Heart & Lung 44 (2015) 317e320

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Heart & Lung

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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
Infectious Disease Division, Winthrop-University Hospital, Mineola, NY, USA
b
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: Antibiotic treatment of native valve infective endocarditis (IE) traditionally consists of 4e6 weeks of
Received 7 January 2015 intravenous (IV) antibiotic therapy. Oral (PO) antibiotic therapy is being used more frequently, for part or
Received in revised form all of treatment for IE but experience in treating IE with PO antibiotics is limited. Preferable agents for
16 April 2015
oral therapy of IE are antibiotics with a high degree of activity against the IE pathogen and that have high
Accepted 20 April 2015
Available online 19 May 2015
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
Keywords:
Oral antibiotic endocarditis therapy
weeks and decreases hospital length of stay (LOS). Secondly, oral antibiotics (administered at the same
Levofloxacin dose, frequency and duration) costs much less than their IV counterparts. Thirdly, with PO therapy for IE
Prosthetic valve endocarditis there are no central venous catheter (CVC) associated complications, e.g., phlebitis, bacteremia, funge-
Haemophilus endocarditis treatment mia. 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.

Introduction replacement) presents and behaves clinically like SBE. Organisms of

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 sub-
acute 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 replacement) is usually due to virulent pathogens,
e.g., S. aureus, like ABE, whereas late PVE (>60 days after valve
Declarations: Funding: None. Competing interests: None. Ethical approval: None.
* Corresponding author. Infectious Disease Division, Winthrop-University Hos-
pital, 222 Station Plaza North (Suite #432), Mineola, NY 11501, USA. Tel.: þ1 516 663
2505; fax: þ1 516 663 2753.
E-mail address: bacunha@winthrop.org (B.A. Cunha).
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 coagu-
lase negative staphylococci (CoNS). Excluding embolic and suppu-
rative 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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318 B.A. Cunha et al. / Heart & Lung 44 (2015) 317e320
(doxycycline) have been used successfully for decades to treat
endocarditis e.g., Brucella endocarditis, Legionella endocarditis,
Chlamydophilia psittaci endocarditis, Tropheryma whippelii endo-
carditis, 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 antibi-
otics 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, fun-
gemia.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 us-
ing 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 symp-
toms was positive for cough and sore throat two weeks before
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admission. Ten days prior to admission he went to the ED with
cough/sore throat and was discharged on azithromycin with tem-
porary 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 echocar-
diogram (TTE) and transesophageal echocardiogram (TEE) which
showed no vegetations. He had no recent dental work or respira-
tory 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/tazo-
bactam which was stopped. Physical examination was unremark-
able with no signs of IE, i.e., no Roth spots, conjunctival
hemorrhages, splinter hemorrhages, Osler nodes or Janeway le-
sions. 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 inter-
vention, but in the absence of embolic phenomena, heart failure, or
paravalvular abscess, continued medical treatment was recom-
mended. 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 dis-
charged 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
 B.A. Cunha et al. / Heart & Lung 44 (2015) 317e320 319

Table 1
Oral antibiotic therapy of endocarditis.

Type of Infective Endocarditis (IE) Usual Pathogens Usual IV antibiotic Equivalent PO antibiotic Oral bioavailability Usual MIC Peak serum
of Pathogens concentration
Subacute bacterial endocarditis (SBE) Viridans streptococci  Penicillin or Cephalexin 1 g (PO) q6h or 99% <1 mcg/ml 36 mcg/ml
 Cefazolin or Amoxicillin 1 g (PO) q8h or 90% <1 mcg/ml 16 mcg/ml
 Ceftriaxone Levofloxacin 500 mg 100% <1 mcg/ml 5 mcg/ml
Haemophilus sp.  Ceftriaxone Levofloxacin 500 mg 100% <1 mcg/ml 5 mcg/ml
Acute bacterial endocarditis (ABE) S. aureus (MSSA)  Nafcillin or Cephalexin 1 g (PO) q6h or 99% <2 mcg/ml 36 mcg/ml
 Cefazolin Linezolid 600 mg (PO) q12h 100% <1 mcg/ml 20 mcg/ml
S. aureus (MRSA)  Daptomycin or Levofloxacin 500 mg or 100% <1 mcg/ml 20 mcg/ml
 Vancomycin or Minocycline 100 mg (PO) q12h or 100% <1 mcg/ml 20 mcg/ml
 Minocycline or Linezolid 600 mg (PO) q12h or 95% <1 mcg/ml 4 mcg/ml
 Linezolid Levofloxacin 500 mg 100% <1 mcg/ml 20 mcg/ml

ABE, acute bacterial endocarditis; SBE, subacute bacterial endocarditis; IV, intravenous; PO, oral/by mouth; MSSA, methicillin sensitive Staphylococcus aureus; MRSA,
methicillin resistant Staphylococcus aureus. Adapted from: Cunha, BA (Editor). Antibiotic Essentials (12th ed.). Jones & Bartlett, Sudbury, MA, 2014; 70e77.

parenteral therapy of ABE is usually for those that are critically
ill.4,17 Non-critically ill patients may safely and efficaciously be
treated with oral antimicrobials soon after clinical defervescence
with initial IV therapy may be treated entirely via the oral
route.9,12,20 If the oral antibiotic selected has the same spectrum
and PK characteristics, there is no difference between IV or PO
therapy as long as the patient is able to absorb the antibiotic.10,11,19
Oral antibiotics which have been used most frequently to treat
serious systemic infections including IE due to susceptible organ-
isms include amoxicillin, quinolones, TMP-SMX, doxycycline,
minocycline, and linezolid.10,18 All of these antibiotics have excel-
lent bioavailability and have been successfully used to treat IE due
to various IE pathogens.10,11 Among the quinolones, the most clin-
ical experience in IV-to-PO switch regimens and for PO therapy is
with levofloxacin. Levofloxacin administered IV has the same blood
and tissue levels as when administered at the same dose via the
oral route. Oral antimicrobial therapy of IE has other advantages
besides cost and safety, e.g., oral therapy also provides for earlier
discharge and less exposure to the potential of nosocomial patho-
gens during therapy.18e21 While it is thought that bactericidal ac-
tivity is needed for endocarditis therapy, there are many examples
of bacteriostatic antibiotics, e.g., doxycycline, minocycline, linezolid
which are efficacious and have been successful in treating IE, e.g.,
amoxicillin for viridans streptococci and doxycycline for Q fever
endocarditis. 11Quinolones have many advantages in the oral
treatment of IE, in that they are bactericidal, have high bioavail-
ability, may be dosed once or twice daily and, in addition, have
excellent tissue penetration, e.g., into cardiac vegetations with few
side effects10,11 (Table 1).
The case presented was that of a young man with previous AV
and PVE replacement for rheumatic fever damaged heart valves.
Table 2
Clinical features of Hemophilus parainfluenzae endocarditis.
Clinical features Parameter
Mean age 31 years
Predisposing conditions
Underlying heart disease 52%
Oral infections/dental procedures 45%
Drug abuse 3%
Sinus infections 10%
Peripheral stigmata 59%
Congestive heart failure 10%
Arterial embolization 85%
Involved valve
Aortic 17%
Mitral 67%
Mortality 10e35%
Adapted from: Brusch, JL. Infective Endocarditis. Informa New York 2007; 58e61.
The source of his H. parainfluenzae was probably his antecedent
respiratory tract infection H. parainfluenzae IE is uncommon, and
H. parainfluenzae PVE is rare. H. parainfluenzae IE is a relatively
virulent pathogen and is associated with frequent complications
(Table 2).22e30 H. parainfluenzae, a rare cause of PVE, would
expectedly be difficult to cure. He had no peripheral manifestation
of PVE and his course was free of embolic complications. This case
of uncomplicated H. parainfluenzae aortic PVE successfully treated
mainly with oral levofloxacin adds to the literature of experience in
treating serious infections, including PVE, with oral antibiotics.31
To the best of our knowledge, this is the first reported case of
successful therapy of H. parainfluenzae aortic PVE with mainly oral
levofloxacin for 5 weeks (6 weeks total). This case adds to the
literature of successful oral therapy of IE, in general, and PVE in
particular with oral levofloxacin.
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