Adequate Antifungal Therapy Research Articles

Impact on hospital mortality of catheter removal and adequate antifungal therapy in Candida spp. bloodstream infections

We set out to identify the prognostic factors in adult patients with Candida spp. bloodstream infection, assessing the impact on in-hospital mortality of catheter removal and adequacy of antifungal therapy. Patients with positive blood culture for Candida spp. and a central venous catheter in place at the time of candidaemia were included. Data collected included demographics, underlying diseases, severity of illness, clinical presentation, catheter withdrawal and adequacy of empirical therapy. We included 188 patients (mortality 36.7%). The mortality rate was 34.9% (23/66) in patients with early adequate antifungal treatment and 18.9% (7/37) in patients with early adequate antifungal therapy and catheter withdrawal in the first 48 h. The APACHE (Acute Physiology and Chronic Health Evaluation) II score on the day of candidaemia [adjusted hazard ratio (aHR) 1.12; 95% CI 1.06-1.17; P < 0.001] was associated with death whereas early adequate therapy (aHR 0.4; 95% CI 0.23-0.83; P = 0.012) and catheter withdrawal (aHR 0.34; 95% CI 0.16-0.70; P = 0.03) were protective factors. In primary candidaemia, mortality was 28% (14/50) in patients with adequate therapy and decreased to 17.7% (6/34) in patients with both interventions in the first 48 h. Catheter removal was a protective factor and adequacy of antifungal therapy in the first 48 h showed a strong tendency to protection against death (aHR 0.46; 95% CI 0.19-1.08; P = 0.07). In secondary non-catheter-related candidaemia, only early adequate therapy was a protective factor for mortality. Delay in catheter withdrawal and in administration of adequate antifungal therapy was associated with increased mortality in candidaemic patients. Catheter management did not influence the prognosis of secondary non-catheter-related candidaemia.

Amphotericin B cement beads: A good adjunctive treatment for musculoskeletal mucormycosis

Mucormycosis is one among the aggressive, invasive fungal infections usually seen in immunocompromised patients. Mucormycosis osteomyelitis is very rare. We present a patient with acute myeloid leukemia who complained of pain over the right proximal thigh. Plain radiograph revealed ill defined osteolytic lesion of proximal femur. MRI showed altered signal in proximal femur with focal collection and cortical breach. Biopsy and tissue culture diagnosed mucormycosis both histologically and microbiologically. He was treated with aggressive debridement, skeletal stabilization, and amphotericin antifungal cement beads. He recovered with no residual pain, minimal limb shortening, and no clinical or radiological evidence of recurrence at 3 years followup. The high index of suspicion, early diagnosis, aggressive surgical debridement, and adequate antifungal therapy play a significant role in the treatment of musculoskeletal mucormycosis.

Risk Factors and Outcomes of Candidemia Caused by Biofilm-Forming Isolates in a Tertiary Care Hospital

BackgroundVery few data exist on risk factors for developing biofilm-forming Candida bloodstream infection (CBSI) or on variables associated with the outcome of patients treated for this infection.Methods and FindingsWe identified 207 patients with CBSI, from whom 84 biofilm-forming and 123 non biofilm-forming Candida isolates were recovered. A case-case-control study to identify risk factors and a cohort study to analyze outcomes were conducted. In addition, two sub-groups of case patients were analyzed after matching for age, sex, APACHE III score, and receipt of adequate antifungal therapy. Independent predictors of biofilm-forming CBSI were presence of central venous catheter (odds ratio [OR], 6.44; 95% confidence interval [95% CI], 3.21–12.92) or urinary catheter (OR, 2.40; 95% CI, 1.18–4.91), use of total parenteral nutrition (OR, 5.21; 95% CI, 2.59–10.48), and diabetes mellitus (OR, 4.47; 95% CI, 2.03–9.83). Hospital mortality, post-CBSI hospital length of stay (LOS) (calculated only among survivors), and costs of antifungal therapy were significantly greater among patients infected by biofilm-forming isolates than those infected by non-biofilm-forming isolates. Among biofilm-forming CBSI patients receiving adequate antifungal therapy, those treated with highly active anti-biofilm (HAAB) agents (e.g., caspofungin) had significantly shorter post-CBSI hospital LOS than those treated with non-HAAB antifungal agents (e.g., fluconazole); this difference was confirmed when this analysis was conducted only among survivors. After matching, all the outcomes were still favorable for patients with non-biofilm-forming CBSI. Furthermore, the biofilm-forming CBSI was significantly associated with a matched excess risk for hospital death of 1.77 compared to non-biofilm-forming CBSI.ConclusionsOur data show that biofilm growth by Candida has an adverse impact on clinical and economic outcomes of CBSI. Of note, better outcomes were seen for those CBSI patients who received HAAB antifungal therapy.

Septic Shock Attributed to Candida Infection: Importance of Empiric Therapy and Source Control

Delayed treatment of candidemia has previously been shown to be an important determinant of patient outcome. However, septic shock attributed to Candida infection and its determinants of outcome have not been previously evaluated in a large patient population. A retrospective cohort study of hospitalized patients with septic shock and blood cultures positive for Candida species was conducted at Barnes-Jewish Hospital, a 1250-bed urban teaching hospital (January 2002-December 2010). Two hundred twenty-four consecutive patients with septic shock and a positive blood culture for Candida species were identified. Death during hospitalization occurred among 155 (63.5%) patients. The hospital mortality rate for patients having adequate source control and antifungal therapy administered within 24 hours of the onset of shock was 52.8% (n = 142), compared to a mortality rate of 97.6% (n = 82) in patients who did not have these goals attained (P < .001). Multivariate logistic regression analysis demonstrated that delayed antifungal treatment (adjusted odds ratio [AOR], 33.75; 95% confidence interval [CI], 9.65-118.04; P = .005) and failure to achieve timely source control (AOR, 77.40; 95% CI, 21.52-278.38; P = .001) were independently associated with a greater risk of hospital mortality. The risk of death is exceptionally high among patients with septic shock attributed to Candida infection. Efforts aimed at timely source control and antifungal treatment are likely to be associated with improved clinical outcomes.

A rare skin presentation of Penicillium marneffei infection in an AIDS patient

Penicillium marneffei is an opportunistic fungal pathogen in HIV disease. We report the case of a patient with AIDS who presented with general weakness and generalized skin rashes. No specific allergic history or recent medication were reported. The skin lesions disappeared after adequate antifungal therapy. A blood culture obtained from the patient confirmed the presence of P. marneffei, infection which is characterized by cutaneous umbilicated lesions in AIDS patients. We report this case on account of the unusual skin presentation.

Current aspects of invasive candidiasis and aspergillosis in adult intensive care patients

Sepsis is a leading cause of death in the intensive care unit (ICU), with Candida spp. in the forefront among the important pathogens. As recent studies have shown, survival outcome is strongly influenced by adequate antifungal therapy at an early stage that is often delayed by the time lag associated with microbiological diagnosis. Risk factor-based prediction models have a high negative predictive value, but positive prediction of candidaemia in the individual patient remains elusive. New antigen- or DNA-based methods for early diagnosis still await clinical validation. Their routine use is hampered by methodological issues. Species distribution of invasive Candida isolates in the ICU appears to be influenced primarily by age, previous hospitalisation and colonising species. In the context of the importance of adequate first-line treatment, recent guidelines favour the use of echinocandins in critically ill patients with symptoms evoking high suspicion of invasive candidiasis. This is supported by robust clinical trial data, a few interactions and low toxicity. Fluconazole is characterised by reduced activity against some important Candida species, elevated rates of persistent infection seen in comparative trials. Amphotericin B deoxycholate should be considered obsolete in ICU patients because of its high toxicity. Invasive aspergillosis (IA) is a rare devastating infection in the general ICU population, but some centres have reported elevated incidences and underdiagnosis as determined in autopsy-controlled studies. Treatment with mould-active agents such as voriconazole must be initiated early in patients with suspected IA.

Antifungal Drug Resistance: Clinical Relevance and Impact of Antifungal Drug Use

Antifungal drug resistance significantly impacts treatment outcomes in patients with invasive fungal infections (IFIs). Although primary (intrinsic) resistance may occur independent of previous therapy, prior concomitant antifungal exposure increases the risk for secondary (acquired) resistance and subsequent colonization or infection with less-susceptible pathogens. Among various pathogen-antifungal combinations, this effect has been best studied clinically with azole exposure and the risk of Candida spp. with reduced susceptibility. The rapid development of secondary resistance to flucytosine in Candida spp. has limited its use as monotherapy. Secondary resistance to amphotericin B is infrequent. In contrast, secondary resistance in Aspergillus spp. is less of a concern. Recent reports of secondary resistance in patients receiving fluconazole for cryptococcal infections may justify susceptibility testing in the setting of prior therapy or treatment failure. Despite numerous patient-focused, drug-focused, and disease-focused strategies to improve treatment outcomes, clinical resistance (manifesting as treatment failures despite adequate antifungal therapy) continues to be problematic in patients with serious IFIs.

Surgery for Pulmonary Coccidioidomycosis: A 10-Year Experience

Coccidioidomycosis results from infection with Coccidioides species endemic to the southwestern United States. The mobile US population has resulted in incremental cases being found throughout the world. The fungal infection can result in pulmonary sequelae, including nodules, cavities, and complications requiring treatment by the thoracic surgeon. A retrospective chart review was conducted of 1,496 patients with coccidioidomycosis treated at our institution (January 1998 to December 2008) to identify those requiring surgery. Of the 1,496 patients, 86 (6%; mean age, 58 years [range, 18 to 81], 48 women) underwent operations. Radiographs revealed 59 nodules, 18 cavities, 2 infiltrates, and 7 complications of disease (e.g., effusion, pneumothorax, and empyema). Of the 86 patients, 40% underwent resection for persistent symptoms or disease progression despite adequate antifungal therapy. One third of the operations were performed by video-assisted thoracoscopic surgery. Morbidity, 21% (18 patients), and in-hospital mortality, 2% (2 patients), were greater after resection for cavitary lesions with resultant complications versus for nodular disease: 41% versus 12% (p < or = 0.002) and 8% versus 0% (p < 0.005). Prolonged air leaks or bronchopleural fistulas were the most common complications (13 patients). Postoperative antifungal therapy was administered to 42% of patients (89% of cavitary and complicated). There were no cases of recurrence at follow-up (mean, 24 months). Surgical intervention was indicated for only a few patients, most commonly for diagnostic dilemmas involving nodular disease, symptomatic nonresponsive cavitary disease, or complications. Prolonged air leaks were the main cause of morbidity. Resection should result in symptom resolution and long-term freedom from recurrence.

Necrotizing Fasciitis following Liver Transplantation

Necrotizing fasciitis is a rapidly spreading subcutaneous infection. It can occur in patients after solid organ transplantation. But, the reports for necrotizing fasciitis after liver transplantation are very unusual. We report 2 patients with necrotizing fasciitis caused by bacterial and Aspergillus species infection. Their pre-transplantation condition was very poor due to hepatic encephalopathy, pressure sore, and admission for several months . Patients had a fulminant course for early potent immunosuppression period, despite of aggressive surgical debridement, withdrawal of immunosuppression, and adequate antibacterial and antifungal therapy. Therefore, necrotizing fasciitis has to be recognized as a potential complication after liver transplantation and Aspergillus species has to be added to the list of potential pathogens of surgical wound infections, especially in the setting of liver transplantation.

Fatal consequences of an ear infection

In August, 2006, a 75-year-old non-diabetic, non-alcoholic man with hypertension and atrial fi brillation was ad mitted to the Internal Medicine department with low grade fever, increasing otalgia, otorrhoea, dysphagia, and hoarseness. He had suff ered from bilateral tympanic membrane perforation, intermittent otalgia, and otor rhoea for 12 years. In May, 2006, his otolaryngologist had prescribed ofl oxacin ear drops and oral ciprofl oxacin for otalgia and otorrhoea. In June, 2006, he was admitted to the Ear, Nose and Throat department with a 3-week history of left peripheral facial nerve palsy, left trigeminal sensory loss, and general discomfort. He was afebrile, with a serum C-reactive protein concentration of 72 mg/L; other laboratory tests were normal. CT and MRI of the head showed clouding of the left mastoid without intra cranial pathology or menin geal enhancement (fi gure A); chest radiography was normal. A diagnosis of mastoiditis was made, and ceftazidime and fl ucloxacillin were started. Surgical exploration of the left mastoid showed granulation tissue in the external auditory canal and around the ossicles. Microscopically this tissue showed chronic-active necrotising infl ammation; cultures (in cluding those for fungi) were negative. After 2 weeks, the patient was discharged in fair condition. In the current admission, besides earlier described cranial nerve dysfunction, a partial left glossopharyngeal and vagal nerve palsy were diagnosed by the consulting oto laryngologist. C-reactive protein was 57 mg/L with normal white cells. Culture of discharge from the ear grew Pseudomonas aeruginosa, and amoxicillin (empirically started on admission) was replaced by meropenem. 2 weeks later, still in hospital and being treated with meropenem, he developed headache, neck pain, and a left abducens nerve palsy. Repeated chest radiography and MRI of the brain were normal. Cerebrospinal fl uid (CSF) analysis showed only a mild pleocytosis (leucocytes 17×106 per L). The clinical picture suggested a chronic (basal) meningitis, but blood and CSF cultures remained negative. The patient refused meningeal biopsy and further treatment, had progressive diffi culty in swallowing, and died 3 weeks later in hospital from pneumonia. Autopsy showed a focal purulent pre pontine lepto meningeal exudate (fi gure B). Micro scopically, multiple septated and branched hyphae were detected in this exudate and in the left middle and internal ear (fi gure C), combined with chronic-active necrotising infl am mation. The infl ammation extended into the skull base and cranial nerves. A mould cultured from the exudate was characterised as Pseudallescheria boydii by sequence-analysis of parts of the β-tubulin gene. P boydii can cause a wide variety of clinical diseases and is commonly found in soil, polluted water, and manure. P boydii infections of the central nervous system (CNS), meninges, and mastoid are very rare and generally occur in immunocompromised, near drowning, and trauma patients, but have also been reported in patients without one of these risk factors. There was no suspicion of immunocompromise in our patient, and post mortem HIV PCR analysis from lymph node and heart tissues were negative. Diagnosis of CNS involvement by P boydii is often delayed because of non-specifi c clinical presentation, diffi culty in obtaining and culturing appro priate specimens, and because of histological similarity of P boydii to other fungi, such as aspergillus. In our patient the fungus most likely gained access to the ear and CNS through tympanic membrane perforation. In patients with P boydii mastoiditis, surgical intervention, adequate anti-fungal therapy, and identi fi cation and control of underlying immunological conditions are essential. Voriconazole is suggested as the treatment of choice. Awareness of P boydii as a cause of chronic mastoiditis and meningitis may allow early diagnosis and treatment, thereby increasing the chance of resolution.

Moulds: diagnosis and treatment

Changes in fungal epidemiology and the emergence of resistance have increased the complexity of the management of patients with invasive fungal infections, as timely diagnosis and initiation of adequate antifungal therapy are key factors for improving outcomes. Therefore, alternative approaches to the empirical use of antifungal agents, which incorporate non-culture-based microbiological tools and high-resolution computed tomography of the chest, are under increasing investigation.

Influence of Pretransplantation Bacterial and Fungal Culture Positivity on Outcome after Living Donor Liver Transplantation

Backgrounds Bacterial and fungal infections are serious complications in patients with cirrhosis and are among the main causes of morbidity and mortality. The effects of pretransplantation infection on the outcome after orthotopic liver transplantation (OLT), however, have not been fully described. Objective To assess the influence of pretransplantation infection on OLT by analyzing the clinical profiles of liver recipients with preexisting bacterial or fungal infection. Patients and Methods We retrospectively reviewed the medical records of 223 adult patients who underwent living donor OLT between October 1, 2005, and September 30, 2006. In all patients, routine blood culture, was performed, and in patients with suspected bacterial or fungal infection; sputum, urine, and ascitic fluid cultures were performed. Results Of 223 patients, 37 (16.6%) had a positive culture in one or more samples. Culture-positive and culture-negative groups differed significantly in end-stage liver disease score but showed no differences in Child-Turcotte-Pugh score, existence of spontaneous bacterial peritonitis, hemodialysis, or duration of stay in the intensive care unit or hospital. Six of 37 patients with positive cultures (16.2%) and 4 (2.2%) of 186 patients with negative cultures (2.2%) died during the first 90 days after OLT ( P = .007). The causes of death among culture-positive patients were brain edema (n = 2), brain hemorrhage (n = 1), hepatic dysfunction (n = 1), and sepsis (n = 2), whereas all 4 culture-negative patients died of infectious complications. Conclusion Prompt OLT accompanied by adequate antibiotic or antifungal therapy may be acceptable in patients with preexisting bacterial or fungal infection unless there are overt manifestations of active infection.

Timely selection of adequate antifungal therapy for candidemia in the critically ill: Donʼt let the yeast rise!*

Timely selection of adequate antifungal therapy for candidemia in the critically ill: Donʼt let the yeast rise!*

Interferon-γ and Granulocyte-Macrophage Colony Stimulating Factor Therapy in Three Patients with Pulmonary Aspergillosis

An immune response mediated by type 2 cytokines is thought to contribute to the development and unfavorable outcome of aspergillosis. Adjuvant therapy with interferon-gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF) was added to antifungal treatment in three nonneutropenic patients (one HIV-positive and two HIV-negative patients) with culture proven aspergillosis refractory to classical antifungal therapy. Clinical improvement was observed concomitantly with an increase in peripheral blood leukocyte proliferation and type 1 cytokines production. Our findings suggest an association between the improvement in type 1 cytokine production observed during IFN-gamma and GM-CSF administration and a better control of Aspergillus infection in patients with progressive disease despite adequate antifungal therapy.

Developments in the epidemiolgy of invasive fungal infections – implications for the empiric and targeted antifungal therapy

Invasive fungal infections are significant causes of morbidity and mortality in hospitalized, immunocompromised patients. Whereas in hematologic patients aspergilli represent the major problem along with Candida spp., in surgery departments yeast infections are more prevalent. For the empiric as well as the targeted therapy of mould infections with high mortality rates, several antifungals can be given alone or in combination. So far, resistance among aspergilli is uncommon. In yeast infections one has to respect that a relatively large number of causative agents, especially Candida glabrata and C. krusei, can be resistant to azoles, in particular to fluconazole; cross-resistance with other triazoles, such as voriconazole, may occur as well. Coverage of most pathogens involved in life-threatening fungal infections is crucial for empiric treatment. Since caspofungin has a broad spectrum of antifungal activities and is effective even against fungi with azole resistance, this drug should be preferred for initial, empiric therapy of yeast infections, since there are practically no caspofungin resistant strains among clinical isolates. Early start with an adequate empirical antifungal therapy is associated with an improved survival of patients with invasive Candida infections. Once the diagnosis is completed and a susceptibility pattern of the causative agent is available, a targeted therapy can be given respecting pharmacology, side effects and interactions with co-administered drugs.

Fièvre prolongée et candidose hépatosplénique, efficacité de la corticothérapie

We report the case of a young male treated for lymphoma and presenting with hepatosplenic candidiasis when recovering from aplasia. Prolonged and adequate antifungal therapy failed to produce apyrexia, which was rapidly obtained with corticosteroid therapy suggesting the existence of an underlying immune reconstitution inflammatory syndrome.

Invasive Candida species infection: the importance of adequate empirical antifungal therapy

Candida species are a common cause of bloodstream and invasive infection in critically ill and immunosuppressed patients. Furthermore, invasive Candida infection carries a poor prognosis and may initially be mistaken for bacterial infection. An article in this issue of the Journal investigates the relationship between adequacy of initial empirical therapy and outcome from invasive Candida infection. This study shows that adequate empirical therapy is received by only a quarter of patients, and that inappropriate therapy is associated with increased mortality. These findings highlight the importance of appropriate empirical therapy in invasive Candida infection.

Epidemiology, Risk Factors, and Outcomes of Candida albicans Versus Non-albicans Candidemia in Nonneutropenic Patients

Candidemia is a major cause of morbidity and mortality in hospitalized patients. To describe the epidemiology of and risk factors for non-albicans candidemia (NAC) in nonneutropenic adults and the impact of NAC on patient outcomes and treatment cost. We conducted a retrospective cohort analysis comparing demographics and risk factors for Candida albicans candidemia (CAC) versus NAC in 144 nonneutropenic patients with candidemia over a 6 year period (1997-2002) at Detroit Receiving Hospital. Candida species distribution included albicans (50%), parapsilosis (13%), tropicalis (10%), and glabrata (13%). Predominant species varied by patient care unit, with C. glabrata more common in the medical intensive care unit (ICU) and C. parapsilosis in the burn ICU. In multivariate analysis, NAC was associated with the absence of antibiotic use at the onset of candidemia, recent history of solid tumor, and male sex. NAC was not associated with an increase in mortality or length of stay compared with CAC, but was found to have a higher cost of antifungal therapy ($2030 vs $780; p = 0.05). The epidemiology of candidemia is complex and varies among the different patient care units. Specifically, patients appear less likely to develop NAC if they are receiving antibiotics at the onset of candidemia. Increased awareness of risk factors for NAC can be used to guide adequate initial antifungal therapy.

Cryptococcal meningitis: Clinical, diagnostic and therapeutic overviews

Cryptococcal meningitis has emerged as a leading cause of infectious morbidity and mortality in patients with AIDS. Among the human immunodeficiency virus (HIV)-seropositive subjects, cryptococcal meningitis is the second most common cause of opportunistic neuro-infection. Current trends are changing due to the marked improvement of quality and length of life produced by highly active antiretroviral therapy (HAART). The introduction of generic HAART in India has resulted in an increase in the number of individuals getting treatment for HIV infection, as the cost of highly active antiretroviral therapy (HAART) has decreased 20- fold. Cryptococcal meningitis occurs in non-HIV patients who are immunodeficient due to diabetes, cancer, solid organ transplants, chemotherapeutic drugs, hematological malignancies etc and rarely in healthy individuals with no obvious predisposing factors. Diagnosis of cryptococcal meningitis is fairly straightforward once the diagnosis is considered in the differential diagnosis of chronic meningitis. Treatment of a patient with cryptococcal infection is a challenge for both the physician and the patient, but rewarding, as many would recover with timely and adequate antifungal therapy.

Phacoemulsification in isolated endogenous Candida albicans anterior uveitis with lens abscess in an intravenous methadone user

We report the clinical course of a 31-year-old former intravenous drug user on methadone substitution therapy who injected methadone mixed with orange juice. She developed isolated metastatic Candida albicans anterior uveitis, which was treated with adequate systemic and local antifungal therapy. The uveitis regressed, but despite adequate local and systemic treatment, a lens abscess developed. Phacoemulsification and endocapsular intraocular lens implantation were performed, and the patient recovered 20/20 visual acuity in the affected eye. In patients with a history of injection drug use, persisting intravenous drug or substitution therapy abuse must be considered. Quick diagnosis and adequate treatment can prevent the development of widespread C albicans endophthalmitis, which has a poor visual prognosis. Early administration of antifungal and surgical therapy is crucial for achieving good functional results.