Cure of recurring Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae septic shock episodes due to complicated soft tissue infection using a ceftazidime and avibactam-based regimen: a case report.

BACKGROUND: Infections caused by multidrug-resistant Enterobacteriaceae are hard to treat and life-threatening due to reduced therapeutic options. Systemic infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae strains have increased in many European regions, becoming frequent in many clinical settings, and are associated with high mortality. The co-formulation of ceftazidime, a third-generation cephalosporin, with avibactam, a new suicide inhibitor beta-lactamase inhibitor able to block most Klebsiella pneumoniae carbapenemases, has been recently licensed, with promising results in patients with limited or absent therapeutic options. Little is known, however, as to the efficacy of such a combination in patients with soft tissue infections caused by multidrug-resistant Klebsiella pneumoniae carbapenemase-producing strains of Klebsiella pneumoniae. CASE PRESENTATION: A Caucasian 53-year-old man with paraplegia suffered multiple vertebral fractures due to a car crash. He was treated with external fixators that became infected early after insertion and were repeatedly and inefficiently treated with multiple antibiotics. He suffered repeated septic episodes caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae strains with a multidrug-resistant profile. Meropenem, tigecycline, and colistin combinations allowed only temporary improvements, but septic shock episodes recurred, in spite of removal of infected external fixators. After approval of pre-marketing prescription by our local Ethics Committee, full clinical resolution was obtained with a compassionate treatment using meropenem and ceftazidime/avibactam in combination for 16 days. CONCLUSIONS: Our experience provides additional evidence that ceftazidime/avibactam, possibly in combination with meropenem rescued by avibactam, may be an efficacious treatment option also for complicated skin and soft tissue infections caused by multidrug-resistant strains of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae.

Five-year retrospective Italian multicenter study of visceral leishmaniasis treatment.

The treatment of visceral leishmaniasis (VL) is poorly standardized in Italy in spite of the existing evidence. All consecutive patients with VL admitted at 15 Italian centers as inpatients or outpatients between January 2004 and December 2008 were retrospectively considered; outcome data at 1 year after treatment were obtained for all but 1 patient. Demographic characteristics, underlying diseases, diagnostic procedures, treatment regimens and outcomes, as well as side effects were recorded. A confirmed diagnosis of VL was reported for 166 patients: 120 (72.3%) immunocompetent, 21 (12.6%) patients with immune deficiencies other than HIV infection, and 25 (15.1%) coinfected with HIV. Liposomal amphotericin B (L-AmB) was the drug almost universally used for treatment, administered to 153 (92.2%) patients. Thirty-seven different regimens, including L-AmB were used. The mean doses were 29.4 ± 7.9 mg/kg in immunocompetent patients, 32.9 ± 8.6 mg/kg in patients with non-HIV-related immunodeficiencies, and 40.8 ± 6.7 mg/kg in HIV-infected patients (P < 0.001). The mean numbers of infusion days were 7.8 ± 3.1 in immunocompetent patients, 9.6 ± 3.9 in non-HIV-immunodeficient patients, and 12.0 ± 3.4 in HIV-infected patients (P < 0.001). Mild and reversible adverse events were observed in 12.2% of cases. Responsive patients were 154 (93.3%). Successes were 98.4% among immunocompetent patients, 90.5% among non-HIV-immunodeficient patients, and 72.0% among HIV-infected patients. Among predictors of primary response to treatment, HIV infection and age held independent associations in the final multivariate models, whereas the doses and duration of L-AmB treatment were not significantly associated. Longer treatments and higher doses of L-AmB were not able to significantly modify treatment outcomes either in the immunocompetent or in the immunocompromised population.

A simple rule to personalize standard dual therapy across all genotypes in naive chronic hepatitis C patients: the TT4 randomized trial.

BACKGROUND: Rapid and early virological responses to peginterferon-alpha and ribavirin are predictive of sustained virological response (SVR) in hepatitis C virus (HCV) infection. We aimed at finding a simple rule to determine the shortest duration of dual therapy for all HCV genotypes, obtained by multiplying time to Initial Viral Response, IVR (first undetectable HCV-RNA) by 4 (Tailored Therapy-4, or TT4). METHOD: 267 naïve HCV-infected patients with compensated liver disease were randomized (2:1) to the TT4 (n=180) or current standard-of-care (SoC, n=87) and received peginterferon-alpha plus ribavirin. Patients with HCV-RNA decrease ≤2log10 at week 12 or detectable HCV-RNA at week 24 discontinued treatment. RESULTS: Both groups had comparable baseline characteristics, SVR rates were similar in the whole population (60.6% vs. 60.9%) and within each genotype subgroup (G1: 46.6% vs. 55.6%; G2: 90.2% vs. 94.4%; G3: 74.1% vs. 58.3%; G4: 45.8% vs. 33.3%). Relapse rate was higher in G1-TT4 than G1-SoC. Treatment duration in SVR patients was shorter in TT4 compared to SoC, both overall [25±15 vs. 36±12.1 weeks], and for subgroups: G1 [35.3±16.7 vs. 47.3±2.6 weeks], G2 [18.3±7.5 vs. 24±2.8 weeks], G3 [15.2±8.7 vs. 22.8±3 weeks] and G4 [26.9±13 vs. 48 weeks]. CONCLUSIONS: In HCV-naive patients, TT4-rule treatment yields similar SVR rates compared to SoC but with shorter treatment duration and remarkable cost reduction.

Post-herpetic neuralgia.

BACKGROUND: In spite of the large body of evidence available in the literature, definition and treatment of Post-Herpetic Neuralgia (PHN) are still lacking a consistent and universally recognized standardization. Furthermore, many issues concerning diagnosis, prediction and prevention of PHN need to be clarified in view of recent contributions. OBJECTIVES: To assess whether PHN may be better defined, predicted, treated and prevented in light of recent data, and whether available alternative or adjunctive therapies may improve pain relief in treatment recalcitrant PHN. METHODS: Systematic reviews, meta-analyses, randomized controlled trials, cohort studies and protocols were searched; the search sources included PubMed, Cochrane Library, NICE, and DARE. More than 130 papers were selected and evaluated. RESULTS: Diagnosis of PHN is essentially clinical, but it can be improved by resorting to the many tools available, including some practical and accessible questionnaires. Prediction of PHN can be now much more accurate, taking into consideration a few well validated clinical and anamnestic variables. Treatment of PHN is presently based on a well characterized array of drugs and drug associations, including, among others, tricyclic antidepressants, gabapentinoids, opioids and many topical formulations. It is still unsatisfactory, however, in a substantial proportion of patients, especially those with many comorbidities and intense pain at herpes zoster (HZ) presentation, so that this frequent complication of HZ still strongly impacts on the quality of life of affected patients. CONCLUSION: Further efforts are needed to improve the management of PHN. Potentially relevant interventions may include early antiviral therapy of acute HZ, prevention of HZ by adult vaccination, as well as new therapeutic approaches for patients experiencing PHN.

Tinea incognito Caused by Microsporum gypseum in a Patient with Advanced HIV Infection: A Case Report.

The prevalence and the clinical relevance of dermatophytoses in HIV-infected patients are poorly documented, particularly for those caused by tinea incognito. Here, we report a case of widespread facial tinea incognito occurring in an Italian patient with advanced HIV infection, showing both skin and brain lesions. Second-line treatment with liposomal amphotericin B and cotrimoxazole, administered after a microbiological characterization of the skin scrapings, led to complete clearance of all lesions.

Predictors of pain intensity and persistence in a prospective Italian cohort of patients with herpes zoster: relevance of smoking, trauma and antiviral therapy.

BACKGROUND: Herpes zoster (HZ) is a common disease, characterized by rash-associated localized pain. Its main complication, post-herpetic neuralgia (PHN), is difficult to treat and may last for months to years in the wake of rash resolution. Uncertainties remain as to the knowledge of predictors of HZ-related pain, including the role of antiviral therapy in preventing PHN in ordinary clinical practice. This prospective cohort study was aimed at investigating pain intensity at HZ presentation and its correlates, as well as the incidence of PHN and its predictors. METHODS: Patients diagnosed with HZ were consecutively enrolled by a network of Italian General Practitioners and Hospital Units in the health district of Pescara, Italy, over two years. Uncertain cases were referred for microbiological investigation. Data were collected through electronic case report form (e-CRFs) at enrollment and at 1, 3, 6 and 12 months after enrollment. Pain intensity was coded on a five-degree semi-quantitative scale at each time point. PHN was defined as pain of any intensity during follow-up and quantified using an area-under-the-curve (AUC) method. RESULTS: Four hundred and forty-one patients composed the final sample. Mean age was 58.1 years (SD = 20.4 years); 43.5% of patients were males; 7.9% did not receive prescription of antivirals. Intense/very intense pain at presentation was reported by 25.2% of patients and was significantly associated with female gender, older age, cigarette smoking, trauma and/or surgery at HZ site (logistic regression). PHN was diagnosed in 51.2% of patients at one month and in 30.0% of patients at three months. PHN was significantly associated with pain intensity at presentation, age, smoking, trauma and missed antiviral prescription (generalized estimating equations model). The same factors were also independent predictors of the overall pain burden as described by the AUC method (linear regression). CONCLUSIONS: Smoking, traumas and surgery at the HZ site emerged as new predictors of both HZ-related pain intensity and persistence, opening new perspectives in the prevention of HZ-related pain. An independent line of evidence was provided for the efficacy of antiviral therapy in preventing PHN and reducing total pain burden.

Rapidly progressive and fatal EBV-related encephalitis in a patient with advanced HIV-1 infection at presentation: a case report and review of the literature.

Epstein-Barr virus (EBV) has been associated with primary central nervous system lymphoma and other EBV-related malignancies in HIV infected patients, and detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) has been demonstrated to be a good marker of PCNSL. Conversely, EBV has been rarely associated with encephalitis in HIV patients. Here we describe for the first time the case of an HIV-infected, late presenter Caucasian man, diagnosed with a rapidly progressive diffuse encephalitis at presentation. A very high viral load for EBV was detected in CSF by PCR. The patient died 12 days after the onset of encephalitis in spite of supportive, antiviral and antiretroviral therapy. Our experience would suggest that in profoundly immunosuppressed HIV patients EBV may cause severe encephalitis in the absence of lymphoproliferative disorders.

Rapid prediction of sustained virological response in patients chronically infected with HCV by evaluation of RNA decay 48h after the start of treatment with pegylated interferon and ribavirin.

The combination of pegylated interferons (PEG-IFNs) and ribavirin represents the standard of care for the treatment of chronic HCV-infected patients, yet with a success rate around 50% in genotypes 1 and 4, high costs and side effects. Therefore, early prediction of sustained virological response (SVR) is a relevant issue for HCV-patients. We evaluated the association between SVR and decline of HCV-RNA at 48h in a prospective cohort of 145 HCV-patients treated with PEG-IFNs and ribavirin (males=69.1%; genotypes 1/4=51.0%; HIV-1 coinfected=6.7%). SVR was obtained in 65.5% of patients, while 16.6% experienced relapse and 17.9% no response. The first-phase of HCV-RNA decline clearly differentiated patients with SVR from relapsers and non-responders, independently of genotype (P<0.001). In univariate and multivariate analyses, different infralogaritmic thresholds of HCV-RNA decay at 48h were tested, observing the highest predictive potential at 0.5log: decays above this threshold showed a 76.2% negative predictive value for SVR, whereas decays >0.5log indicated a 6.8 odds ratio (95% C.I.: 2.0-23.2) for SVR after controlling for genotype, baseline viremia, adherence to therapy and HIV coinfection. Decays beyond the 0.5log threshold were also strongly associated with and highly predictive of early virological response (95.0% positive predictive value, P<0.001).

Fatal reactivation of HBV and HDV during a long-lasting interruption of HAART in a patient co-infected with HIV, HCV, HBV and HDV.

Coinfection by the Human Immunodeficiency Virus (HIV) and hepatitis viruses is a frequent condition in drug addicts. In the present study we report on the case of a patient with a history of drug and alcohol abuse who was sequentially infected with HIV, HCV, HBV and HDV. He died of an overwhelming reactivation of HBV and HDV in spite of a recent interferon treatment. HBV and HDV resumed their active replication after over 20 years of complete latency, that is after long-lasting viral undetectability, when the patient deliberately discontinued his last HAART regimen. HBV and HDV reactivated in spite of a relatively preserved immune system and a recent immune stimulatory treatment with pegylated interferon.

Sequential transmission and long-term persistence of an HIV strain partially resistant to protease inhibitors.

Transmission of drug-resistant HIV-1 variants has been increasingly documented. The most commonly observed resistance-associated mutations are thymidine analogue mutations as well as non-nucleoside reverse transcriptase inhibitor mutations. We report on a case of secondary transmission of a protease inhibitor (PI) primary mutation from an infected untreated subject to his sexual partner. Sequences isolated from the 2 patients showed a high level of identity (>99%), both carrying the major IAS PI mutation M46I. The latter mutation persisted in the bloodstream of the female partner 1 year after its first detection.

Rapid and persistent selection of the K103N mutation as a majority quasispecies in a HIV1-patient exposed to efavirenz for three weeks: a case report and review of the literature.

INTRODUCTION: Selection of the K103N mutation is associated with moderately reduced in vitro fitness of HIV. Strains bearing K103N in vivo tend to persist, even in the absence of additional drug pressure, as minority quasispecies, often undetectable in genotyping resistance testing assays, performed at standard conditions. Here, we report on the rapid and long lasting selection of a K103N bearing strain as the dominant quasispecies after very short exposure to efavirenz in vivo. CASE PRESENTATION: A 55-year-old Caucasian man was switched to efavirenz, zidovudine and lamivudine in February 2003, while on viral suppression in his first-line highly active anti-retroviral treatment regimen. One month later, he reported inconsistent adherence and his viremia level was 5700 c/mL. He did not attend further checkups until September 2005, when his viral load was 181,000 c/mL. The patient reported interrupting his medications approximately three weeks after simplification. The genotyping resistance testing assay was performed both on HIV RNA and HIV DNA from plasma, yielding an identical pattern with the isolate presence of the K103N mutation in the prevalent strain. CONCLUSION: Persistence of the K103N mutation as a majority quasispecies may ensue after a very short exposure to efavirenz. Our case would therefore suggest that the presence of the K103N mutation should always be ruled out by genotyping resistance testing assays, even after minimal exposures to efavirenz.