Yao Zhang,Hua Zhang,Jun Xu,Chan Wu,and Xiao-jun Ma＊

1Department of Infectious Diseases,4Department of Ophthalmology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100730,China

2Department of Scientific Researches,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100730,China

3Department of Medicine,Provincial Infectious Disease Hospital of Uygur Autonomous Region,Urumqi 830013,China

PNEUMOCYSTIS pneumonia (PCP) is among the most common opportunistic infections in patients with acquired immune deficiency syndrome(AIDS).Although trimethoprim-sulfamethoxazole (TMP-SMX) is the first line therapy for that condition given its efficacy,approximately one third of patients experienced dose-limiting toxicity.1For cases of severe to moderate PCP,if TMP-SMX treatment fails or is contraindicated,primaquine combined with clindamycin or intravenous pentamidine is recommended as second line therapy.2However,both primaquine and pentamidine are associated with severe adverse reactions and often unavailable at hospitals in China.3As a result,other treatment options have been explored.

Caspofungin,an echinocandin,has broad antifungal activity against a wide range of fungi including Candida and Aspergillus species.Cases of PCP patients treated with caspofungin have been reported,although conflicting conclusions have been arrived at.4-7In addition,the use of caspofungin and clindamycin as the first line therapy for severe PCP in AIDS patients has not been reported yet.This article described an AIDS case with severe PCP,treated with the combination of caspofungin and clindamycin.

CASE DESCRIPTION

A 44-year-old male patient was hospitalized for non-productive cough and progressive dyspnea during the previous 2 months,accompanied by low grade fever.He had been empirically treated with ceftriaxone and azithromycin,yet without improvement.On admission,physical examination showed that the temperature was 38.4°C,the respiratory rate was 34 breaths per minute,and the oxygen saturation was ＜85% on room air.His partial pressure of oxygen was 53 mm Hg,with an alveolar-arterial gradient of 65 mm Hg,and serum lactate dehydrogenase (LDH) of 534 U/L.A high resolution computed tomography (CT) scan showed bilateral diffused groundglass appearance and interstitial infiltration (Fig.1).PCP was clinically diagnosed,and later confirmed by Gomori methenamine silver staining of sputum revealingPneumocystis jirovecicysts.

The HIV anti-body test in that patient turned out positive,which was later confirmed with a Western blot assay.CD4+count was 24 cells/μL at presentation.Significant medical history includes TMP-SMX application for suspected upper respiratory tract infection ten years ago.The patient experienced severe adverse reaction at that time,developing skin rash,oral ulcers,and severe pancytopenia.

Given that primaquine,pentamidine,and atovaquan were not available,and the history of severe adverse reaction associated with TMP-SMX was self-reported,caspofungin was administered at a dose of 70 mg intravenously on the first day,followed by 50 mg daily,plus clindamycin 600 mg intravenously every 12 hours,and ceftazidime 1 g intravenously every 8 hours.Methylprednisolone 40 mg intravenously every 12 hours was initiated and tapered according to the standard schedule.Ganciclovir [10 mg/(kg·day)]was also started on the second day given the detection of cytomegalovirus pp65 antigenemia and was continued for 14 days.The patient remained febrile despite this combination therapy.Because of his progressive dyspnea and worsening respiratory function with oxygen saturation decreasing to lower than 90%under maximal oxygen support through oxygen-saving mask,non-invasive ventilation was used (FiO280%).On day 13,a repeat chest radiograph revealed worsening pulmonary infiltration.On day 14,caspofungin and clindamycin were stopped,while TMP-SMX desensitization was conducted followed by full-dose treatment [TMP 15 mg/(kg·day),SMX 75 mg/(kg·day) in 4 divided doses].The fever was immediately reduced on day 15.During the following days,his respiratory function improved rapidly and he was weaned from non-invasive ventilation on day 18.Serum LDH level returned to normal on day 26.Follow-up chest radiographs showed marked improvement.His hospital course was complicated by two episodes of pneumothorax and pancytopenia associated with TMP-SMX.As a result,TMP-SMX was temporarily suspended and folic acid was applied.As the blood counts improved,TMP-SMX was resumed.

Figure 1.Initial computed tomography scan shows bilateral extensive ground-glass appearance and diffused interstitial infiltration.

The patient’s clinical condition continued to improve.Four weeks later,he was discharged without oxygen support,and received secondary TMP-SMX prophylaxis and combined antiretroviral therapy.

DISCUSSION

This is a case report of severe PCP in an AIDS patient treated with caspofungin and clindamycin as the first line therapy.This combination treatment was continued for 13 days but the clinical condition deteriorated.After the initiation of TMP-SMX combination,his condition improved rapidly.

The role of caspofungin in treating PCP is still controversial and case reports are difficult to evaluate,largely because caspofungin was used in combination with other antibiotics active against PCP.Utili et al5summarized 4 cases of solid organ transplantation in whom caspofungin was used to treat severe PCP and produced satisfactory outcomes.It is important to note that TMP-SMX was also applied in all those patients,including two who were initially unresponsive to TMP-SMX but improved after caspofungin was added.Mu et al3reported a 76-year-old man with severe PCP and baseline chronic myelomonocytic leukemia,who was treated with caspofungin as first line therapy and full-dose methylprednisone.The patient’s condition improved after 3 days of caspofungin treatment when TMP-SMX was added and continued until discharge.In another case of a 60-year-old man with Wegener’s granulomatosis and atypical pneumonia,caspofungin was used in monotherapy for 3 weeks,bringing complete recovery.Pulmonary CT scan showed only partial atelectasis of the left upper lobe and the diagnosis of PCP was made microbiologically based on a bronchial lavage sample.6In contrast,Kamboj et al4reported 2 cases in which PCP progressed despite the use of echinocandins in addition to standard therapies.

Being an inhibitor of beta-1,3-glucan synthesis,caspofungin was effective in monotherapy in animal PCP models,leading to 90% decrease in cyst forms of pneumocystis,but with a lesser and slower reduction of trophic pneumocystis.Also in that animal model,caspofungin prophylaxis prevented both forms of pneumocystis,implying that the cyst forms may be needed for trophic proliferation.Since TMP-SMX only affects the trophic forms of pneumocystis,caspofungin as well as other echinocandins may work synergistically for their efficacy against cyst forms.8In another animal experiment by Ito et al,9caspofungin demonstrated excellent prophylactic effect,resulting in elimination of cysts but not the trophic form of pneumocystis.A study on experimental mice showed that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms.10Because the trophic form of pneumocystis is more important in PCP progression than the cystic form,the relatively weak efficacy of caspofungin against trophic form raised the concern for it usage as the sole therapy without other potent agents in treating PCP.

In conclusion,caution is necessary when caspofungin and clindamycin are administered as the initial therapy in AIDS patients with severe PCP.The more established therapy options are better choices.Given the results in animal studies and case reports,caspofungin may be considered in patients in whom standard therapy is contraindicated.However,the effect may be limited and established therapy might be indicated despite its risks in some patients.

1.Kaplan JE,Benson C,Holmes KH,et al.Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents:recommendations from CDC,the National Institutes of Health,and the HIV Medicine Association of the Infectious Diseases Society of America.MMWR Recomm Rep 2009;58:1-207.

2.Benfield T,Atzori C,Miller RF,et al.Second-line salvage treatment of AIDS-associated Pneumocystis jirovecii pneumonia:a case series and systematic review.J Acquir Immune Defic Syndr 2008;48:63-7.

3.Mu XD,Que CL,He B,et al.Caspofungin in salvage treatment of severe pneumocystis pneumonia:case report and literature review.Chin Med J (Engl) 2009;122:996-9.

4.Kamboj M,Weinstock D,Sepkowitz KA.Progression of Pneumocystis jiroveci pneumonia in patients receiving echinocandin therapy.Clin Infect Dis 2006;43:e92-4.

5.Utili R,Durante-Mangoni E,Basilico C,et al.Efficacy of caspofungin addition to trimethoprim-sulfamethoxazole treatment for severe pneumocystis pneumonia in solid organ transplant recipients.Transplantation 2007;84:685-8.

6.Hof H,Schnülle P.Pneumocystis jiroveci pneumonia in a patient with Wegener's granulomatosis treated efficiently with caspofungin.Mycoses 2008;51 Suppl 1:65-7.

7.Annaloro C,Della Volpe A,Usardi P,et al.Caspofungin treatment of Pneumocystis pneumonia during conditioning for bone marrow transplantation.Eur J Clin Microbiol Infect Dis 2006;25:52-4.

8.Powles MA,Liberator P,Anderson J,et al.Efficacy of MK-991 (L-743,872),a semisynthetic pneumocandin,in murine models of Pneumocystis carinii.Antimicrob Agents Chemother 1998;42:1985-9.

9.Ito M,Nozu R,Kuramochi T,et al.Prophylactic effect of FK463,a novel antifungal lipopeptide,against Pneumocystis carinii infection in mice.Antimicrob Agents Chemother 2000;44:2259-62.

10.Cushion MT,Linke MJ,Ashbaugh A,et al.Echinocandin treatment of pneumocystis pneumonia in rodent models depletes cysts leaving trophic burdens that cannot transmit the infection.PLoS One 2010;5:e8524.