalis with a minimum of 8 weeks of therapy. Consultation with an infectious diseases specialist is recommended.

Gram-Negative Organisms

Identification of the exact isolate is crucial in gram-negative IE because treatment decisions depend on which organism is isolated. Therapy is usually targeted to the most susceptible antibiotics. Combination therapy (usually the addition of an aminoglycoside) is commonly used. For example, Pseudomonas spp. are treated with an anti-pseudomonal (e.g., piperacillin, cefepime, imipenem, etc.) plus high-dose aminoglyc-oside (typically tobramycin 8 mg/kg/day). However, exact dosing of antibiotics depends on the organism isolated. Length of treatment is usually a minimum of 6 weeks.

HACEK Group

The HACEK group is difficult to isolate, often taking weeks for identification. If one of these organisms is suspected (e.g., subacute disease, embolism, large vegetations, etc.), it is important to initiate appropriate empirical treatment. The preferred regimen is ceftriaxone (or another third- or fourth-generation cephalosporin), followed by ampicillin-sulbactam. However, for patients who are intolerant of these treatments, ciprofloxacin may be used. The length of treatment typically is 4 weeks for these organisms.

Culture-Negative

Treatment for culture-negative IE presents a significant dilemma. Therapeutic regimens are guided by specific isolated organisms. When cultures fail to identify a specific organism, decisions regarding treatment should cover the most common causative organisms. If the patient is unresponsive to this initial treatment, then additional coverage for less common organisms is warranted. An infectious diseases specialist should be consulted for managing a patient with this type of infection.

Fungi

Treatment of fungal IE is exceptionally difficult. There is a significant lack of studies to identify and recommend the most appropriate therapy. Currently, amphotericin B is the most common treatment. However, valve replacement surgery is often considered an adjunct therapy. IV antifungal therapy requires high doses for a minimum of 8 weeks of treatment. Oral azoles (e.g., fluconazole) are used as long-term suppressive therapy to prevent relapse. The exact role of some of the newer antifungals (e.g., voriconazole and caspofungin) is unknown, but they should provide a viable op-

tion.46,47

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