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389 ( 45 )具CASE REPORT 典

Successful combination therapy with vancomycin and arbekacin
against infective endocarditis caused by MRSAKENTARO TO, NORIKO MIYAKE, YOJI NAGASAKI and NOBUYUKI SHIMONO
Department of Clinical Immunology and Rheumatology/
Infectious Diseases, Kyushu University Hospital(Received for publication September 7, 2011)

Infective endocarditis caused by methicillin-resistant Staphylococcus aureus(MRSA) is a serious disease and sometimes leads to poor prognosis. We should haveseveral therapeutic options. Arbekacin is one of the aminoglycoside antibiotics, which
is more active against MRSA and less nephrotoxic than gentamicin. Here we presented
a successfully treated case of severe MRSA endocarditis without any adverse effect bymonitoring therapeutic level of vancomycin and arbekacin.

Introduction
Infective endocarditis is a serious disease and sometimes leads to thrombosis and metastatic infections. Methicillin-resistant Staphylococcus aureus (MRSA) endocarditis has a much higher mortality than endocarditis caused by methicillin-susceptible Staphylococcus aureus (MSSA)1. In spiteof aggressive antimicrobial therapy against MRSA, we sometimes experience the treatment failure.
We should have several therapeutic options for this severe infection, however the optimal therapy
has not been established yet. Here we experienced a successful MRSA infective endocarditis casetreated by combination therapy of vancomycin and arbekacin.

Case report
A 38-year-old woman (Ht 160 cm, Wt 45 kg) was admitted to a hospital with a month-long history of high fever, chills, general malaise and leukocytosis. She visited the home doctor and was diagnosed as having upper respiratory infection, however her symptoms did not respond to several
short courses of therapy with levoﬂoxacin. She had four teeth removed within one month before theonset. She had also received ﬂu vaccine on the day before the high fever. She had untreated hyperthyroidism but had not been hospitalized nor had a history of drug abuse. A chest X-ray showed
multiple cavity formations in the lung ﬁelds and several blood cultures were positive for MRSA.

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Fig. 1
A: Echocardiogram showed vegetation on tricuspid valve.
B: Chest CT showed cavitary lesion with surrounding inﬂammation.

Cultures of bronchoalveolar lavage yielded MRSA and Candida albicans. The sensitivity test ofMRSA showed sensitive for clindamycin, aminoglycosides, quinolones, vancomycin andteicoplanin. In spite of intravenous antibiotic therapy, including vancomycin, teicoplanin,
ciproﬂoxacin, pazuﬂoxacin and clindamycin, blood cultures were persistently positive for MRSA
and ﬁnally the third echocardiogram revealed verrucous vegetations affecting the tricuspid valve(Fig. 1A). Disseminated intravascular coagulation (DIC) developed.
On transfer to our hospital, 4/6 holosystolic heart murmur was heard with maximum loudness at
the apex. Subcutaneous hemorrhage was observed on bilateral knees. Laboratory examinations
revealed a hemoglobin level of 8.3 g/dL, white blood cells count of 1,660/mm3 and platelets count of
28,000/mm3. The liver function tests revealed AST of 104 IU/L, ALT of 76 IU/L, ALP of 1,113 IU/L
and LDH of 663 IU/L. Thyroid function test revealed a free T4 level of 1.69 ng/dL and TSH level of0.01 m IU/mL. A chest CT scan revealed multiple cysts and nodules in the right lung ﬁeld (Fig. 1B).
The patient was diagnosed as having MRSA endocarditis with lung abscesses and DIC. Under theadministration of vancomycin (0.5 g every 6 h), the trough concentration of vancomycin 5 days afteradministration in the previous hospital was 5.7 m g/mL. The regimen of vancomycin was changed to1 g every 12 h and combined with arbekacin (200 mg every 24 h) and panipenem (1 g every 12 h).
Through therapeutic drug monitoring (TDM), the trough concentration of vancomycin wasincreased and maintained from around 15 to 20 m g/mL. As to arbekacin, the dose was increased to
300 mg per day, to raise peak concentration at approximately around 20 m g/mL.
Iodine was given for hyperthyroidism and granulocyte colony stimulating factor was given forFig. 2.

Clinical course.

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neutropenia for 2 days. Antithrombin III was compensated, and heparin was given for DIC. The
patient status improved immediately and panipenem was stopped after 14 days. In total, arbekacin
was given for 6 weeks and vancomycin was given for 8 weeks (Fig. 2).

Discussion
Right sided infective endocarditis is usually associated with intravenous drug users and the presence of intravascular catheters or pacemakers. The symptoms of right sided endocarditis are similar
to those of respiratory infection. In this case she had received subcutaneous vaccination before theonset, but lacked the common predisposing factors. At the initial phase of this case, there revealed
no vegetation on tricuspid valve, which did not fulﬁll the Duke deﬁnite diagnostic criteria. In thiscase, these facts might lead to the delay of the correct diagnosis. Considering of these characteristics
of right sided endocarditis, several reports pointed that the Duke criteria are not appropriate andshould be modiﬁed2,3.
Infective endocarditis caused by MRSA is very severe and the outcome is poor. At present, there
is no optimal therapy for the disease, and vancomycin has become the standard treatment. However,vancomycin has shown only a bacteriostatic effect on MRSA, which might be one of the reasons forthe poor outcome4. Several trials of treatments alternative to vancomycin have been performed.
Besides, some newer antibiotics have been tried against bacteremia or infective endocarditis causedby MRSA. Linezolid has successfully been used to treat individual cases of MRSA endocarditis5. But
the long-term safety is questionable because of its suppression of hematopoiesis. In this case, showing thrombocytopenia, it was difﬁcult to use linezolid. Moreover, this drug has shown bacteriostatic
effect on MRSA. Daptomycin has recently been proven well tolerated and effective against MRSA
bacteremia, including right-sided endocarditis6,7. This drug is considered to be bactericidal, however, it is not available in Japan now. Arbekacin is an aminoglycoside antibiotic with antibacterial
activity against both Gram-positive and Gram-negative bacteria. It also exerts bactericidal effect onMRSA. But there has not been any report on arbekacin monotherapy for infective endocarditis.
When vancomycin monotherapy fails, combination therapy is the next choice. Combination therapy with vancomycin and gentamicin is recommended in the guideline, based on the fact that thiscombination showed synergistic effect against the majority of MRSA strains. However, this synergism was not observed with any of the strains highly resistant to gentamicin8. Because of the poorsusceptibility of MRSA to gentamicin, especially in Japan9, we could not expect a vancomycin-gentamicin synergism. Arbekacin, unlike other aminoglycosides, is stable in the presence of aminoglycoside-inactivating enzymes produced by MRSA. Moreover, arbekacin showed rapid killing activity
against MRSA10 and the frequency of renal dysfunction is much lower than that observed with gentamicin. In vitro studies also showed that arbekacin plus vancomycin exerted a synergistic effectagainst gentamicin-resistant MRSA11. In our patient, several antimicrobial agents were ineffective,Dec. 2011

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64—56393 ( 49 )and in the end she was complicated with lung abscesses and DIC. In order to treat such a severe
patient, we selected combination therapy with vancomycin and arbekacin. And panipenem was also
used during the ﬁrst 14 days.
The major adverse effects of vancomycin, gentamicin and arbekacin are renal dysfunction andauditory disorder. So extreme caution should be paid, when using these drugs simultaneously. TDM
is important to achieve favorable outcome and to avoid adverse reactions12,13. Theoretically, thepharmacokinetic-pharmacodynamic (PK/PD) analysis of vancomycin and arbekacin shows that their
efﬁcacy depends on the area under the concentration-time curve/minimum inhibitory concentration(AUC/MIC) and peak concentration/MIC (Cmax/MIC), respectively. Before this patient was transferred to our hospital, she was administered vancomycin 4 times per day. Unfortunately the concentration was not enough in the previous hospital. Thus we changed the regimen of vancomycin totwice per day and arbekacin to once per day. It is recommended to keep the trough concentration ofvancomycin at least 10 to 15 m g/mL. As to arbekacin, it is recommended to keep the peak concentration at around 12 m g/mL and the trough concentration under 2 m g/mL. In a severe situation likethis case, the concentration should be kept higher. Therefore, we frequently monitored and raised
the trough concentration of vancomycin to around 20 m g/mL and the peak concentration ofarbekacin to approximately around 20 m g/mL. Fortunately, our patient suffered no adverse effects.
This frequent TDM might be very important to achieve a good outcome and to avoid adverseeffects14.

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