Heart & Lung xxx (2015) 1e4

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Haemophilus parainfluenzae aortic prosthetic valve endocarditis (PVE) successfully treated with oral levofloxacin Burke A. Cunha, MD a, b, *, Kunal Brahmbhatt, MD a, Muhammad Raza, MBBS a a b

Infectious Disease Division, Winthrop-University Hospital, Mineola, NY, USA State University of New York, School of Medicine, Stony Brook, NY, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 7 January 2015 Received in revised form 16 April 2015 Accepted 20 April 2015 Available online xxx

Antibiotic treatment of native valve infective endocarditis (IE) traditionally consists of 4e6 weeks of intravenous (IV) antibiotic therapy. Oral (PO) antibiotic therapy is being used more frequently, for part or all of treatment for IE but experience in treating IE with PO antibiotics is limited. Preferable agents for oral therapy of IE are antibiotics with a high degree of activity against the IE pathogen and that have high bioavailability (>90%) so that achievable serum and tissue levels are the same as with equivalent IV antibiotics. Oral antibiotic therapy of IE has several advantages over IV therapy given the long duration of treatment, i.e., 4e6 weeks for IE. Firstly, outpatient oral therapy for IE is easily administered over 4e6 weeks and decreases hospital length of stay (LOS). Secondly, oral antibiotics (administered at the same dose, frequency and duration) costs much less than their IV counterparts. Thirdly, with PO therapy for IE there are no central venous catheter (CVC) associated complications, e.g., phlebitis, bacteremia, fungemia. Compared to native valve IE, prosthetic valve endocarditis (PVE), depending on the IE pathogen, requires prolonged therapy and usually valve replacement. Haemophilus sp. IE is relatively virulent and often complicated by heart failure and/or embolic phenomena. We describe the first reported case of Haemophilus parainfluenzae aortic PVE successfully treated with oral levofloxacin without aortic valve replacement. Ó 2015 Elsevier Inc. All rights reserved.

Keywords: Oral antibiotic endocarditis therapy Levofloxacin Prosthetic valve endocarditis Haemophilus endocarditis treatment

Introduction Infectious endocarditis (IE) may occur on undamaged heart valves, as in the case of acute bacterial endocarditis (ABE) or may occur on damaged cardiac valves or endothelium in the case of subacute bacterial endocarditis (SBE). The pathogens causing ABE are virulent and invasive and for this reason do not require previous damage to cause infection on the heart valve. In contrast, the pathogens causing SBE are relatively avirulent pathogens, e.g., viridans streptococci and require a damaged valve to establish infection. Clinically, prosthetic valve endocarditis (PVE) presents as early (occurring < 60 days post-valve replacement and usually due to virulent pathogens, e.g., Staphylococcus. aureus). Early PVE (60 days after valve

Declarations: Funding: None. Competing interests: None. Ethical approval: None. * Corresponding author. Infectious Disease Division, Winthrop-University Hospital, 222 Station Plaza North (Suite #432), Mineola, NY 11501, USA. Tel.: þ1 516 663 2505; fax: þ1 516 663 2753. E-mail address: [email protected] (B.A. Cunha). 0147-9563/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2015.04.006

replacement) presents and behaves clinically like SBE. Organisms of intermediate severity, e.g., Hemophilus sp. may cause SBE and less commonly PVE. Late PVE (occurring > 60 days post-valve replacement and usually due to relatively avirulent non-invasive pathogens, e.g., Staphylococcus epidermidis), also known as coagulase negative staphylococci (CoNS). Excluding embolic and suppurative complications, SBE is nearly always curable by antimicrobial therapy. Although ABE is more virulent, often with outcomes more complicated and worse than with SBE. The outcome of PVE depends upon the pathogen and the time interval between valve infection and implantation. Because PVE involves a prosthetic device either natural or metallic, particularly with virulent pathogens, removal/ replacement of the prosthetic valve is usually required for cure of PVE.1e8 Rarely, PVE has been cured with antimicrobial therapy (IV/ PO) alone without valve replacement.9 Infectious disease and cardiology groups have developed endocarditis treatment guidelines that recommend intravenous (IV) antibiotics for 4e6 weeks for IE.4e8 Oral therapy is acceptable alternative therapy if no IV access or if IE is uncomplicated. Effective antimicrobial therapy for IE are based on three principles. Firstly, preferably the antibiotic should be bactericidal (vs bacteriostatic), but there are many exceptions to this rule. Bacteriostatic antibiotics

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(doxycycline) have been used successfully for decades to treat endocarditis e.g., Brucella endocarditis, Legionella endocarditis, Chlamydophilia psittaci endocarditis, Tropheryma whippelii endocarditis, Bartonella endocarditis, Q fever endocarditis. Secondly, the antibiotic should have a high degree of activity against the IE pathogen (high serum levels relative to the MIC of the pathogen). Thirdly, to be effective the antibiotic must penetrate (achievable therapeutic concentrations in the cardiac vegetation) and sterilize the cardiac vegetation. Parenteral therapy of IE has been the traditional approach for several reasons. Firstly, there is the notion that parenteral antibiotics act more quickly and may be more effective than their oral counterparts.10,11 Secondly, until the last two decades there have been relatively few oral antibiotics available with excellent bioavailability that would be suitable for use in the oral therapy of IE. In recent years, there has been an increased understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) properties of antibiotics. More and more serious systemic infectious diseases have been successfully treated partially or entirely via the PO (oral) route.9e12 Intravenous drug abusers (IVDSs) with right sided (tricuspid valve) MSSA/MRSA ABE have been successfully treated with a 2 week course of oral antibiotics.13e15 It is well known that ABE and IVDAs due to S. aureus has a more benign course and a better prognosis than in ABE in non-IVDAs.1,4 As experience and confidence has increased over the years, there have been more reports of cases of serious infections treated via the oral route, including IE.9 At the present time, there are several antibiotics available that meet criteria to treat IE, i.e., bactericidal, with same blood and tissue (cardiac valve/vegetation) levels as their parenteral counterparts. For the treatment of IE oral antibiotics used should have a high degree of activity against the IE pathogen and bioavailability, i.e., >90% gastrointestinal absorption to achieve serum and tissue levels which are essentially the same as their IV equivalent.16 Oral antimicrobial therapy has many advantages over equivalent IV therapy including lower cost, elimination of the need to administer the antibiotic via central venous catheters (CVCs), and elimination of IV side effects e.g., phlebitis, bacteremia, fungemia.9e12 Currently, oral antimicrobial therapy is used most often for completion of treatment of IE following initial IV therapy after clinical defervescence and negative blood cultures.9e11,17 There are drug cost savings using PO therapy and considerable cost savings decreasing hospital length of stay (LOS).10e12 In treating IE, after initial IV therapy switching to PO (after 3 days ortherapy/clinical defervescence) has been frequently used in patients without complications.9,17 A few days or a week of initial IV therapy followed by 3e5 weeks of PO therapy in a 4e6 week course of antibiotics for IE makes no difference, in terms of an efficacy and outcome, is essentially the same oral antibiotic therapy for the entire duration of IE therapy.12 From animal models to human experience, as more clinicians gain experience and confidence using oral antimicrobial therapy for the treatment of IE, the benefits of PO therapy will be appreciated, e.g., decreased antibiotic costs, decreased hospital length of stay (LOS), and elimination of IV related complications.10e12,18 We present a case of Haemophilus parainfluenzae aortic PVE successfully treated initially with IV therapy for one week followed by 5 weeks of oral levofloxacin therapy without valve replacement. Case A 36 year old male presented to the Emergency Department (ED) with a chief complaint of fever for 2 weeks. Daily fevers were associated with chills and myalgias/arthralgias. Review of symptoms was positive for cough and sore throat two weeks before

admission. Ten days prior to admission he went to the ED with cough/sore throat and was discharged on azithromycin with temporary improvement in symptoms which relapsed following completion of antibiotic therapy. He had rheumatic fever as a child, complicated by valvular heart disease requiring mechanical aortic valve (AV) replacement and mitral valve (MV) replacement 17 years ago. Six months ago he had paroxysmal atrial fibrillation treated with cardioversion. At the time, he had a transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE) which showed no vegetations. He had no recent dental work or respiratory tract infections. On admission, he had a temperature of 102.8 F, with pulse of 102/min. In the ED he was empirically given a dose of piperacillin/ tazobactam. The patient developed a rash to piperacillin/tazobactam which was stopped. Physical examination was unremarkable with no signs of IE, i.e., no Roth spots, conjunctival hemorrhages, splinter hemorrhages, Osler nodes or Janeway lesions. Laboratory tests on admission revealed a WBC count of 8.1 k/ mm3, CRP of 89 mg/L (n < 3 mg/L) and ESR of 29 mm/h (n ¼ 1e 16 mm/h). Additional laboratory studies included an LDH of 284 mg/dl and a ferritin of 160 ng/dl (n ¼ 14e235 ng/dl). On admission, the main diagnostic consideration was PVE with his history of fevers and prosthetic heart valves. Given the allergic reaction to a ß-lactam e.g., piperacillin/tazobactam, the patient was started empirically on levofloxacin 500 mg (IV) q24h pending blood culture results. His serum creatinine was 0.9 mg/dl. TTE showed no vegetations, but a TEE which revealed a small vegetation on the prosthetic aortic valve and extensive intimal thickening due to atherotic disease in the descending aorta. Cardiothoracic surgery was consulted for possible surgical intervention, but in the absence of embolic phenomena, heart failure, or paravalvular abscess, continued medical treatment was recommended. Admission blood cultures were reported positive for Gram negative bacilli (GNB) on hospital day #4, and the patient was continued on IV levofloxacin (500 mg (IV) q24h). On hospital day #5, blood culture isolates were identified as Hemophilus sp. and later confirmed as H. parainfluenzae susceptible to levofloxacin. He rapidly became afebrile, and was switched to oral levofloxacin 500 mg q24h on hospital day # 5. On hospital day #7, he was discharged home and completed 6 weeks of oral levofloxacin therapy. Repeat blood cultures were negative. Discussion Oral antimicrobial therapy of IE has many obvious advantages, including decreased cost, absence of CVC related complications, and decreased LOS.9 The gradual introduction of IV to PO switch programs for a variety of serious systemic infections has led to increased use of oral antimicrobial therapy including treatment of IE.9,12 Most widely used has been oral therapy of tricuspid valve (TV) ABE in intravenous drug abusers (IVDAs) due to methicillin resistant S. aureus (MRSA) or methicillin sensitive S. aureus (MSSA).13 IVDAs with TV MSSA/MRSA have been treated entirely by the oral route for a short duration (2 weeks) by us and others.2,6,8 Minocycline has been the mainstay of the oral treatment of MRSA/MSSA TV ABE in IVDAs.12,13 With the general acceptance of IV to PO switch programs in treating a variety of systemic infections, there have been cases of treating IE via the oral route.12,18,19 While there are no large studies on the oral antibiotic therapy of IE to date, the literature consists primarily of case reports.9 The oral therapy of IE is a therapeutic option if the IE organism is highly susceptible and the patient is able to take oral medications, with good absorption of and high bioavailability (>90%). Pharmacokinetically (PK), with carefully selected therapy, the same blood and tissue levels are achieved for oral and IV antibiotics at equivalent doses.10,11,19 Initial

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Table 1 Oral antibiotic therapy of endocarditis. Type of Infective Endocarditis (IE)

Usual Pathogens

Usual IV antibiotic Equivalent PO antibiotic

Subacute bacterial endocarditis (SBE) Viridans streptococci    Haemophilus sp.  Acute bacterial endocarditis (ABE) S. aureus (MSSA)   S. aureus (MRSA)    

Penicillin or Cefazolin or Ceftriaxone Ceftriaxone Nafcillin or Cefazolin Daptomycin or Vancomycin or Minocycline or Linezolid

Oral bioavailability Usual MIC Peak serum of Pathogens concentration

99% Cephalexin 1 g (PO) q6h or 90% Amoxicillin 1 g (PO) q8h or 100% Levofloxacin 500 mg Levofloxacin 500 mg 100% Cephalexin 1 g (PO) q6h or 99% Linezolid 600 mg (PO) q12h 100% 100% Levofloxacin 500 mg or Minocycline 100 mg (PO) q12h or 100% 95% Linezolid 600 mg (PO) q12h or 100% Levofloxacin 500 mg