Treatment of Neonatal Candidiasis with Liposomal Amphotericin B

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Treatment of Neonatal Candidiasis                            persisting fungal infections and in fact,
with Liposomal Amphotericin B                                may have been treatment failures. This is
                                                             the rationale behind an intent-to-treat
                                                             analysis, where all patients who receive
    I read with interest the recent paper(1)                 atleast one dose of study drug treatment
on the treatment of neonatal candidiasis                     must be included in the efficacy
with a novel liposomal formulation of                        analysis. Viewed in this way according
amphotericin B. Though a cheap and                           to the results presented in Table I of the
effective antifungal has been the dream of                   article, 13 of 23 patients treated had
every clinician, I would like to draw                        favourable outcomes, a response rate of
attention to some salient features of the                    56.5%.
study.                                                    4. It should also be noted that all patients in
1. It is interesting to note that this                       this report had infections with Candida
   formulation is delivered in a normal                      albicans. The other reports referenced
   saline infusion. All Amphotericin B                       included cases of non-albicans species of
   formulations, including the conventional                  Candida as well, which are known to be
   deoxycholate and all currently available                  more difficult to treat and many require
   lipid formulations carry explicit pre-                    longer courses of treatment. Thus, the
   cautions regarding incompatibility of                     response rate of treatment as well as the
   Amphotericin B and saline solutions.                      total doses of Amphotericin B needed to
   How does this current preparation get                     treat in this paper are not appropriately
   around this incompatibility?                              comparable to those reported in the
2. It should also be noted that LD 50 for                    references cited.
   Ambisome® is 175 mg/kg, a more                         5. Too many patients in this study have
   accurate value than the <17.5 mg/kg                       required significant amount of blood
   cited in the article. This is a ten-fold                  transfusion. Authors do not mention
   greater value than that of the current                    whether that was due to ongoing sepsis
   liposomal preparation being described.                    or an adverse effect of the drug
3. To claim a 100% response rate in the                      itself.
   assessable cases fails to consider the fact            6. Step up doses (or inability to use an
   that the patients who died or were                        optimal dose) right from the begining
   otherwise non-evaluable could have had                    may be deterimental to the outcome of

INDIAN PEDIATRICS                                   522                        VOLUME   41__MAY 17, 2004

   such life threatening infections, as               REFERENCE
   systemic fungosis. In such patients, we             1.     Kotwani RN, Bodhe PV, Kirodian BG,
   have often used successfully, de-                          Mehta KP, Ali US, Kshirsagar NA. Treatment
   escalting standard doses of liposomal                      of neonatal candidiasis with Liposomal
   Amphotericin B (Ambisome®). This                           Amphotericin B CL-AMP-LRC-1). Phase II
                                                              Study. Indian Pediatr 2003; 40: 545-
   could be the reason behind compro-
   mised efficacy with the novel prepara-
   tion in this study.
7. Also three of the authors of the current           Reply
   study are the manufacturers of this new
                                                            Our response to the letter is as follows:
   molecule. So surely there would be a
   conflict of interest in reporting the              1. In the liposomal amphotericin formula-
   results of this pilot study.                          tion, amphotericin (which is lipid
8. In our own experience of significant and              soluble) is intercalated in the lipid which
   severe fungal infections in immuno-                   form the liposome. Aqueous phase is
   competent and immunocompromized                       normal saline. There is no incompati-
   patients, the use of coventional Ampho-               bility(1).
   tericin B has been fraught with serious            2. LD50 of Ambisome is 175mg/kg and
   nephrotoxicity or adverse effects during              LD50 of Indian liposomal amphotericin
   administration of the drug, invariably                is 14-17 mg/kg(2). However, LD50
   forcing us to go back to standard lipo-               values are from animal studies. Dose,
   somal Amphotericin B (Ambisome®).                     efficacy and safety in clinical studies
9. As a small noncomparative phase 2 trial,              should be considered for comparing
   these results do not provide any proof                Ambsiome with Indian liposomal
   that this liposomal preparation of                    amphotericin.
   Amphotericin B is comparable in safety             3. The assessment criteria used and
   or efficacy to the currently available                followed were as per the previous
   Amphotericin B products. Larger,                      studies done(3-7), which were modified
   controlled prospective trials in both                 and were made more stringent. Accord-
   children and adults, against a variety of             ingly, those babies who died before a
   clinically relevant fungal pathogens,                 week of therapy were considered non
   comparing this agent to both Ampho-                   assessable. The incomplete treatment
   tericin B deoxycholate and the standard               will not give complete clearing of fungal
   liposomal Amphotericin B product                      infection.
   (Ambisome®) are needed in order to                 4. Our study clearly shows the efficacy of
   fully assess the relative merits of this              Indian liposomal amphotericin B against
   new fungal formulation.                               systemic Candida albicans infection in
                        Dharmesh Kapoor,                 neonates, which is the most common
                   Consultant Hepatologist,              fungal infection seen in NICUs. The
       6-1-1070/1 to 4, Near Hotel Dwarka,               liposomal preparation used is easy to
                             Lakdi-ka-Pool,              use, can be given over one hour with no
                       Hyderabad 500 004,                thrombophlebitis, has no nephrotoxicity,
                                       India.            safe even in preterm, is less expensive

INDIAN PEDIATRICS                               523                         VOLUME   41__MAY 17, 2004