Reducing Tissue Burden Research Articles

The diagnosis of nontuberculous cervicofacial lymphadenitis: A systematic review

BackgroundNontuberculous mycobacterial cervicofacial lymphadenitis (NTMCL) is an uncommon condition detected in young immunocompetent children who typically present with a nontender neck mass. Various tests have been proposed to assist in the work-up of suspected NTMCL, with varying diagnostic utility. This systematic review investigates the sensitivity of the various diagnostic methods used in the work-up of pediatric NTMCL. MethodsA systematic review in accordance with PRISMA guidelines was performed using the Pubmed, EMBASE, and Web of Science databases. Searches were filtered for English language studies published prior to 05/10/22. Studies meeting criteria included studies featuring 15+ pediatric patients with confirmed or suspected NTMCL. Studies with any reported diagnostic methodology used in the workup of NTMCL were included. ResultsOf 836 abstracts/articles reviewed, 21 studies met inclusion criteria. Diagnostic methods included culture(n = 11 studies), PPD-Tb(Tuberculin)(n = 12), PPD-Scrofulaceum, −Avium, or -Kansasii(n = 6), staining techniques(n = 4), IGRA(n = 3), and ultrasound(n = 2). All studies had an overall low risk of bias.Among patients confirmed to have NTMCL based on PCR and/or culture, the most sensitive tests were PPD-A(0.94, 95 % CI 0.91 to 0.97; n = 210 patients) and PPD-S(0.75, 95 % CI 0.68 to 0.81; n = 171). Auramine and Ziehl-Neelsen staining techniques had moderately high sensitivity(0.85 and 0.60 respectively), though were limited by low patient numbers(n = 20). PPD-Tb(0.45, 95 % CI 0.39 to 0.50; n = 300) and IGRA(0.02; 95 % CI 0 to 0.06; n = 48) demonstrated poor sensitivity.Among patients suspected to have NTM lymphadenitis based on global assessment, the most sensitive tests included combined PPD-S + A + K(0.92, 95 % CI 0.86 to 0.98; n = 85), PCR(0.82, 95 % CI 0.75 to 0.88; n = 136), and PPD-A(0.72, 95 % CI 0.62 to 0.81; n = 84). Culture showed a sensitivity of 0.54(95 % CI 0.50 to 0.58; n = 494). PPD-K, PPD-S, IGRA, and staining techniques demonstrated lower sensitivity. ConclusionsThis systematic review is the largest study investigating the sensitivity of the various diagnostic methods used in the work-up of pediatric NTMCL. Patients with clinical suspicion for NTMCL and a positive PPD-Tb should first have tuberculous lymphadenitis ruled out with IGRA. Patients with a positive PPD-Tb and negative IGRA and high clinical suspicion for NTMCL can undergo presumptive surgical intervention. Patients with a negative PPD-Tb can undergo NTM antigen skin testing if available, or if high clinical suspicion exists, surgical intervention to reduce tissue burden and elicit additional tissue data.

Efficacy of echinocandins against murine infections by Diutina (Candida) rugosa

Echinocandins are recommended as a first-line therapy for invasive candidiasis. Candida rugosa was recently transferred to the new genus Diutina. We have determined the in vitro killing kinetics of two echinocandins, anidulafungin, and caspofungin and their in vivo efficacy, administering doses of 5 or 10 mg/kg, and 1 or 5 mg/kg, respectively against 2 clinical strains of D. rugosa. Both drugs showed a fungicidal concentration-dependent activity and, in a neutropenic murine model of disseminated infection, were able to reduce tissue burden and to prolong survival of mice. These results suggest that both echinocandins could be useful to treat infections by this fungus when isolates show minimal inhibitory concentrations within the range of susceptibility for both drugs.

Voriconazole and posaconazole therapy for experimental Candida lusitaniae infection

The in vitro activity of posaconazole (PSC) and voriconazole (VRC) was tested by using time-kill studies against 3 strains of Candida lusitaniae. Both drugs showed fungistatic activity against all strains. The efficacy of those compounds was evaluated by reducing kidney fungal burden and by determining (1→3)-β-d-glucan serum levels in a murine model of invasive infection of C. lusitaniae. The therapies tested were VRC at 10, 25, or 40mg/kg/day and PSC at 5, 12.5, or 20mg/kg/twice a day. All the dosages showed efficacy in a dose-dependant manner being high doses of both antifungals able to sterilize some kidneys after 10days. With the exception of the strain FMR 9474, against which PSC was more effective than VRC, no differences in reducing tissue burden were found between the treatments. All doses of both antifungals were able to significantly reduce (1→3)-β-d-glucan serum levels with no significant differences between treatments and between the same doses of both drugs.

Efficacy of Amphotericin B at Suboptimal Dose Combined with Voriconazole in a Murine Model of Aspergillus fumigatus Infection with Poor In Vivo Response to the Azole

The combination of amphotericin B at a suboptimal dose (0.3 mg/kg) with voriconazole has shown efficacy in prolonging survival and reducing tissue burden in a murine model of disseminated infection by an isolate of Aspergillus fumigatus that had showed a poor in vivo response to the azole. The efficacy of the combined treatment was higher than that obtained with amphotericin B at 0.8 mg/kg.

Efficacy of anidulafungin against Aspergillus niger in vitro and in vivo

In this study, anidulafungin (AFG) showed high in vitro activity against 10 isolates of Aspergillus niger by broth microdilution and disk diffusion methods. The efficacy of AFG at 1, 5 and 10mg/kg was tested against six of the isolates in a murine model of disseminated infection. AFG was able to reduce mortality, showing survival rates of 70–100%, 60–100% and 30–60% in mice treated with AFG at 10, 5 and 1mg/kg, respectively. AFG also showed a dose–response efficacy in reducing tissue burden in kidneys and spleen. A parallel experiment demonstrated that administration of AFG did not reduce serum concentrations of galactomannan in mice. Histopathological studies confirmed the efficacy of AFG.

Caspofungin Dose Escalation for Invasive Candidiasis Due to Resistant Candida albicans

Previous in vivo studies have reported caspofungin dose escalation to be effective against Candida glabrata with reduced susceptibility. We hypothesized that higher doses of caspofungin would be effective against invasive candidiasis caused by the more virulent species Candida albicans, including isolates resistant to this echinocandin. Immunocompetent mice were inoculated with one of three C. albicans isolates, including one susceptible and two resistant isolates with different FKS1 hot spot 1 point mutations. Mice received daily caspofungin treatment for 7 days and were then followed off therapy for 2 weeks to assess survival. Kidney tissue and blood were collected, and fungal burden and serum (1 → 3)-β-D-glucan were measured. Significant differences in virulence were observed among the three C. albicans isolates, which translated into differences in responses to caspofungin. The most virulent of the resistant isolates studied (isolate 43001; Fks1p F641S) did not respond to caspofungin doses of up to 10 mg/kg of body weight, as there were no differences in survival (survival range, 0 to 12% with treatment), tissue burden, or (1 → 3)-β-D-glucan concentration compared to those for untreated controls. Higher doses of caspofungin did improve survival against the second resistant isolate (53264; Fks1p S645P) that demonstrated reduced virulence (5 and 10 mg/kg; 80% survival). In contrast, caspofungin doses as low as 1 mg/kg improved survival (85 to 95%) and reduced tissue burden and (1 → 3)-β-D-glucan concentration against the susceptible isolate (ATCC 90028). These data suggest that caspofungin dose escalation for invasive candidiasis may not be consistently effective against resistant C. albicans isolates, and this may be associated with the virulence of the strain.

In Vitro Activity and In Vivo Efficacy of Anidulafungin in Murine Infections by Aspergillus flavus

Anidulafungin (AFG) showed high activity against 27 strains of Aspergillus flavus by use of broth microdilution and disk diffusion methods. This drug was effective in vivo in a murine model of disseminated infection with five isolates tested. AFG was able to prolong survival and reduce tissue burden of infected mice but not able to reduce galactomannan serum concentrations. The AFG serum levels were above the corresponding minimum effective concentrations (MEC) for all of the strains tested.

Combined Therapy Against Murine-Disseminated Infection by Fusarium verticillioides

Using a murine model of disseminated infection by two strains of Fusarium verticillioides, we have evaluated the efficacy of high doses of amphotericin B (AMB) (3 mg/kg of body weight/day), voriconazole (VRC) (60 mg/kg of body weight/day), posaconazole (PSC) (100 mg/kg of body weight/day), and the combinations of AMB plus VRC or PSC. In general, our results were very modest. Neither combination was superior to the respective monotherapies. VRC alone and in combination with AMB was able to prolong survival but not to reduce tissue burden, and AMB plus PSC was able to reduce fungal load in organs but not to prolong survival.

Antifungal Therapy in a Murine Model of Disseminated Infection by Cryptococcus gattii

We have evaluated the efficacy of posaconazole (PSC), voriconazole (VRC), and amphotericin B (AMB) in a murine model of systemic infection by Cryptococcus gattii using immunocompromised animals and three clinical strains of the fungus. AMB was the most effective drug in prolonging the survival of mice and also in reducing tissue burden in all organs tested. To a lesser degree, VRC at 60 mg/kg of body weight in lung tissue and PSC at 40 mg/kg also in spleen demonstrated good efficacy in reducing the fungal load. The PSC and VRC levels in serum and brain tissue, determined by an agar diffusion bioassay method at 4 h after the last dose of the therapy, were above the corresponding MIC values. However, these drugs were not able to reduce the fungal load in brain tissue. Our results demonstrated that PSC and, to a lesser degree, VRC, have fungistatic activity and potential for the treatment of human pulmonary cryptococcosis.

Efficacy of Liposomal Amphotericin B Combined with Gamma Interferon or Granulocyte-Macrophage Colony-Stimulating Factor for Treatment of Systemic Zygomycosis in Mice

Granulocyte-macrophage colony-stimulating factor enhanced the efficacy of liposomal amphotericin B (LAMB) in a murine model of disseminated infection by Rhizopus oryzae, significantly prolonging survival and reducing tissue burden. The use of gamma interferon (IFN-gamma) alone was ineffective, and IFN-gamma combined with LAMB did not improve the results obtained with LAMB alone.

Efficacy of isavuconazole, voriconazole and fluconazole in temporarily neutropenic murine models of disseminated Candida tropicalis and Candida krusei

The aim of this study was to assess the dose-response of isavuconazole, voriconazole and fluconazole in disseminated Candida tropicalis and Candida krusei infections. Mice were immunosuppressed using either one dose [temporarily neutropenic (TN)] or two doses [persistently neutropenic (PN)] of cyclophosphamide. Treatment was started 5 h after infection with oral isavuconazole (6, 15, 30, 60, 90, 120 or 150 mg/kg equivalent active compound), intravenous voriconazole (5, 20 or 40 mg/kg plus grapefruit gavage twice daily) or oral fluconazole (15, 50 or 150 mg/kg) all administered twice daily. Kidney burden was assessed for C. tropicalis, and kidney and brain burden for C. krusei. Vehicle controls developed a non-lethal infection with high burdens in both models. In the TN models, isavuconazole, voriconazole and fluconazole (>50 mg/kg) reduced kidney burden compared with controls; >60 mg/kg isavuconazole and 50 mg/kg fluconazole were superior to alternative treatments (other than voriconazole 40 mg/kg). Isavuconazole (all doses) reduced brain burden (P<0.05) in the C. krusei model; fluconazole (all doses) and voriconazole (5 and 20 mg/kg) did not. In the C. krusei kidney burden model, isavuconazole 120 and 150 mg/kg and voriconazole 40 mg/kg were superior to controls and fluconazole. In the C. tropicalis model, PN isavuconazole (all doses), voriconazole (>5 mg/kg) and fluconazole (all doses) reduced kidney burden (P<0.05). Only isavuconazole (all doses) and 40 mg/kg voriconazole were effective against C. krusei in the brain, isavuconazole and voriconazole reduced tissue burden (P<0.05). Fluconazole had no significant effect on brain burden even at 150 mg/kg. Isavuconazole significantly reduced kidney burden in mice infected with C. tropicalis and both kidney and brain burdens in mice infected with C. krusei. Isavuconazole was as effective as voriconazole and much more effective than fluconazole at reducing brain burden.

Posaconazole Combined with Amphotericin B, an Effective Therapy for a Murine Disseminated Infection Caused by Rhizopus oryzae

In a murine model of disseminated zygomycosis, low doses of amphotericin B (0.3 mg/kg body weight/day) combined with posaconazole (40 mg/kg/day) prolonged survival and reduced tissue burden with respect to that of controls and that of both drugs administered alone. Results were similar to those obtained with amphotericin B given alone at 0.8 mg/kg/day.

Combined therapy in treatment of murine infection by Fusarium solani

We evaluated the efficacy of voriconazole, amphotericin B and micafungin alone and combined in a murine model of disseminated infection by Fusarium solani. Immunosuppressed mice were treated with voriconazole at 60 mg/kg/day, amphotericin B at 3 mg/kg/day, micafungin at 10 mg/kg/day or combinations of these antifungal drugs. For survival studies, treatment began 1 day after infection and continued for 10 days. For tissue burden studies, animals were sacrificed on day 6 of the treatment and the fungal load in the kidneys and spleens was measured. The experiments were carried out using two different clinical strains of F. solani. Only the combination of voriconazole plus amphotericin B prolonged the survival of the mice versus the controls for the two strains tested. However, this combination only reduced tissue burden in the kidney and spleen of mice infected by one strain. The other treatments were clearly less effective. Voriconazole plus amphotericin B may have a role in the treatment of fusariosis.

Combined antifungal therapy in a murine infection by Candida glabrata

To develop proper treatments for patients who do not respond to current antifungal treatments, we tested new combinations of antifungal drugs for treating disseminated infections by Candida glabrata in a murine model. Mice were rendered neutropenic by intraperitoneal cyclophosphamide and intravenous 5-fluorouracil administration. The animals were infected intravenously with 2 x 10(8) cfu of C. glabrata. The efficacies of micafungin combined with amphotericin B, fluconazole or flucytosine, and of amphotericin B combined with fluconazole were evaluated by survival and tissue burden reduction. Micafungin plus amphotericin B was the most effective combination at reducing tissue burden. Micafungin at 10 mg/kg combined with amphotericin B at 0.75, 1.5 or 3 mg/kg prolonged survival with respect to the monotherapies, but only the second combination showed a synergistic effect in reducing fungal load in spleen and kidney. Amphotericin B at 1.5 mg/kg combined with micafungin at 5, 10 or 20 mg/kg reduced tissue burden with respect to the monotherapies, but the effects of the three combinations were very similar. These results suggest that amphotericin B in combination with micafungin is promising for the treatment of disseminated C. glabrata infections.

Efficacy of Voriconazole in a Guinea Pig Model of Invasive Trichosporonosis

We have evaluated the efficacy of voriconazole (VRC) in a systemic infection by Trichosporon asahii in immunosuppressed guinea pigs. VRC was more effective than amphotericin B in prolonging survival and reducing tissue burden. The best results were obtained with VRC at 10 mg/kg of body weight/day.

Efficacy of albaconazole (UR-9825) in treatment of disseminated Scedosporium prolificans infection in rabbits.

There are no effective therapeutics for treating invasive Scedosporium prolificans infections. Doses of 15, 25, and 50 mg/kg of body weight/day for the new triazole albaconazole (ABC) were evaluated in an immunocompetent rabbit model of systemic infection with this mold. Treatments were begun 1 day after challenge and given for 10 days. ABC at any dose was more effective than amphotericin B (AMB) at 0.8 mg/kg/day at clearing S. prolificans from tissue (P < 0.007). The percentages of survival at 25 mg of ABC/kg/day were similar to those obtained with AMB. Rabbits showed 100% survival when they were treated with 50 mg of ABC per kg (P < 0.0001 versus control group), and only this dosage was able to reduce tissue burden significantly in the five organs studied, i.e., spleen, kidneys, liver, lungs, and brain.

In vivo activity of posaconazole against Mucor spp. in an immunosuppressed-mouse model.

The in vivo activities of posaconazole, itraconazole, and amphotericin B in neutropenic mice with zygomycosis were compared. The in vitro MICs of posaconazole and itraconazole for the strains of Mucor spp. used in this study ranged from 0.125 to 8 microg/ml and 0.25 to 8 microg/ml, respectively. The in vitro MIC range for amphotericin B is 0.125 to 0.25 microg/ml. At twice-daily doses of >or=15 mg/kg of body weight, posaconazole prolonged the survival of the mice and reduced tissue burden.

Role of vitamins in treatment of lead intoxication

The efficacy of thiamine, ascorbic acid, and becozinc (a pharmacological preparation containing vitamins of the B-complex group, vitamin C, and zinc) in enhancing excretion and reducing tissue burden of lead and reversing lead-sensitive biochemical alterations was investigated in lead pre-exposed rat. These vitamins were effective in mobilizing lead from blood, liver, and kidney into urine and/or feces and in restoring partially blood zinc protoporphyrin level. All the vitamins were effective in reversing completely the lead-induced increase in blood and renal calcium levels, and becozinc was particularly effective in restoring the decreased hepatic and tibia zinc content. However, the inhibition of blood δ-aminolevulinic acid dehydratase activity and increase in urinary aminolevulinic acid excretion due to lead remained uninfluenced, which may require more time for recovery. The results suggest the use of becozinc as a safe alternate to treatment of lead poisoning with the chelating agents. J. Trace Elem. Exp. Med. 13:305–315, 2000. © 2000 Wiley-Liss, Inc.