BONURA, Celestino

D'ALESSANDRO, Natale

DI CARLO, Paola

GIARRATANO, Antonino

GUADAGNINO, Giuliana

LUNETTA, Monica

MAMMINA, Caterina

NOVO, Salvatore

Archivio istituzionale della ricerca - Università di Palermo

452013High dose of trimethoprim-sulfamethoxazole anddaptomycin as a therapeuticoption for MRSA endocarditiswith large vegetationcomplicated by embolicstroke: a case report andliterature reviewTrimetoprim-sulfametossazolo e daptomicina a dosi elevatequale opzione terapeutica nel trattamento dell’endocarditeda MRSA con vegetazioni estese complicata da strokeembolico: caso clinico e rassegna della letteraturaPaola Di Carlo1, Natale D’Alessandro1, Giuliana Guadagnino1, Celestino Bonura1, Caterina Mammina1, Monica Lunetta2, Salvatore Novo2, Antonino Giarratano31Department of Sciences for Health Promotion “G. D’Alessandro”, University Hospital P. Giaccone, Palermo, Italy;2Department of Internal Medicine, Cardiovascular, and Nephrological Diseases,University Hospital P. Giaccone, Palermo, Italy;3Intensive Care Unit Dept of Emergency, Critical Care and NeuroScience, University Hospital P. Giaccone, Palermo, Italyn INTRODUCTIONStaphylococcus aureus is one of the maincauses of infective endocarditis (IE) in in-dustrialised countries, and S. aureus endo-carditis is often associated with several clinicalmanifestations and complications in the form offever with metastatic infection, heart failureand central nervous system involvement [1-3].An increasing proportion of S. aureus endo-carditis cases are methicillin-resistant S. aureus(MRSA), and methicillin-resistance is on therise in intravenous drug users who generallyshow less favourable outcomes after treatment,as well as more frequent and potentially life-threatening complications [3, 4].Large vegetation carries a poor prognosis andhigh mortality risk, especially if associated withMRSA infection [5]. Early diagnosis and imme-diate commencement of effective antibiotic ther-apy is imperative in saving lives. Although op-timal medical management consists of antimi-crobial medications, extensive and complicatedcases of IE are currently mainly treated withparenteral antibiotics and cardiac surgery [6, 7].To contribute to better management of severecomplicated IE, in terms of determining treat-ment strategies, we describe a complex case ofrecurrent MRSA mitral valve endocarditis.n CASE PRESENTATIONIn June 2010, a 35-year-old male HCV-positiveintravenous drug user of Italian origin came tothe Emergency Department of the Paolo Giac-cone University Hospital, Palermo, with fever,CasoclinicoCasereportLe Infezioni in Medicina, n. 1, 45-49, 2013*Corresponding authorPaola Di CarloE-mail: paola.dicarlo@unipa.it462013mental confusion and numbness of the limbsthat he had been experiencing for five days. Areview of his medical history revealed previousMSSA endocarditis and mitral valve repairsurgery. A human immunodeficiency virus testperformer on admission was negative. Clinical examination revealed his blood pres-sure to be 100/80 mmHg and his pulse was 110beats/min and regular. His electrocardiogramwas unremarkable. Auscultation revealed aharsh 3/6 holosystolic murmur, best heard atthe cardiac apex, radiating to the sternum. Ini-tial laboratory tests showed a WBC count of7.54×103/L (85.4% neutrophils, 9% lympho-cytes, and 4.9% monocytes), Hb 12.8 g/L, ALT53 U/L (normal range 5-45 U/L), AST 58 U/L(normal range 5-45 U/L), GGT 120 U/L (nor-mal range 4-50 U/L), ALP 224 U/L (normalrange 42-128 U/L) and serum C-reactive pro-tein levels (CRP) of 15 mg/dl (normal range0.08-1.5 mg/dl). Coagulation parameters, renalfunction and urine and OGTT were all normal. The stroke team was alerted and the patientwas given standard emergency room assess-ment and treatment. A CT image of the brainshowed frontal and insular sub-arachnoidhaemorrhage. His angiogram was normal. Atransthoracic echocardiogram revealed a largevegetation 1 cm x 1 cm adhering to the mitralleaflets and protruding into the left atrium(Figure 1). S. aureus DNA was detected by LightCyclerSeptiFast and empiric intravenous antimicro-bial treatment with vancomycin (35 mg/kg perday by continuous infusion) and gentamicin (5mg/kg/day) was started [8]. 12 hours after admission, the patient showedcardiac conduction abnormalities progressingto Mobitz type I second-degree atrioventricularblock (ECG findings) and he was moved to theCardiac Intensive Care Unit (CICU). The pa-tient’s condition steadily worsened and pe-techial exanthema appeared. Blood culture grew MRSA. The antimicrobialsusceptibility test was carried out using previ-ously described methods, in accordance withClinical and Laboratory Standards Instituteguidelines [9]. The isolate was susceptible to co-trimoxazole (TMP/SMX), linezolid, tigecyclineand daptomycin and resistant to rifampin,tetracycline, ciprofloxacin, piperacillin-tazobac-tam, aminoglycosides and macrolides. Van-comycin minimum inhibitory concentration(MIC) was 2 µg/ml. SCCmec type was deter-mined using previously described primers andconditions (10). The isolate was attributed withSCCmec IVa. We decided to shift antibiotic treatment to 8mg/kg/day of daptomycin every 24 hours and15 mg/kg/day of TMP/SMX administered in-travenously in three equal doses. By the 25thday, the vegetation had reduced from 1 cm to0.6 cm and the patient’s clinical conditions hadimproved. Considering the size of the vegetation, its hypermobility and the associated systemic embolicevent, surgical re-repair was judged to be es-sential and proposed to the patient. Neverthe-less, despite our concerns for his health, he didnot consent to cardiac surgery. After six weeks of combination intravenous an-tibiotic treatment with daptomycin plusTMP/SMX, the patient was discharged on ahigh dose of TMP/SMX (320 mg/1,600 mgtwice daily) for six weeks and referred for out-patient follow-up. High-dose TMP/SMX treat-ment was well tolerated in our patient through-out the treatment course. At the end of the pre-scribed course of treatment, the patient cameback for a check-up: trans-oesophageal echocar-diography showed that the vegetation had dis-appeared and edges had thickened.n DISCUSSIONOur results further contribute to showing thatit may be difficult to follow guidelines on start-ing antimicrobial therapy because differentMRSA isolates have varying antimicrobial sus-ceptibility patterns in different geographic ar-eas [10-12]. Figure 1 - Image along the parasternal axis. The lar-ge vegetation, about 1x1 cm, can be seen in the an-terior leaflet of the mitral valve, causing outflow ob-struction.472013Because severe infections such as cerebral em-bolism in the course of infective endocarditisrequire quick and effective treatment, we re-sorted to SeptiFast to identify the isolate rapid-ly and adopt more accurate empiric treatment.In our patient’s case, we believe the Septifastprocedure was in support of microbiological di-agnosis. Accurate identification of blood isolateand its antimicrobial susceptibility was centralto the optimal management of our case report. Our initial therapeutic approach was to sup-pose that the S. aureus strain was methicillin-re-sistant as the patient had a history of surgery,previous anti-staphylococcal treatment andchronic liver disease. Moreover, we took intoaccount our recent epidemiology and the circu-lation patterns of MRSA clones, as well as theliterature which frequently shows different an-timicrobial susceptibility patterns of thesestrains [12]. Our patient‘s history and the phe-notypic and molecular characteristics of theMRSA isolate would suggest a communitystrain, though susceptibility to non--lactamsand SCCmecIV have proved to be also sharedby some epidemic clones of HA-MRSA, such asEMRSA-15, that are widely circulating in ourgeographic area [11].For several years, glycopeptides have been con-sidered the antimicrobials of choice for seriousMRSA and methicillin-resistant coagulase-neg-ative staphylococci (MR-CoNS) infections [13-15]. However, a literature search found no pub-lished studies of the effects of vancomycin ex-posure on outcomes and hospital costs in pa-tients with complicated bacteraemia or IE dueto MRSA. In our patient’s case, we initially consideredcontinuous vancomycin infusion because thisdrug remains the first line antimicrobial forcommunity-acquired and nosocomial infec-tions due to MRSA, and because data supporttheoretical arguments that higher and moresustained serum levels of vancomycin, ob-tained by continuous infusion, may enhanceclinical efficacy. In our patient’s case, the S. aureus isolateshowed a vancomycin MIC of 2 mg/mL whichwas considered to be perhaps less effectiveagainst serious methicillin resistance, or a“bridge too far” in that the doses required car-ried a significant risk of toxicity [14]. Guidelinestherefore recommend therapy with alternativeantimicrobials [16]. Close et al. have recently shown that TMP-SMX15 mg/kg/day is an option in the managementof GISA infection [17]. Although some anecdo-tal reports suggest successful therapy withTMP-SMX for a variety of S. aureus infections,clonal outbreaks of MRSA resistant to TMP-SMX have been described [17-19]. The role offolate antagonist for treatment of MRSA infec-tion has been recently suggested because TMP-SMX is bactericidal and well tolerated; it is an-timicrobial with high tissue penetration that re-duced cytokine production after SA toxin expo-sure [20]. It is also inexpensive. [19]. On the other hand, antimicrobial associationagainst S. aureus may be chosen to increase bac-tericidal activity in cases of severe infection, es-pecially during complicated IE. Over thedecades, in vitro and in vivo studies of bacterici-dal interactions of antimicrobial moleculesagainst S. aureus have yielded conflicting re-sults [21]. Daptomycin is a well-known alternative treat-ment option for infective endocarditis; studieson the synergistic effects of daptomycin in com-bination with other antibiotics including gen-tamicin, rifampin, beta-lactams, TMP-SMX orclarithromycin present a new therapeutic ap-proach [22-24]. In our case report, the antimi-crobial susceptibility of the strain led us to com-bine new molecules like daptomycin with old-er, low cost antibiotics such as TMP/SMX.Moreover, the combination of TMP/SMX anddaptomycin is justified by how they act syner-gistically to provide rapid bactericidal activityand reduce daptomycin resistance. In conclusion, our case report could expand theclinician’s understanding of contemporarydrug therapy and represent a challenging casein currently-debated filed of research. Futurestudies are needed to evaluate available clinicaland pharmacokinetic/pharmacodynamic (PK/PD) evidence regarding TMP/SMX, particular-ly in association with other antibacterials suchas daptomycin. Keywords: Staphylococcus aureus, infective endo-carditis, antimicrobial combination.482013Large cardiac vegetation carries a poor prognosisand high mortality risk, especially if associatedwith methicillin-resistant Staphylococcus aureus(MRSA) infection. We share our experience of arare and complicated large cardiac vegetationwhich had a favourable outcome with combina-tion antibiotic treatment alone. A 35-year-old HIV-negative, HCV-positive male patient with a previ-ous history of methicillin-susceptible S. aureus en-docarditis showed MRSA mitral valve endocardi-tis with large vegetation, complicated by embolicstroke. The strain was soon identified by PCR butonly after culture did the patient receive effica-cious antibiotics. A combination of daptomycinplus trimethoprim/sulfamethoxazole (TMP/SMX)was administered for six weeks, followed by ahigh dosage of TMP/SMX for a further six weeks.Effectiveness of the treatment was demonstratedby the patient’s clinical improvement and instru-mental evidence of cardiac mitral vegetation clear-ance. Innovative antibiotic strategies in patientmanagement are needed to fight Staphylococcus au-reus endocarditis because strains show varying an-timicrobial susceptibility patterns in different geo-graphic areas. Timely initiation of targeted antimi-crobial therapy remains a crucial step to reducemorbidity and mortality but culture is crucial forappropriate fine-tuning of antibiotic therapy.SUMMARYLa presenza di un’estesa vegetazione cardiaca comportauna prognosi sfavorevole e un alto rischio di mortalità,soprattutto se questa è associata a un’infezione daStaphylococcus aureus meticillino resistente (MR-SA). Qui di seguito gli autori riportano un caso di en-docardite su valvola mitralica da MRSA caratterizzatada un’estesa e mobile vegetazione (>1,2cm) e complica-ta da stroke embolico, in un paziente di 35 anni HIV-ne-gativo, HCV-positivo con pregressa storia clinica di en-docardite da S. aureus meticillino-sensibile (MSSA) edintervento di valve repair. Lo S. aureus è stato ini-zialmente identificato con metodica di LightCycler Sep-tiFast, ma solo dopo esame colturale il paziente ha rice-vuto una terapia antibiotica efficace. La combinazione didaptomicina e trimetoprim-sulfametossazolo (TMP/SMX) per via e.v. è stata somministrata per sei setti-mane e poi continuata nelle successive sei settimane consolo TMP/SMX ad alte dosi per os. L’efficacia del trat-tamento è stata dimostrata dal miglioramento delle con-dizioni cliniche del paziente e dalla clearance della ve-getazione. Trattamenti antibiotici innovativi nella ge-stione del paziente sono necessari per contrastare le en-docarditi da S. aureus, e in particolare da MRSA, poi-ché i ceppi hanno mostrato variegati profili di sensibilitàagli antimicrobici in differenti aree geografiche del no-stro paese. RIASSUNTOn REFERENCES[1] Fowler V.G. Jr, Miro J.M., Hoen B., et al. ICE In-vestigators. Staphylococcus aureus endocarditis: a con-sequence of medical progress. 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High dose of trimethoprim-sulfamethoxazole and daptomycin as a therapeutic option for MRSA endocarditis with large vegetation complicated by embolic stroke: a case report and literature review.

https://iris.unipa.it/retrieve/handle/10447/99252/133205/Infez.%20Med..pdf

High dose of trimethoprim-sulfamethoxazole and daptomycin as a therapeutic option for MRSA endocarditis with large vegetation complicated by embolic stroke: a case report and literature review.

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Archivio istituzionale della ricerca - Università di Palermo