Aspergillus Species En arditis by mikesanye


									Aspergillus                        Species Endocarditis

The New Face of a Not So Rare Disease

 ROBERT      B. KAMMER.           M.D.’                            Aspergillus flavus endocarditis    developed in a 13 year old girl
 JOHN      P. UTZ,    M.D.7                                        after mitral valve replacement.    Thirty-nine other cases of Asper-
Richmond.       Virginia                                           gillus species endocarditis were found in the medical literature.
                                                                   Twenty-nine    of these infections occurred in postcardiac surgery
                                                                   patients. Fever was the most common presenting manifestation
                                                                   (35 patients). Cardiac murmurs were present in 25. Lesions were
                                                                   in the left side of the heart in 38 (95 per cent), and there were
                                                                   major arterial emboli in 33 (83 per cent).
                                                                       The diagnosis was made antemortem in only nine patients. The
                                                                   diagnostic specimen in eight of these was an embolus. Aspergil-
                                                                   lus sp. were cultured from the blood of only three (8 per cent).
                                                                   Two (5 per cent) patients survived; in both infected prostheses
                                                                   were replaced, and one received antifungal chemotherapy.         As-
                                                                   pergillus sp. endocarditis should be suspected in any postcardiac
                                                                   surgery patient presenting with endocarditis      and emboli whose
                                                                   blood yields no organisms in culture.
                                                                       Careful surveillance and control of fungal contamination of the
                                                                   surgical environment is urged. Cultures of arterial blood should be
                                                                   obtained, and both solid and liquid microbiological media utilized.
                                                                   Early valve replacement    and chemotherapy     with both amphoteri-
                                                                   tin B and flucytosine are recommended.

                                                                   In 1958, Merchant et al. [l] reviewed the medical literature on en-
                                                                   docarditis caused by fungi. Aspergillus species were the etiologic
                                                                   agents in only four [2-51 of the 34 cases reported to that date.
                                                                   Fourteen years later, reported cases of Aspergillus sp. endocarditis
                                                                   alone number 39 [2-341.
                                                                       This marked increase in prevalence parallels the rise of cardiac
                                                                   surgery. The first report of a case occurring after cardiac surgery
                                                                   was that of Hadorn [7] in 1960. Newman and Cordell [ 1 l] pub-
                                                                   lished the first case involving an intracardiac prosthesis. In 29 of
From the Medical       College    of Virginia,      Richmond,
Virginia   23298.    Requests     for reprints       should   be   the 39 reported cases, Aspergillus sp. endocarditis occurred within
addressed    to Dr. Robert       B. Kammer.         Manuscript     the 1st year of cardiovascular surgery. Twenty-four patients re-
accepted   September         17. 1973.                             ceived prosthetic valves or homografts.
   * Present address:         Lilly Laboratory        for Clini-
                                                                      The correct antemortem diagnosis was made only nine times.
cal Research,       Marion    County      General     Hospital,
960 Locke Street, Indianapolis,  Indiana 46207.
                                                                   Furthermore, only two patients survived, despite therapy. Means of
   t Present  address:   Georgetown     University                 prevention, accurate diagnosis and effective treatment remain un-
School of Medicine, Washington,    D.C. 20007.                     solved problems.

506         April 1974        The American Journal of Medicine          Volume 56
                                                                                                                                ASPERGILLUS         SPECIES ENDOCARDITIS-KAMMER,                         UTZ

CASE REPORT                                                                                                   a dose of 10 mg intravenously.                       The Starr-Edwards                   mitral
                                                                                                              prosthesis        was      replaced        12 hours         later    on June       28. The
When patient L. F. (g-38-62-84), a black girl born on Au-                                                     excised      valve     was coated            with friable     clots from which             As-
gust 18, 1958, was first seen at the Medical College of Vir-                                                  pergillus     flavus      was     subsequently          cultured.       Fever      and leu-
ginia Hospital in 1964, she had severe pulmonary edema.                                                       kocytosis         persisted,         and       azotemia             developed,       which
Marked cardiomegaly was present, and grade 316 apical                                                         forced reduction of the amphotericin   B dose from 20 to 5
murmurs were audible in systole and diastole. Acute rheu-                                                     mg on July 1. The hemiparesis   diminished, and the patient
matic fever with myocarditis and mitral valvulitis was diag-                                                  began       to speak.        A brain       scan     on July 6 demonstrated                       a
nosed,       and therapy              with   digoxin,        mercurial         diuretics,       oxy-          focal    area of increased               uptake    in the left posterior            tempo-
gen      and     corticoids           was     begun.         Her     condition          improved              ral area.     The apical          systolic     murmur        was heard           again     that
slowly,      but murmurs              and cardiomegaly               persisted.         After    a 3          day.     She was          given     20 mg of amphotericin                   B on July 7,
month       hospitalization,            she was discharged                  on a regimen           of         bringing     the total to 115 mg. A few hours later she sudden-
benzathine          penicillin,         1.2 million       units      every       28 days,         di-         ly became            tachypneic,          ventricular        fibrillation    developed,
goxin      and sodium           restriction.          She did well until June                   1970          and she died. No autopsy                  was permitted.
when        exertional         dyspnea         and      ankle       edema         prompted           a           This case is typical and illustrates the more com-
brief     readmission           for     cardiac       catheterization.             Severe        mi-
                                                                                                              mon features of Aspergillus sp. endocarditis:           (1) or-
tral regurgitation            was demonstrated.                    Diuretics      were      added
                                                                                                              ganic heart disease with valve prosthesis;          (2) previ-
to the therapeutic              regimen.        Atrial    fibrillation         led to intracta-
                                                                                                              ous antibacterial   therapy;     (3) unexplained   fever: (4)
ble heart failure in January 197 1.
   On February 1, 1971, the deformed                                 mitral valve        was re-              polymorphonuclear       leukocytosis;   (5) anemia; (6) pyu-
placed       by a Starr-Edwards                    prosthesis.          Surgery          was     un-          ria and microscopic       hematuria;   (7) emboli to major
complicated,           but fever         developed            8 hours        later.     Nafcillin,            vessels, especially to central nervous system and ex-
benzyl      penicillin        and streptomycin                were      administered            pre-          tremities;  (8) sterile    blood cultures;     (9) diagnosis
and      postoperatively.               The        patient         remained           febrile     to          made by histology and culture of embolus; and (10)
38.9OC         (102’F).          Polymorphonuclear                     leukocytosis             was           death.
noted. No bacteria or fungi                       were cultured             from blood           and
urine specimens.   Antibiotic                     therapy  was              discontinued          on
                                                                                                              REVIEW AND ANALYSIS                            OF THE LITERATURE
February         8, and her temperature                      returned        to normal          over
the next        week.         Her temperature                rose      again     on February
                                                                                                             The clinical and pathologic      features of 40 cases of
19, she was treated                   with phenoxymethyl                penicillin,      and de-
                                                                                                             Aspergillus   sp. endocarditis   are presented in Tables I
fervesced.         No cause            for the pyrexia           and leukocytosis               was
found.      On February               28, following           electrical       cardioversion,
                                                                                                             and II. An analysis of these data follows.
she was discharged                    on a regimen             of benzathine            penicillin           Fungus Isolated.     From 30 patients, a species of As-
every      28 days,       quinidine,         warfarin        sodium        and digitoxin.                    pergillus   was cultured     from valves,       vegetations    or
   Atrial      fibrillation     recurred,         and the patient              was briefly       ad-         emboli. Of these, 14 were A. fumigatus,             6 A. flavus
mitted      in April       1971        for    cardioversion.            She      was     afebrile            and 5 not speciated.     There was one isolate each of
and otherwise            doing well. No murmurs                      were      heard.                        A. niger, A. ustus, A. terreus, A. glaucus and A. sy-
   On June          24, she was readmitted                     after     the sudden            onset         dowi. There were no clinically      distinctive    features  re-
of severe         pain    in the right          lower      extremity.           Her oral tem-
                                                                                                             lated to species.
perature       was 37.4’C              (99.4’F).       Pulse rate was 68/min                     and
                                                                                                             Age and Sex.                   Aspergillus sp. endocarditis                         occurs
regular.       A grade         276 apical          systolic      murmur         was present.
                                                                                                             most frequently               in young men. The average                             age      at
Absence         of the right           femoral,        popliteal       and dorsalis            pedia
                                                                                                              onset       was      31    years,        the   range        was       5 1 days      to     63
pulses was noted.                 Hemoglobin              level was            9.8 g/100  ml,
                                                                                                              years,      and    78 per         cent    of the subjects              affected      were
and the leukocyte                 count was              25,200/mm3               with 99 per
cent polymorphonuclear                       cells.    The prothrombin                 time     was           male.
21 seconds,            the control           was       12 seconds.             Urine     had     1-F         Presenting     Manifestations    and Physical Findings.
protein,       many      leukocytes          and 15 erythrocyteslhpf.                                        The protean clinical presentations       of Aspergillus     sp.
   A large        embolus         was        removed          from     the right        common               endocarditis    are catalogued     in Table I. Frequency
iliac artery 6 hours after admission.  On the following day,                                                 data for the more commonly           encountered      findings
June 25, re-exploration    was performed   because    of poor                                                are listed in Table Ill. These signs and symptoms
blood flow, and 3 more emboli                             were         removed          from     the
                                                                                                             suggest the diagnosis of endocarditis.        However,      the
right iliac and femoral arteries.
                                                                                                             great frequency     of emboli to major vessels of the
   Benzyl        penicillin,      nafcillin     and streptomycin                 were       admin-
                                                                                                             central nervous system and extremities         distinguishes
istered    postoperatively.   Temperature    spikes  to 38.9’C
                                                                                                             Aspergillus    sp. and Candida sp. endocarditis           from
(102’F)    and 40.6OC (105’F)     occurred on June 26 and 27,
respectively.    A right hemiparesis   and aphasia were noted                                                that due to aerobic bacteria [35].
on June 27 as well as subconjunctival        hemorrhages.   The                                                  The clinical diagnosis was bacterial endocarditis         in
systolic  murmur disappeared. Again no organisms could                                                        19 cases. In five patients,      primary disease of the
be cultured from 10 blood specimens. On June 28 fungal                                                       central nervous system, i.e., brain abscess or menin-
hyphae resembling   Aspergillus                         sp. were seen in sections                            gitis, was suspected.    Specific reference    to fungal eti-
of the emboli. and amphotericin                         B therapy was begun with                             ology was conspicuously       absent in every case.

                                                                                                         April 1974       The American          Journal of Medicine               Volume 56              507

TABLE      I       Aspergillus            sp. Endocarditis:     Clinical

                                                                                                                                     Physical Findings

  Case                                                                 Age (yr)            Presenting                 Heart                              Spleno-   Hepato-
  No.                    Source                     Fungus             and Sex            Manifestations             Murmur   Fever       Petechiae      megaly    megaly
      1          Cawley [2]                    A. fumigatus                8, M          Central nervous               ...      ..          ...                      ...

      2          Zimmerman                     Aspergillus     sp.         25, M         Emboli,      fever            +       +             ..            +         ...
                   (31                                                                                                                                                       _
      3          Welsh, Buch-                  A. flavus                   18, M         Fever                         ...     -I-           .                       ...
                  ness [4]

      4          Kirschstein,                  A. flavus                   50, M         Fever                         ...     +             ...           +         +
      5          Grcevic,                       Aspergillus    sp.         22, M         Fever, arthritis,             -       +             +             -         +
                   Mathews,                                                                coma
                 Case 3

      6           Hadorn     [7]               A. fumigatus                33, M         Fever                         +       +             ...                     -

      7           Luke et al. (81               A. fumigatus               51            Fever                         +       +             -             +         +

      8           Vogel, Heinitz                Aspergillus    sp.         48, M         Headache                      +       +             -             -         -

                    PI             ..___
      9           Paradis,                      A. fumigatus               2 mo,         Dyspnea,       coma           ...      -            +             +         +
                    Roberts        [lo]                                      F

      10          Newman,                       A. fumigatus               24, M         Fever, petechiae              +       f             +             ...       ...
                   Cordell [ll]

      11          ::hoo et al.                  A. flavus                  2 mo,         Diahrrhea,          fever      -       +            -             -         +
                    VI                                                          F

      12          Darrell 1131                  A. fumigatus               40, F         Eye pain,                     -       f             +             . *       ...
                                                                                           blurred vision

      13          Leffert,                      Aspergillus    sp.         26, M         Fever                         +        f            -             -
                    Hackett        [14]

                                                                                                 ~~     _______
      14          Satoyoshi                     Aspergillus    sp.         62, M         Orbital      pain             +        +            -             -          +
                    et al. (151

      15          Doughten,                     Aspergillus    sp.         5, M          Fever                          +       f            +             +          +
                    Pearson        [16]

508            April 1974         The American       Journal    of Medicine         Volume 56
                                                                                               ASPERGILLUS         SPECIES ENDOCARDITIS---KAMMER.                   UTZ

    Ewdence of                                                                                                              From
   Major Emboli                                        Associated                          Drug Therapy                   Probable                Clrnrcal
          t0                      Other                  Disease                            Before Onset                 Onset (mo)            Diagnosis
                          Pneumonia           None                                   Sulfonamides                           6          Dmlssemrnated

Leg                                           Septic      amputation                 Penrcilliri                             l/2       Bacterial        endo-

               .                              Neutropenia,                           ACTH.         antibiotics              1          Connective            tis-
                                                interstitial                                                                              sue disease

                                              Chronic       lyrnpho-                 ACTH,         antrbiotics              1          Leukemia
                                                cytic      leukemia

Brain                     Pneumonia           None                                   Penicillin,       tetracy-                 l/10   Brain       abscess
                                                                                        cline,      streptomy-
                                                                                        cin,     sulfonamide

Femoral     arteries,                         Subaortic         stenosis,            Erythromycin.                           3/4       Endocarditis
  brain                                         postoperative                           chloramphenicol,

Brain                                         Erytlrrobiastosis                      Penicillrn,                                11’2   Menrngitis

Brain,    eyes                                                                                                              2          Menrngitis

Brain                                         Prematurity,                                                                      1,‘2   Acute       lympho-
                                                cytomegalovirus                                                                           cytic     leukemia

Brain,    leg,     hand                       Rheumatic           heart              Penicillin,       strepto-            1 3,!4      E.ndocarditis
                                                disease,         Starr-                 mycin,        chlor-
                                                 Etlwards         mitral                amphenicol

Brain                                                                                                                           1’2

Brain                     Uveitis             Rheumatic           heart              Penicillin,        strepto-            1          Llveitis.      bacterial
                                                 disease,        mitral                 mycin                                             endocarditis
                                                 valve      prosthesis

                                              Congenital          heart              Penicillin,       strepto-             11/2       Bacterial        endo-
                                                disease,         Starr-                 mycin                                             carditis
                                                 Edwards          aortic

Brain                     Arthritis,                                                                                        3          t3acterial       endo-
                             adenopathy                                                                                                   carditis

Meninges                                      Congenital          heart                                                         213    13acterial       endo-
                                                disease,         atrial                                                                   carditis,
                                                 septal      defect                                                                       disseminated
                                                 repair,       mitral                                                                     intravascular
                                                 repair                                                                                   coagulation


                                                                        April 1974      The American             Journal 01 Medicine    Volume        56            509

TABLE I (Cont’d)                 Aspergillus   sp. Endocarditis:         Clinical Aspects

                                                                                                                           Physical Findings

 Case                                                                 Age (yr)          Presenting         Heart                               Spleno-   Hepato-
  No.                Source                    Fungus                 and Sex          Manifestations     Murmur   fever       Petechiae       megaly    megaly

      16    Caplan          et al.        A. fumigatus                39, M         Anorexia,  mal-         +       +              -             +         +
               1171                                                                   aise, weight
      17     Khan      et al.             A. fumigatus,               41, M         Tachycardia             -t      +              +             +          +
               1181                         C. albicans

      18     Mahvi         et al.         A. niger                     9, M          Leg pain,    fever     -t      +              +             +          -

      19     Mershon          etal.       A. terreus                   15, M         Low back     pain      -I      +              +             -          -
      20     Hairston,           Lee      A. fumigatus                26, M         Fever                   +       +              ...            ...      ...
             Case      2

      21     Hairston,           Lee      A. fumigatus                13, M          Fever                  +       +              ...            ...       ...
             Case     4

      22     Hairston,           Lee     A. fumigatus                 63, M          Fever, central         +       +              +              ...       . ..
               VI                                                                       nervous sys-
             Case      5                                                               tern symptoms

      23     Hairston,           Lee      A. flavus                    31, M         Fever                  +       +              ...            ...       ...
             Case      6

      24     Jones         et al.         Aspergillus     sp.          46, F         Fever, abdomi-         +       +              +              ...       . *.
                WI                                                                     nal pain

      25     Br Med          J            A. sydowi                    31, F         Numbness               +       +              +              ...       ...
                1231                                                                   right leg,
                                                                                       Osler’s nodes,

      26     Aslam         et al.         Aspergillus     sp.          51, M         Fever                  +       +              -              -         -

      27     Hairston,           Lee      Aspergillus     sp.          14, F         Valve dysfunc-         +        ...               ...        ...       ...
               ~251                                                                     tion
             Case 6

510        April 1974            The American Journal of Medicine                Volume 56
                                                                                                  ASPERGILLUS SPECIES ENDOCARMTIS-KAMMER,                              UT2

                                                                                                                                                 - ~~___
              Evidence 01                                                                                                    From
             Major Emboli                                      Associated                         Drug Therapy             Probable              Clinical
                     t0                      Other              Disease                           Before Onset            Onset (mo)            Diagnosis
____~~~        _~
          Aortic bifurca-                     ...        Alcoholism,   post-                Penicillin,                       1 l/2       Endocarditis
            tion, brain                                    gastrectomy                        chloramphenicol

                                              ...        Rheumatic   heart                  Penicillin, rnethi-                   114     Bacterial            endo-
                                                           disease, Hufnagel                  cillin, streptomycin                          carditis
                                                           mitral prosthesis

          Brain, distal aorta          Calf tenderness   Congenital    aortic               Penicillin                        3           Bacterial endo-
                                                           stenosis,    post-                                                               carditis
                                                           operative    valvu-
          Brain                               ..         Fibrous body                       Oxacillin,     strepto-           2           Bacterial endo-
                                                           aneurysm,   post-                  mycin,      ampicillin                        carditis
                                                           operative repair
                          ~~ ~~___~~
                     .                         ..        Rheumatic    heart                 Penicillin,    strepto-           112                          .
                                                           disease, Starr-                    mycin
                                                           Edwards aortic
          Left leg                            ...        Congenital    heart                Penicillin,    strepto-           4
                                                           disease, Starr-                    mycin
                                                           Edwards aortic
                                                           pros1 hesis

          Brain,   left heel                             Aortic insufficiency,          Cephalothin,          corti-          314
                                                           Starr-Edwards                  coids

          None                                ...        Mitral prosthesls,                 Cephalothin                       1112                     .
                                                           tricuspid repair                   preoperatively,
                                                                                              “multiple”      anti-
                                                                                              biotics postoper.
                                                                                                          ~~        .~_____             .___
          Brain                               . .        Rheumatic    heart                 Penicillin, oxacillin,            3            Bacterial endo-
                                                           disease, Starr-                    methicillin                                    carditis
                                                           Edwards aortic
          Right femoral                            .     Aortic insufficiency,                                                7            Bacterial           endo-
            artery, right                                  fascia lata                                                                      carditis
            axillary artery                                repair

          Brain,   left leg                   ...        Myxomatous                         Erythromycin,                     1                            .
                                                           degeneration,                      streptcmycin,
                                                           Starr-Edwards                      cephalothin
                                                           aortic prosthesis

                     .                        ...        Mitral and                         Methicillin,                       ...        Mitral insufficiency
                                                           tricuspid insuf-                   penicillin, strepto-
                                                           ficiency, mitral                   mycin, corticoids


                                                                               April 1974       The American Journal ot Medicine             Volume 56                  511

TABLE I (Cont’d)             Aspergillus   sp. Endocarditis:       Clinical Aspects

                                                                                                                     Physical Findings

  Case                                                       Age W              Presenting         Heart                                 Spleno-     Hepato-
   No.              Source                 Fungus            and Sex           Manifestations     Murmur     Fever      Petechiae        megaly      megaly
      28     Chaudhuri                A. fumigatus               28, M       Fever, renal              . .   +                             ...         .
               WI                                                              failure
             Case 1

      29     Chaudhuri                Aspergillus    sp.         33, M       Fever                     ...    .. .          +                  .       ...
              Case 4

      30     Gage et al.              A. fumigatus               36, M       Fever                     ...    +             -              -           -
             Case 2

~~                                                                                                                                                   ~~__
      31     Gage et al.              A. fumigatus               43, M       Fever,                    . .   ...             +             -           -
               ]271                                                          convulsions
             Case 3
                                                                                                  _.                                           ~__
      32      Br Med J 1281           A. fumigatus               58, M                 ..              ..     +              ...           ...         ...

      33     Doshi [29]               A. fumigatus               40, M       Fever, hemipare-          ...    ...            +             ...         ...

                        ~~__~~~~                                                     ~~~~~___~~~
      34     Ostermiller              Aspergillus    sp.         57, F       Dyspnea                    -     +              -             -           -
               et al. [30]
             Case 4
_____~_          ~~                                                                                                                                            -.
    35       Lawrence                 A. ustus                   41, M                                  +      -             -             -           -
               et al. [31]
             Case 1

      36     Lawrence                 Aspergillus    sp.         48, M       Leukocytosis               -     +              +             -           -
               et al. [31]
             Case 2

~~                                                                                    __~~._______~~
      37     Chelloul    et al.       Aspergillus    sp.         50, M       Fever, aphasia       ...          +            ...           ..           +

                                                                                        ._~_~          ~~~
      38      Malcolm    et al.       A. flavus                  34, M       Foot and calf              +      +             -t            -           -
               ]331                                                            pain

                        _____                                        __.
      39      Schelbert,              A. glaucus                 31, F       Pain in right leg,         +     -4             -t-           +           -
                Muller 1341                                                   fever

                                                                 _~__                                                                                _~
      40      Kammer                  A. flavus                  13, F       Leg pain                   +      +             -t            -           +

512        April 1974     The American Journal of Medicine               Volume 56
                                                                                                       ASPERGILLUS           SPECIES       ENDOCARDITIS-KAMMER,                 UT2

       Evidence of                                                                                                                     From
   Major Emboll                                                Associated                           Drtlg Therapy                  Probable                   Clinical
             t0                    Other                         Disease                             Before Onset                 Onset (mo)                Diagnosis

              .            Pneumonia                  Rheumatic           heart              Penicillir                                l/2           Endocarditis
                                                         disease,         Starr-
                                                         Edwards          aortic

Brain,      eyes,          Jaundice                   Rheumatic            heart             Penicillin                                2             Bacterial          endo-
  femoral           and                                 disease,          Starr-                                                                       carditis
  brachial                                               Edwards          mitral
  arteries                                               prosthesis

                           Weakness                   Rheumatic            heart             Penicillin,                                   l/2       Bacterial          endo-
                                                         disease,         Starr-                methicillin,                                           carditis
                                                         Edwards          aortic                streptomycin,
                                                         prosthesis                             oxaciilin

Brain                      Hypotension                Aortic     stenosis,                   Penicillin,        cephalo-                   l/l0
                                                         Starr-Edwards                          thin

                                                      Aortic     repair

Brain                                                 Rheumatic            heart                                                       3             Bacterial          endo-
                                                         disease,         aortic                                                                        carditis
                                                         homograft           repair

                                                      Aortic     stenosis,                   Methicillin

Femoral           artery   Valve       click          Aortic     stenosis,                   Cephalothin                               5            Valve      dysfunc-
                              disappeared                Starr-Edwards                                                                                 tion

Femoral           artery                 .            Aortic     stenosis,                    Penicillin,                                    112
                                                         Starr-Edwards                           methiclllin,
                                                          prosthesis                             chloramphenicol,

Brain                      Jaundice,           calf   Mitral     stenosis,                   Antibiotics,         corti-               4
                             tenderness                 Starr-Edwards                           coids

Brain,      leg            Arthritis                  Bicuspid        aortic                  Penicillin                                             Embolic            phenom-
                                                         valve       postval-                                                                           ena

Left     femoral                       ...             Rheumatic            heart             None                                                   Bacterial          endo-
   artery                                                disease,         Starr-                                                                        carditis
                                                          Edwards          mitral

Brain,       leg                         .             Rheumatic            heart             Penicillin,       nafcillin,                            Endocarditis
                                                          disease,         Starr-                streptomycin
                                                          Edwards          mitral

                                                                              April   1974    The American            Journal    of Medicine         Volume        56           513
TABLE II         Aspergillus    sp. Endocarditis:     Laboratory     and Anatomic     Pathology
                                                                                                                            Fungus                                                                            Y
                                                              Hemogram                                                                                                                                        G)
                                                                                                       Location of         Identified                                                                         c
                                                          Total                                        Vegetation         Microscop-        Culture of                                                        t
                                                       Leukocyte                                     (Endocardial or        ically in     Vegetation or         Previous               Major                  cl3
Case                                                     Count                                         Endothelial        Vegetation      Embolus (for          Valvular              Emboli                  4
No.             Source               Urine            (per mm3)          Anemia    Blood Culture        Lesions)          or Embolus     Aspergillus sp.)       Damage                  to                    $
  1    Cawley [2]                      ...                    ...          ...          ...        Left ventricle            V+                V+                    -          Spleen,     kidneys,          2
                                                                                                                                                                                   brain                      B
                                                                                        -                                                                            -                                        Z
  2    Zimmerman                       ...                   ...           ...                     Aortic and tricus-        V+                 ..                              Kidneys
           (31                                                                                       pid valves                                                                                               =i
  3    Welsh, Buch-                    ...           1,100to 3,500         ..           -          Right ventricle           V+                V+                    ...                   ...
        ness (41                                                                                                                                                                                              F
                                                                                                                                   _~                                                                         E
  4    Kirschstein,             Normal               850                   +            ...        Tricuspid    valve        V+                V+                    -          Lungs                         a
         Sidransky                                                                                                                                                                                            C
           ]5]                                                                                                                                                                                                2

  5    Grcevic,                 Albumin,             35,200                +            -          “Endocardium”             V+         Aspergillus sp.              -          Brain, thyroid,
         Mathews                  pyuria                                                                                                  grown from pul-                           kidneys, lungs
           161                     hematuria                                                                                              monary lesions

  6    Hadorn        (71               ...                    . ..          +           -          Supravalvular              V+               V+           Subaortic           Legs, brain
                                                                                                     aorta                    E+               E+             stenosis,
  7    Luke et al. [8]          Proteinuria,                  .. .          +     One culture      Right and left            V+                V+                    -          Brain,     kidneys
                                  pyuria                                            “overgrown       ventricles
                                                                                    by mold”

  8    Vogel, Heinitz           Occasional           6,200                 -            -          Mitral   valve            V+                 ...                  -          Meninges,         eyes
           PI                     erythrocyte

  9    Paradis,                        ..            37,000                 +           -          Left ventricle            V+         Fungus cultured              -          Eyes, brain,
         Roberts         [lo]                                                                                                             from pleura                             kidneys, thy-
                                                                                                                                                                                  roid, jejunum
 10    Newman,                  Granular     casts   Normal                -      Postmortem       Starr-Edwards             V+                ...          Mitral pros-        All major vicera,
        Cordell [ll]                                                                    +             mitral prosthe-                                         thesis               legs
                                                                                                      s/s (Teflon@ sew-
                                                                                                     ing ring)

 11    Khoo et al.                     . .           17,600                -            ...        Right atrium,              V+               V+                    -          Brain, kidneys,
           VI                                                                                        right ventricle,                                                             spleen, thyroid
                                                                                                     left ventricle

 12    Darrell [13]             Many erythro-        20,000                 +           -          Prosthetic                V+                V+           Mitral   prosthe-   Brain,     eyes
                                 cytes,                                                              Starr-Edwards                                            sis
                                 albumin                                                               mitral valve
     13   Leffert,                        -                    .               -   Valve ring, supra-    V+        -               Aortic   prosthe-     Kidney
            Hackett      [14]                                                        valvular aorta                                  sis

     14   Satoyoshi                               4,100            +           -   Mitral and aortic     V+                                              Brain, kidneys,
            et al. 115)                                                              valves                                                                spleen, liver

     15   Doughten,                               11,000 to        +           -   Atrial septum         v+                        Atrial septal         Meninges
            Pearson       [16]                      143,750                                                                           defect repair,
                                                                                                                                      mitral repair

     16   Caplan      et al.     Normal           Normal           +           -   Aortic valve,         v+    V+                  Rheumatic             Brain, kidneys,
           1171                                                                      mitral valve,       E+    E+                    valvulitis            spleen, liver,
                                                                                     mycotic                                                               aortic bifurca-
                                                                                     aneurysm                                                              tion

     17   Kahn et al.                  ..         13,300           +           -   Mitral   prosthesis   V+    E+                  Mitral   prosthe-     Spleen
            ]I81                                                                                         E+                          sis
--                                                                                                                                                                           ._
     18   Mahvi et al.                        .   24,000               .       -   Mitral valve,         V+    E+                  Aortic valvulo-       Brain, spleen,
            f191                                                                     thrombus    in      E+                          plasty                aortic bifurca-
                                                                                     aortic root                                                           tion
                                                                                                                                                  ____       __
     19   Mershon                Many erythro-    13,000           -           -   Left atrium, pos-     V+    V+                  Fascia lata           “Every   organ”
           et al. [20]            cytes, pro-                                        terior leaflet                                  graft repair
                                  tein l+                                            mitral valve,                                   of mitral
                                                                                     over homograft                                  leaflet

     20   Hairston,      Lee           ...                ..       ...         -   Aortic prosthetic     V+    V+                  Aortic pros-          None
            [211                                                                     valve                                           thetic valve
          Case 2
     21   Hairston,      Lee                                                   -   Aortic   prosthesis   V+                        Aortic pros-          Renal artery,     leg    x
                                                                           .                                   V+
                                                                                                         E+                          thetic valve                                 p
          Case 4                                                                                                                                                                  E
     22   Hairston,      Lee           ...                . .      ...         -   Aortic   prosthesis   V+    V+                  Aortic pros-                   . .             4
            [211                                                                                                                     thetic valve                                 R
          Case 5                                                                                                                                                                  v)
     23   Hairston,      Lee           .                  ...          ..      +   Mitral   prosthesis   V+    ?                   Mitral prosthe-                ...
                                                                                                                                     sis, tricuspid
          Case 6                                                                                                                     repair                                       P
     24   Jones et al.           Protein 2+       12,000 to        +           -   Starr-Edwards         v+   . .                  Aortic   prosthe-              ...
            VI                     leukocytes,      34,000                            valve ring,                                    sis                                          F
                                   erythrocytes                                      cage, and ball                                                                               E
                                                                                                                       ._.   -..     ~~~~
                                                                                                                                                                  Continued       N
TABLE II (Cont’d)             Aspergillus    sp. Endocarditis:     Laboratory    and Anatomic     Pathology
                                                                                                         Location of         Identified
                                                         Total                                           Vegetation         Microscop-      Culture of                                                      E
                                                       Leukocyte                                       (Endocardial or        ically in    Vegetation or          Previous              Major
 Case                                                    Count                                           Endothelial        Vegetation     Embolus (for           Valvular              Emboli              Fl
 No.        Source                                                                                                                                                                                          0
                                     Urine            (per mml)       Anemia      Blood Culture           Lesions)          or Embolus    Aspergillus sp.)        Damage                 to
  25    Br Med J [23]                  ..:          Leukocyte                .         -            Aortic valve cusp          V+              V+            Aortic repair       Axillary    artery,        5!
                                                      count 20,000                                                             Et-                             (homograft)         right                    8
  26    Aslam et al.                   ...                ..             ...           -            Prosthetic valve          V+               ...           Aortic   prosthe-   Kidneys,         spleen    $
          1241                                                                                        ring, supraval-                                          sis                                          F7J
                                                                                                      vular aorta
  27    Hairston,    Lee               ...                .              ...          -             Annulus      of pros-       ..             v+            Mitral prothe-                 ...             E
          1251                                                                                        thetic     mitral                                         sis, tricuspid                              .::
        Case 6                                                                                        valve                                                     repair                                      c

  28    Chaudhuri      [26]            ...                ...            ...           -            Prosthetic valve,          V+              V+            Prosthetic          Kidneys
        Case 1                                                                                        aorta, left ven-                                         aortic valve

  29    Chaudhuri                      ...                ...            +             -            Prosthetic mitral         V+                ...          Prosthetic          Brain, kidneys,
          1261                                                                                        valve, atrial and                                        mitral valve        spleen
        Case 4                                                                                        ventricular

  30    Gage et al.                    ...          Leukocytosis         +             -            Prosthetic aortic          V+                            Prosthetic                     ..
          (271                                                                                        valve, mycotic                                           aortic valve
        Case 2                                                                                        aneurysm of

  31    Gage et al.                    ...          Leukocytosis         +             -            Prosthetic     aortic      V+                            Prosthetic                     ...
          1271                                                                                        valve                                                    aortic valve
        Case 3

  32    Br Med J 1281                  ...                ...            ...          +             Aortic valve              V+               V+            Aortic homo-                   ...
                                                                                      x2                                                                       graft repair

  33    Doshi [29]              Leukocytes,               ..             ...           -            Cusps of aortic            V+              V-t-          Aortic repair       Kidneys,         spleen
                                  erythrocytes                                                        homograft,   as-                                         homograft
                                   (many)                                                             tending aorta

  34    Ostermiller                    ...                ..             ...           -            Annulus of aortic          V+              V+            Aortic   prosthe-   “Systemic         circu-
         et al. [30]                                                                                  prosthesis                                               sis                 lation”
        Case 4
                         ASPERGILLUS   SPECIES ENDOCARDITIS--KAMMER,         UTZ

             TABLE III     Aspergillus sp. Endocarditis: Presenting
                           Manifestations and Physical Findings
                 Presenting mariifestation
                   Fever                                                24
                   Central nervous system abnormalities                  8
                   Symptoms relating to emboli (exclud-
                     ing central nervous system)                         8
                 Physical findings
                   Fever                                                35
                   Signs relating to emboli                             28
                   Cardiac murmurs                                      25
                   Petechiae                                            15
                   Hepatomegaly                                         11
                   Splenomegaiy                                          9

            Associated      Disease.    Organic    heart disease        was
            present in 30 (75 per cent) cases. Twenty-nine               pa-
            tients had prior cardiovascular      surgery. Cardiac dis-
            ease was defined in 20 cases; rheumatic            in 11, con-
            genital in 9. Prosthetic    valves were implanted         in 20
            patients (12 aortic, 8 mitral). Four patients received
            homografts     for aortic valve repair. Only five patients
            had no apparent underlying disease.
            Drug Therapy Before Onset.          Determining      the onset
            of illness was difficult in many instances. However, of
            the 40 patients,      30 received    antibacterial     therapy
            prior to clinically detected fungal infection. Of the 29
            postoperative     patients, 23 received prior antibacteri-
I   I
            al therapy. Twenty-one        were given antibiotics     at the
            time of the surgical procedure.        Benzyl penicillin was
            administered    to 19 patients, a semisynthetic       penicillin
            to 9, and a cephalosporin        to 5. Twelve patients also
+   +
            received streptomycin.       Of the remaining     10 patients,
            4 received    no prior antibacterials,      and in the last 6
            data were not provided. Corticoids were administered
            to seven patients,
            Hemogram       and Urinalysis.        Of the routine      blood
            studies, anemia was the most frequent abnormality,
            being present in 17 (77 per cent) of the 22 cases in
            which values       were given. Leukocytosis,          primarily
            polymorphonuclear,        was present in 15 (7 1 per cent)
            of 21.
                The urine was described in only 13 case reports.
            In nine some abnormality       was present. Pyuria, hema-
            turia and proteinuria       were encountered       with equal
            Blood Cultures.        Blood was cultured in 37 (93 per
             cent) of 40 patients, but Aspergillus sp. were grown
             in only 3. A. fumigatus was cultured from blood ob-
            tained antemortem         in two patients     (Cases 10 and
            32). In one (Case 10) fungal growth was first noted
             after 2 weeks’ incubation,        and after the patient had

        April 1974   The American   Journal of Medicine   Volume 56          517

TABLE IV        Aspergillus sp. Endocarditis:                                         TABLE V        Aspergillus sp. Endocarditis:
                Site of Vegetations                                                                  Embolic Phenomena
                                                               Patients                                                               Patients
                        Site                                       (no.)                            Organ Involved                     (no.)
                                                    _~ ~            ~____~_           --.                                                  -        _~~ ~
           Left side of the heart                                   38                              Brain                                  18
             Aortic prosthetic valve                                13                              Kidneys                                18
             Mitral prosthetic valve                                 8                              Spleen                                 13
             Ventricle                                               7                              Extremities                            11
             Aorta                                                   7                              Liver                                   6
             Mitral valve                                            5                              Thyroid                                 2
             Aortic valve                                            4                              Eyes                                    2
             Aorta only                                              3                              Meninges                                2
           Right side of the heart                                   5                              Lungs                                   2
             Ventricle                                               3                              Ovaries                                 1
             Tricuspid valve                                         2                              JeJunum                                 1
             Atrium                                                  1
                                                                                                                  ..__~                                ~~~
           Biventricular                                             3
           Other                                                                      Histologic      and   Cultural   Data.     Dichotomously
             Atrial septum                                           1
                                                                                      branching, septate hyphae were found in endocardial
             Mycotic aneurysm                                        4
                                                                                      or aortic lesions in 36 patients, and from surgically
NOTE: Involvement   of multiple sites in several cases results                        removed     emboli in 9. From 22 of these endocardial
in apparent numerical discrepancies.                                                  lesions and from 7 emboli, Aspergillus sp. were cul-
                                                                                      tured. In two patients with endocardial   lesions, Asper-
died. A. flavus was cultured from blood in one patient                                gillus sp. were cultured only from another hyphae-
(Case 23), but only after 20 days’ incubation.                                        containing   site, pulmonary   abscess in one (Case 5)
Location     of Endocardial        or Endothelial      Lesions.                       and pleura in the other (Case 9).
Precise localization      of endocardial   or endothelial      le-                    Anatomic     Pathology-Major      Emboli.     Evidence of
sions was possible in every instance either at surgery                                embolic disease was found in 33 (83 per cent) cases.
or autopsy.      Endocardial    lesions were identified his-                          Brain (55 per cent) and kidneys (55 per cent) were
tologically   in 37 hearts, and endothelial     lesions involv-                       most frequently involved (Table V).
ing the supravalvular aorta in the remaining 3 (Cases                                 Diagnosis, Therapy and Outcome.           The diagnosis,
3, 37 and 38). We have chosen to include the latter                                   therapeutic   regimen and outcome in nine cases diag-
because     their illness was clinically     indistinguishable                        nosed antemortem        appear in Table VI. In eight of
from endocardial       disease.     The pathology     was left-                       these, Aspergillus     sp. were found in surgically    re-
sided in 38 (95 per cent) cases, biventricular             in 3,                      moved emboli. In the remaining case, Aspergillus sp.
and confined to the right side of the heart in only 2.                                were cultured from an infected valve.
Thesedata are summarized in Table IV.                                                     Only in one patient (Case 35) was a prolonged

TABLE VI         Aspergillus     sp. Endocarditis:    Diagnosis, Therapy           and Outcome
                                        _~ -                        ~-~             ~~__
  Case No.          Specimen          Microscopic          Culture                                  Therapy                                     Outcome
__      -~                                                                                                                           ___-__
     6              Embolus                 +                  +              Griseofulvin 2 days                                               Death
    16              Embolus                 +                  +              Amphotericin   B 10 days-? dose                                   Death
    18              Embolus                 +                  +              Amphotericin   B 10 days-? dose                                   Death
    21              Embolus                 +                  +              Amphotericin   B,* debridement  of vegetations                    Death
    25              Embolus                 +                  +              Amphotericin   B, unknown dose or duration;                       Death
                                                                                valve replacement
      27            Valve                   ?                  +              Valve replacement   only                                          Well
                                                                                                                                                (1 year)
      35            Embolus                 +                  +              Valve replacement   and removal of vegetations,                   Well
                                                                                amphotericin   B 30-50 mg/day for 60 days, and
                                                                                flucytosine 8 g/day for 4 mo
      39            Embolus                 +                  +              Amphotericin   B 3 days                                           Death
      40            Embolus                 +                  +              Valve replacement,     amphotericin  B 10 days                    Death
                                                                                total dose 115 mg

* NO dosage or duration        of therapy   was stated,        but the patient     was discharged     from the hospital   which suggests    a completed
course of therapy.

518        April 1974     The American Journal of Medicine                Volume 56
                                                                             ASPERGILLUS    SPECIES ENDOCARDITIS-KAMMER.   UTZ

course   of antifungal therapy administered. The in-              and multiple     venipunctures.       Although   Candida sp.
fected   valve was replaced also. Another patient                 fungemia     and endocarditis       have been reported     in
(Case 21) may have completed a course of ampho-                   heroin addicts [42], and in patients receiving total
tericin B therapy, but his sudden death 3 months af-              parenteral nutrition (hyperalimentation) [ 43,441, en-
terwards may have represented continuing or recur-                docarditis due to Aspergillus   sp. has not been en-
rent disease.                                                     countered in these circumstances.     However, in one
    Seven patients died during therapy. The two who               of our patients (Case 7) infection may have resulted
survived had had their valve prostheses     replaced.             from a nonsterile exchange transfusion      performed
One of these also received long-term antifungal che-              shortly after birth.
motherapy with amphotericin B and flucytosine.                        The presence of an avascular foreign body, such
                                                                  as a prosthetic valve or suture, probably is a factor in
                                                                  perpetuating infection once inoculation has occurred.
Predisposing Factors. It seems clear to us from the               However, this is not a requisite as illustrated in this
review of the literature that Aspergillus sp. endocar-            review by 10 cases in which no surgery had been
ditis is an opportunistic infection. All but five patients        performed. Valvular infections due to relatively aviru-
had another disease with potential for adversely al-              lent organisms such as Staphylococcus epidermidis
tering host defense. As early as 1950, Zimmerman                  are clearly more common in patients with intracardic
[ 31 anticipated the current opportunistic epidemic,              prostheses     [45]. This phenomenon is also seen in
and in 1955 [36] enumerated the major factors. The                neurosurgical patients with intracranial shunts.
detailed discussion of host factor alterations, relating              Thirty (75 per cent) patients received antibacterial
specifically to the opportunistic mycoses, by Hart et             therapy before Aspergillus        sp. endocarditis devel-
al. [37] is recommended in lieu of a multifactorial re-           oped. Those with known rheumatic heart disease had
view here. We will confine our discussion to those                received prophylactic penicillin for years. In none of
host factors having particular relevance to Aspergil-             those known to have rheumatic disease did Aspergil-
lus sp. endocarditis.                                             Ius sp. endocarditis occur before valvular surgery.
    The average age of the 40 patients was 31 years.              Caplan’s patient (Case 16) had rheumatic valvulitis at
This probably reflects selection of young patients for            autopsy but gave no history of rheumatic fever and
valvular cardiac surgery.                                         received no prophylactic penicillin.
   There is a striking male preponderance in this dis-            Diagnostic Problems. The correct antemortem di-
ease. Several investigators have noted similar male               agnosis is rarely made. Failure to recognize the clini-
to female ratios in other forms of aspergillosis   [37-           cal milieu in which Aspergillus sp. endocarditis oc-
40]. In vitro growth of A. fumigatus was inhibited by             curs is one reason. Fungal endocarditis was not sus-
physiologic concentrations of estradiol in studies by             pected in any patient. Of 29 case reports listing a
Mohr et al. [41]. Thus the female milieu, with all its            clinical diagnosis, it was bacterial endocarditis in 19.
estrogens,    may be physiologically hostile to these             Emboli to the central nervous system were misinter-
fungi.                                                            preted as primary neurologic disease in five patients.
    Probably the most important alteration of host de-            Embolization was incorrectly attributed to inadequate
fenses in the postoperative cases is the surgical pro-            anticoagulation in several cases.
cedure itself. Airborne inoculation of the ubiquitous                 Blood obtained antemortem grew Aspergillus sp.
spores during the prolonged operative exposure re-                on only three occasions, yet infected emboli were
mains the most likely source of infection. In the re-             found in almost every organ. Bulky, friable vegeta-
port of Gage et al. [27], Aspergillus sp. were cul-               tions were located in areas of turbulent blood flow.
tured repeatedly from operating room surfaces and                 Fungemia must occur. Perhaps we are sampling the
occasionally from the air. These fungi were also cul-             wrong blood. Left-sided cardiac lesions occurred in
tured from areas near the intake port of the operat-              38 (95 per cent) patients. Is the infective hyphal par-
ing suite’s air conditioning system.     Extracorporeal           ticle too large to traverse the systemic capillary bed
perfusion devices, prosthetic valves or suture materi-            and never, or rarely, enters the venous system? Ar-
al are all potential infective vehicles. Suture lines             terial blood cultures were obtained in only two pa-
were frequently the site of attachment for vegeta-                tients, and these were negative. Intermittent funge-
tions. Careful surveillance of the surgical environ-              mia may be the reason why blood specimens rarely
ment for pathogenic fungi, and their removal, are                 yield Aspergillus sp. in culture.
reasonable preventive measures.                                       Aspergillus sp. grow in most blood culture media.
    Potential nonsurgical sources of infection include             In 1971 these fungi were isolated 18 times in blood
the multiple violations of the vascular system before,             culture bottles at our hospital. Growth may occur too
 during and after surgery, i.e., intravenous catheters,            late to be helpful or to be detected by the laboratory.
 central venous pressure monitors, cardiac catheters               Our blood cultures are discarded after 14 days. In

                                                             April 1974   The American   Journal of Medicine   Volume 56   519

one     of our patients       (Case lo), growth was noted                       One patient (Case 27) was treated with valve re-
after 2 weeks, but the patient was already dead. In                         placement     alone. She survived. In this case, the diag-
another (Case 23), growth occurred after 20 days of                          nosis was made by culturing Aspergillus sp. from the
incubation.     Many laboratories,          including ours, would           infected valve. Thus, this represents            the only case
have discarded these latter cultures 6 days earlier.                        recognized     prior to dissemination.      In all other cases
    It is not entirely clear why growth is delayed. On                      diagnosed,      treatment     followed     embolectomy,        de
glucose peptone          agar, growth of Aspergillus            sp. is      facto evidence        of dissemination.     It is unlikely that
usually apparent        in 48 to 72 hours. However,             molds       such localized       disease   will be encountered         often.
growing in liquid media may not cloud the bottles, as                       Even if arterial blood or other body fluid yields the
bacterial growth frequently does. Inoculating blood or                       fungus in culture, widespread        dissemination    will have
subculturing      onto solid media may permit earlier de-                   already occurred,        and antifungal    chemotherapy        will
tection.   Examining       smears from negative-appearing                   be essential.
 blood cultures may increase the percentage                   of posi-          Four patients      (Cases 21, 25, 35 and 40) were
tive findings.                                                              treated with surgery and antifungal therapy. One sur-
    Cultural results may be misinterpreted.               Aspergillus       vived (Case 35). In three, the infected valves were
sp. are often considered as contaminants                 in the labo-       replaced (Cases 25, 35 and 40). In one (Case 21) the
ratory. In one of our patients (Case 7) the blood cul-                      vegetations    were debrided, but the valve was not re-
ture report read “overgrown              by mold,” and the cul-             placed. Valve replacement          plus chemotherapy        with
ture was thus discarded and disregarded.                                    both amphotericin        B and flucytosine       was the suc-
    Serologic     technics may prove to be useful. They                     cessful regimen in Case 35.
are currently being studied in this disease [46]. Base                          No patient has yet survived without valve replace-
line serum would ideally be obtained before cardiac                         ment. Therefore,         chemotherapy       alone cannot       be
surgery. A titer of precipitins to Aspergillus sp. would                    recommended.        Valve replacement        alone seems un-
be a helpful diagnostic         tool, if it could be correlated             wise also, since most patients had disseminated               dis-
with the presence of disease.                                               ease at the time of diagnosis. Should combined che-
    Perhaps detection of circulating Aspergillus sp. en-                    motherapy     with both amphotericin        B and flucytosine
dotoxin     would facilitate       earlier     diagnosis.     Several       be given? We believe so for the following              reasons.
species,     including A. fumigatus            and A. flavus, are           No available     chemotherapeutic        agent is ideal. Many
known to produce endotoxins.               Latex particle aggluti-          Aspergillus   sp. are resistant to amphotericin           B, and
nation using preformed           antibody is one possible ap-               75 per cent studied by Shadomy            [47] were resistant
proach.     Presence      of endotoxin        might precede anti-           to 12.5 Fug/ml of flucytosine.        However,        amphoteri-
body production or dissemination.                                           tin B and flucytosine       have different       sites of action
Therapeutic        Considerations.           Optimal   therapy      for     on the fungal      cell. Polyene       antibiotics,      such as
Aspergillus sp. endocarditis          cannot be defined at this             amphotericin    B, bind to sterols in the fungal cell
time from this sample. Only nine patients were treat-                       membrane      and induce alterations           in permeability
ed. Four received antifungal chemotherapy                  only. One        [48]. Flucytosine,       a fluoro    pyrimidine,       competes
patient was treated with valve replacement                 only. The        with essential    pyrimidines      and blocks the biosyn-
remaining four patients were treated with chemother-                        thesis of nucleic     acids [49,50].       Medoff et al. [51]
apy and surgery.                                                            recently    demonstrated        in vitro    synergism        using
    All four patients treated with chemotherapy          alone              combinations     of amphotericin          B and flucytosine
died. One (Case 6) received            a 2-day course of                    against Candida sp. and C. neoformans.                 These in-
griseofulvin,   a drug without expected        efficacy.   The              vestigators   postulated     that amphotericin          B altered
other three (Cases 16, 18 and 39) were treated with                         cell membrane      permeability     allowing flucytosine           to
amphotericin     B. None received an adequate           course              enter the fungal cells in greater quantities.              Initiat-
of amphotericin     B, if death is the ultimate standard of                 ing chemotherapy        using both drugs seems reason-
treatment failure.                                                          able pending in vitro sensitivity       data.


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                                                                      April 1974   The American Journal of Medicine     Volume 56        521

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