Bactericidal and synergistic activity of double-carbapenem regimen for infections caused by carbapenemase-producing Klebsiella pneumoniae.

Available therapeutic options against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are limited because of the high level of resistance to other antimicrobial classes including polymyxins. The double-carbapenem regimen has been recently considered a possible therapeutic strategy. In the present study, we evaluated the in vitro bactericidal and synergistic activity of a double-carbapenem regimen consisting of ertapenem plus high-dose meropenem in a series of patients with healthcare-associated CR-Kp infections in whom the use of colistin was not indicated because of potential nephrotoxicity and/or resistance. In vitro synergy was evaluated using checkerboard and killing studies. A total of 15 patients were included in the study, with sepsis, severe sepsis and septic shock found in two (13.3%), five (33.3%) and one (6.7%) patients, respectively. Overall, the clinical/microbiological response was 12/15 (80%). Synergy was observed in 11/14 (78.6%) isolates using the checkerboard method whereas in killing studies 12/14 (85.7%) and 14/14 (100%) strains were synergistic and bactericidal at 24 h at concentrations of 1 × MIC MEM+1 × MIC ERT and 2 × MEM+1 × MIC ERT, respectively, with a significant decrease of log CFU/mL compared with other combinations (p <0.0001). The double-carbapenem regimen showed clinical and in vitro effectiveness in patients with CR-Kp infections.

Breast tuberculosis: rare but still present in Italy--a case of mycobacterium breast infection.

Breast tuberculosis is a rare disease in highly endemic countries, and it is even rarer in Western countries, where only occasionally the local population is affected. The rarity of the disease and particularly the lack of a typical clinical-radiological presentation may cause tuberculosis to be mistaken for breast cancer or a pyogenic abscess. The authors present a case of breast tuberculosis in a 27-year-old nulliparous woman, an Italian citizen of the Caucasian race, who has never resided in a tuberculosis endemic area. She presented with painful retroareolar and para-areolar swelling in the right breast associated with cutaneous hyperemia (without fistulization), resistant to antibiotic therapy. Histopathological examination revealed features of mastitis with epithelioid histiocytes and Langhans giant cells and was characterized by the presence of caseous necrosis which suggested tuberculous inflammation. Ziehl-Neelsen staining showed the presence of acid fast bacilli. In countries where tuberculosis is non-endemic, breast tuberculosis should always be included in the differential diagnosis in cases of inflammatory breast lesions resistant to the usual antibiotic therapies. Early recognition may prevent both clinical progression and surgical excision, as breast tuberculosis usually regresses as a response to appropriate anti-tuberculosis therapy.

Effectiveness of Lactobacillus-containing vaginal tablets in the treatment of symptomatic bacterial vaginosis.

The purpose of this study was to determine the effectiveness of Lactobacillus-containing vaginal tablets in the treatment of bacterial vaginosis (BV) and in the restoration of a healthy vaginal flora. Thirty-nine women with BV were enrolled in a double-blind, placebo-controlled clinical trial. Patients received either one Lactobacillus-containing tablet or placebo daily for 7 days. Clinical criteria, vaginal Gram stain scores and symptoms were compared with those at the initial visit and those at completion of therapy and 2 weeks later. After completion of therapy, all of the patients in the Lactobacillus-treated group (n = 18) were free of BV, showing a normal (83%) or intermediate (17%) vaginal flora, as compared with only two patients free of BV with intermediate flora (12%) from among the 16 placebo-treated women (p <0.001). Two weeks after completion of therapy, treatment was successful (score <7) in 61% of Lactobacillus-treated patients as compared with 19% of those in the placebo group (p <0.05). In the treatment group, the total number of symptomatic patients and the intensity of their symptoms, in particular vaginal malodour, were significantly reduced at both follow-up visits. The data indicate that intravaginal administration of exogenous selected strains of lactobacilli can restore a normal vaginal microbiota and be used in treating bacterial vaginosis.

Anti-inflammatory effects of Lactobacillus brevis (CD2) on periodontal disease.

OBJECTIVES: To analyze the anti-inflammatory effects of Lactobacillus brevis extracts on periodontitis patients and to investigate the involved mechanisms in vitro on activated macrophages. METHODS: Eight healthy subjects and 21 patients with chronic periodontitis were enrolled to analyze the effect of L. brevis-containing lozenges on periodontitis-associated symptoms and signs. Before and after the treatment, the patients received a complete periodontal examination. Saliva samples, collected before and after treatment, were analyzed for metalloproteinase and nitric oxide synthase (NOS) activity, immunoglobulin-A (IgA), prostaglandin E(2) (PGE(2)) and gamma-interferon (IFN-gamma) levels. Arginine deiminase (AD) and NOS activities were determined through a radiometric assay. Metalloproteinases were assayed by zymogram and Western blotting, whereas IgA, PGE(2) and IFN-gamma were assayed by enzyme-linked imunosorbent assay tests. RESULTS: The treatment led to the total disappearance or amelioration of all analyzed clinical parameters in all patients. This was paralleled to a significant decrease of nitrite/nitrate, PGE(2), matrix metalloproteinase, and IFN-gamma levels in saliva samples. CONCLUSION: Our results suggest that the anti-inflammatory effects of L. brevis could be attributed to the presence of AD which prevented nitric oxide generation. Our findings give further insights into the knowledge of the molecular basis of periodontitis and have a potential clinical significance, giving the experimental ground for a new innovative, simple and efficacious therapeutical approach of periodontal disease.

Characterization and selection of vaginal Lactobacillus strains for the preparation of vaginal tablets.

AIMS: To characterize and select Lactobacillus strains for properties that would make them a good alternative to the use of antibiotics to treat human vaginal infections. METHODS AND RESULTS: Ten Lactobacillus strains belonging to four different Lactobacillus species were analysed for properties relating to mucosal colonization or microbial antagonism (adhesion to human epithelial cells, hydrogen peroxide production, antimicrobial activity towards Gardnerella vaginalis and Candida albicans and coaggregation with pathogens). The involvement of electrostatic interactions and the influence of bacterial metabolic state in the binding of lactobacilli to the cell surface were also studied. Adherence to epithelial cells varied greatly among the Lactobacillus species and among different strains belonging to the same Lactobacillus species. The reduction in surface negative electric charge promoted the binding of several Lactobacillus strains to the cell membrane whereas lyophilization reduced the adhesion capacity of many isolates. The antimicrobial activity of lactobacilli culture supernatant fluids was not directly related to the production of H2O2. CONCLUSIONS: Three strains (Lactobacillus brevis CD2, Lact. salivarius FV2 and Lact. gasseri MB335) showed optimal properties and were, therefore, selected for the preparation of vaginal tablets. The selected strains adhered to epithelial cells displacing vaginal pathogens; they produced high levels of H2O2, coaggregated with pathogens and inhibited the growth of G. vaginalis. SIGNIFICANCE AND IMPACT OF THE STUDY: The dosage formulation developed in this study appears to be a good candidate for the probiotic prophylaxis and treatment of human vaginal infections.

Infections, atherosclerosis, and coronary heart disease.

There is growing evidence that the immune response is involved in atherosclerosis. Studies done over the past several years have shown an association between markers of inflammation and coronary atherosclerosis with an exacerbation of the inflammatory process during acute myocardial ischemia. Overall, these data have greatly renewed interest in the infectious theory of atherosclerosis and coronary heart disease. Search of bibliographic databases (from January 1991 through December 1999) and manual scanning of both peer-reviewed publications and other documents were used to identify pertinent literature. Infections and coronary heart disease were indexed as key words. A large number of studies have reported an association of human coronary heart disease and certain persistent bacterial and viral infections. The association between Chlamydia pneumoniae and coronary heart disease appears quite significant although the sequence of infection and disease is uncertain. The association between Helicobacter pylori and coronary heart disease may be accounted for by residual confounding from classic risk factors. Preliminary findings indicate that this association could be due to a higher prevalence of more virulent Helicobacter strains. Infection with Cytomegalovirus appears to be associated with a greater risk of restenosis after angioplasty rather than primary atherosclerosis. Early trials of appropriate antibiotic therapy in subjects with recent acute myocardial infarction have been encouraging. A causal relationship between infections and coronary heart disease is still elusive. Improved studies involving prospective collection of data are required to demonstrate such an association with potential implications for public health worldwide.

Long-term remission of human immunodeficiency virus-associated visceral leishmaniasis after initiation of potent combination antiretroviral treatment: report of two cases.

We describe two cases of human immunodeficiency virus-infected patients with visceral leishmaniasis in whom no clinical and parasitological disease relapses were observed after liposomal amphotericin B therapy combined with potent antiretroviral treatment.

Fulminant purpuric rash.

We report on a fatal case of purpura fulminans caused by severe meningococcaemia. Despite early and aggressive treatment with the use of a specific algorithm and the maintenance of a stable haemodynamic status in the first hour since admission, purpura fulminans developed impressively over a few minutes. Necropsy showed microvascular thrombosis in the dermis but not in visceral organs, suggesting the diagnosis of meningococcal septic shock with purpura fulminans limited to the skin. Acquired deficiency of protein C, which exerts anticoagulant and antiinflammatory functions, is the central mechanism ultimately responsible for purpura fulminans. The disorder predicts a poor outcome of meningococcaemia and early and aggressive resuscitation is recommended in the emergency department with antibiotics, volume expansion, inotropic drugs, and protein C replacement. An attitude of scepticism is appropriate in the management of these patients even when early resuscitation is successful and haemodynamic parameters remain stable.

Ceramide concentrations in septic patients: a possible marker of multiple organ dysfunction syndrome.

OBJECTIVES: To investigate the concentrations of mononuclear cell-associated ceramide and serum tumor necrosis factor-alpha (TNF-alpha) in patients with sepsis and to assess their predictive value for the development of multiple organ dysfunction syndrome (MODS). DESIGN: Prospective, cohort study. SETTING: Intensive care unit and two research laboratories at a university hospital. PATIENTS: Twenty-three adult patients admitted to an intensive care unit meeting the criteria for diagnosis of sepsis. INTERVENTIONS: Blood samples were collected at the time when diagnosis of sepsis was made. MEASUREMENTS AND MAIN RESULTS: Mononuclear cell-associated ceramide and serum TNF-alpha were significantly elevated in the samples from the septic patients compared with the control individuals (318.01+/-270.15 pmol/10(6) cells vs. 99.90+/-52.75 pmol/10(6) cells; p<.001, and 28.52+/-18.77 pg/mL vs. 10.43+/-3.37 pg/mL; p<.0001, respectively), and a direct correlation linked ceramide and TNF-alpha concentrations (r2 = .90, p<.00001). In the septic patients who went on to develop MODS, ceramide and TNF-alpha were significantly higher compared with the no MODS patients (489.22+/-264.93 pmol/10(6) cells vs. 131.23+/-99.02 pmol/10(6) cells; p<.0001, and 40.96+/-18 pg/mL vs. 14.95+/-5.60 pg/mL; p<.001, respectively). The receiver operating characteristic curves demonstrated that both TNF-alpha and ceramide were prognostic of MODS, but ceramide concentrations were more efficient predictors. CONCLUSIONS: These observations suggest that mononuclear cells of peripheral blood from patients with sepsis are committed to undergo apoptosis, because there is evidence that ceramide acts as an endogenous mediator of apoptosis. The strong correlation we found between cell-associated ceramide and serum TNF-alpha supports the hypothesis that this cytokine plays an important role in activating the sphingomyelin pathway and ceramide generation in patients with sepsis. In addition, this study provides evidence that consistent concentrations of mononuclear cell-associated ceramide may predict progression toward MODS in septic patients.

Reduction of glutamate levels in HIV-infected subjects treated with acetylcarnitine.

The excitotoxic amino acid glutamate, which is elevated in blood and cerebrospinal fluid from subjects with AIDS dementia complex, is crucially implicated in the neurotoxicity of HIV infection. We describe a subject with AIDS dementia complex who showed a significant motor and cognitive improvement after a course of intravenous acetylcarnitine therapy. The clinical improvement was paralleled by a significant reduction of glutamate concentrations in both blood and cerebrospinal fluid. A prospective pilot study confirmed that acetylcarnitine administration resulted indeed to reduce the blood levels of glutamate in AIDS patients treated with acetylcarnitine therapy in order to prevent the neurotoxicity of nucleoside analogs. Even though the mechanisms responsible for the reduction of glutamate concentrations remain to be established, we suggest that acetylcarnitine should be added to the list of drugs under investigation for the treatment of AIDS dementia complex. The anti-apoptotic activity of carnitines and their safety profile further support this view.

Central nervous system involvement as a relapse of disseminated histoplasmosis in an Italian AIDS patient.

A case of an Italian AIDS patient who developed both meningitis and cerebral mass lesion as a final relapse of disseminated histoplasmosis is reported. Central nervous system (CNS) involvement occurred while the patient was receiving both amphotericin B and itraconazole as maintenance therapy, thus indicating the difficulty of eradicating histoplasmosis in patients with AIDS.

Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues.

OBJECTIVE: A severe dose limiting axonal peripheral neuropathy may develop in subjects on treatment with the nucleoside analogues didanosine (ddl), zalcitabine (ddC), and stavudine (d4T). The impairment of mitrochondrial DNA synthesis is crucial to the pathogenesis of this disorder although other mechanisms have not been ruled out. The depletion of acetyl-carnitine, which regulates the metabolism and function of peripheral nerves could contribute to the neurotoxicity of these compounds. DESIGN: Non-randomized, cross-sectional study of selected patients. METHODS: We measured the serum levels of acetyl- and total carnitine in 12 subjects with axonal peripheral neuropathy developed on treatment with different regimens of neurotoxic nucleoside analogues (ddl, ddC, d4T). Subjects who did not develop peripheral neuropathy while staying on treatment with ddl (n = 10) or zidovudine (n = 11) served as the control groups. HIV-negative subjects with axonal on demyelinating autoimmune neuropathies (n = 10) and healthy individuals (n = 13) were additional control groups. RESULTS: Subjects experiencing axonal peripheral neuropathy on treatment with ddl, ddC and d4T had significantly reduced levels of acetyl-carnitine in comparison to the control groups. No difference was observed in the levels of total carnitine between study subjects and the control groups. CONCLUSIONS: Our results demonstrate that subjects who developed peripheral neuropathy while staying on treatment with ddl, ddC and d4T had acetyl-carnitine deficiency. The normal levels of total carnitine in the study group appear to indicate the specificity of the defect and rule out coexisting relevant nutritional problems. The critical role of acetyl-carnitine for the metabolism and function of the peripheral nerves supports the view that the acetyl-carnitine deficiency found in these subjects may contribute to the neurotoxicity of ddl, ddC and d4T, even though the interference with mitochondrial DNA synthesis is regarded as the main cause of their toxicity.

[Pancreatitis during treatment of leishmaniasis with n-methylglucamine antimoniate in a subject infected with HIV]. / Pancreatite in corso di trattamento di Leishmaniosi con N-metilglucamina antimoniato in soggetti con infezione da HIV.

In this study the authors report the case of HIV patients with visceral leishmaniasis. He presented a pancreatitis with evident clinical signs and high increase of amilasis (9876 U/L) the twelfth day of treatment with meglumine antimoniate. The interruption of therapy was followed by a rapid disappearance of signs and symptoms and a normalization of amilasis. In accordance with the most recent studies, it is expedient, for every patients treated with antimonial drugs, to undergo an accurate amilasis monitoring.

Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine.

OBJECTIVE: Reduced levels of serum carnitines (3-hydroxy-4-N-trimethyl-ammonio-butanoate) are found in most patients treated with zidovudine. However, since serum carnitines do not strictly reflect cellular concentrations we examined whether a carnitine depletion could be found in peripheral blood mononuclear cells (PBMC) from AIDS patients with normal serum carnitine levels. In addition, we explored whether it was possible to relate the host's immunoreactivity to the content of carnitine in PBMC and whether carnitine levels can be corrected by oral supplementation of L-carnitine. DESIGN: Immunopharmacologic study. METHODS: Twenty male patients with advanced AIDS (Centers for Disease Control and Prevention stage IVCI) and normal serum levels of carnitines were enrolled. Patients were randomly assigned to receive either L-carnitine (6 g/day) or placebo for 2 weeks. At baseline and at the end of the trial, we measured carnitines in both sera and PBMC, serum triglycerides, CD4 cell counts, and the frequency of cells entering the S and G2-M phases of cell cycle following mitogen stimulation. RESULTS: Concentrations of total carnitine in PBMC from AIDS patients was lower than in healthy controls. A significant trend towards the restoration of appropriate intracellular carnitine levels was found in patients treated with high-dose L-carnitine and was associated with an increased frequency of S and G2-M cells following mitogen stimulation. Furthermore, at the end of the trial we found a strong reduction in serum triglycerides in the L-carnitine group compared with baseline levels. CONCLUSIONS: Our data indicate that carnitine deficiency occurs in PBMC from patients with advanced AIDS, despite normal serum concentrations. The increase in cellular carnitine content strongly improved lymphocyte proliferative responsiveness to mitogens. Because carnitine status is an important contributing factor to immune function in patients with advanced AIDS, we therefore believe that L-carnitine supplementation could have a role as a complementary therapy for HIV-infected individuals.

[Cytomegalovirus infection in HIV]. / Il citomegalovirus nell'infezione da HIV.

The data are taken from a retrospective study of 24 patients with AIDS who developed CMV disease. This study was performed to detect the principal characteristics associated with the development of CMV disease. Age, sex, risk factors, the time interval between HIV seropositivity to CMV disease were examined, as well as efficacy of gancyclovir therapy in both groups of patients with symptomatic and asymptomatic retinitis. When the chorioretinitis is still asymptomatic the early treatment of CMV disease may suppress progression of retinic lesions and seems to be efficacious to prevent the evolution of CMV disease.