Extended and Continuous Infusion of Novel Protected ß-Lactam Antibiotics: A Narrative Review.

Consolidated data from pharmacokinetic and pharmacodynamic studies support the administration of ß-lactam antibiotics in prolonged infusion (i.e., extended or continuous) to optimize therapeutic efficacy by increasing the probability of attaining maximal bactericidal activity. This is the longest possible time during which the free drug concentrations are approximately four-fold the minimum inhibitory concentration between dosing intervals. In the context of antimicrobial stewardship strategies, achieving aggressive pharmacokinetic and pharmacodynamic targets is an important tool in the management of multi-drug resistant (MDR) bacterial infections and in the attainment of mutant preventing concentrations. However, prolonged infusion remains an unexploited resource. Novel ß-lactam/ß-lactamase inhibitor (ßL/ßLI) combinations (ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam) have been released in recent years to face the emerging challenge of MDR Gram-negative bacteria. Pre-clinical and real-life evidence has confirmed the promising role of prolonged infusion of these molecules in specific settings and clinical populations. In this narrative review we have summarized available pharmacological and clinical data, future perspectives, and current limitations of prolonged infusion of the novel protected ß-lactams, their application in hospital settings and in the context of outpatient parenteral antimicrobial therapy.

Trichinella britovi outbreak in Piedmont, North-West Italy, 2019-2020: Clinical and epidemiological insights in the one health perspective.

BACKGROUND: Trichinellosis, a foodborne zoonosis due to nematodes of the genus Trichinella, occurs in the form of outbreaks following meat consumption. North Italy has been rarely involved. We report here the most significant wildlife derived trichinellosis outbreak ever registered in the Piedmont region. METHOD: We retrospectively included 96 outpatients referred to our institution (December 20th, 2019-January 15th, 2020) 2020 after consuming raw sausages prepared from a single wild boar hunted in the Susa Valley, 59 km away from Torino, in November 2019. RESULTS: We confirmed 35 cases and found additional 10 probable/suspected cases. Our cohort found that 47% of patients were symptomatic, with a median time from symptoms to presentation at clinic and serology testing of 14 days. Peripheral blood eosinophilia >500/µl and CK alterations were common. Further qualitative and quantitative analysis at the International Trichinella Reference Center c/o ISS, Rome identified T. britovi as the causative agent. CONCLUSIONS: No autochthonous human case has ever been detected in Torino province, and a single wild boar has tested positive for Trichinella since active surveillance was implemented in 2013. This outbreak should raise attention on the preventive role of veterinary surveillance and the need to optimize sampling procedures and targeted health education.

Risk for SARS-CoV-2 Infection in Healthcare Workers, Turin, Italy.

We measured severe acute respiratory syndrome coronavirus 2 spike protein subunits S1/S2 antibodies by using capillary electrophoresis and a chemiluminescence immunoassay for 5,444 active healthcare workers in Italy. Seroprevalence was 6.9% and higher among participants having contact with patients. Seroconversion was not observed in 37/213 previously infected participants.

Presence of Epstein-Barr virus DNA in cerebrospinal fluid is associated with greater HIV RNA and inflammation.

OBJECTIVE: The current study aimed to investigate whether cerebrospinal fluid (CSF) Epstein-Barr virus (EBV) or cytomegalovirus (CMV) DNA was associated with viral, inflammatory and neuronal damage biomarkers in people living with HIV (PLWH). DESIGN: A cross-sectional diagnostic study on CSF fluid samples in patients undergoing lumbar punctures for clinical reasons, to better understand the role of EBV and CMV in the CNS on HIV RNA replication, blood-brain-barrier (BBB) damage and biomarkers of neuronal damage/inflammation. METHODS: EBV, CMV DNA and HIV RNA were measured on CSF, through real time (RT)-PCR, from PLWHs undergoing lumbar punctures for clinical reasons (excluding oncho-haematological comorbidities). Immune-enzymatic assays evaluated blood-brain barrier inflammation and damage. Patients were stratified according to plasma HIV RNA levels in viremic (≥50 copies/ml) and aviremic (<50 copies/ml). RESULTS: We included 297 participants. Among 167 viremic patients CSF EBV and CMV DNA were detectable in 42 (25.1%) and 10 (6.3%) participants; among 130 aviremic individuals CSF EBV and CMV DNA were detectable in 12 (9.2%) and 0 (0%) participants, respectively. In viremic group detectable CSF EBV DNA was associated with CSF pleocytosis (P < 0.001), higher CSF HIV RNA (P < 0.001) and neopterin levels (P = 0.002). In aviremic participants detectable EBV DNA was associated with pleocytosis (P = 0.056), higher neopterin (P = 0.027) and immune globulins (P = 0.016) in the CSF; CSF escape was more common in those with detectable EBV DNA (50 vs. 21.2%, P = 0.036). CONCLUSION: EBV DNA was frequently detected in the CSF of viremic and fewer aviremic patients on antiretroviral treatment. In PLWH without clinical evidence of encephalitis CSF EBV DNA was associated with higher biomarkers levels of neuronal damage/inflammation. The role of EBV reactivation in HIV-associated central nervous system disorders warrants further studies.

Cerebrospinal fluid biomarkers in patients with central nervous system infections: a retrospective study.

BACKGROUND: Central nervous system (CNS) may be infected by several agents, resulting in different presentations and outcomes. Analysis of cerebrospinal fluid (CSF) markers could be helpful to differentiate specific conditions and setting an appropriate therapy. METHODS: Patients presenting with signs and symptoms were enrolled if, before receiving a diagnostic lumbar puncture, signed a written informed consent. We analyzed CSF indexes of blood-brain barrier permeability (CSF to serum albumin ratio or CSAR), inflammation (CSF to serum IgG ratio, neopterin), amyloid deposition (1-42 ß-amyloid), neuronal damage (Total tau (T-tau), Phosphorylated tau (P-tau), and 14.3.3 protein) and astrocyte damage (S-100ß). RESULTS: Two hundred and eighty-one patients were included: they were mainly affected by herpesvirus encephalitis, enterovirus meningoencephalitis, bacterial meningitis (Neisseria meningitidis and Streptococcus pneumoniae), and infection by other etiological agents or unknown pathogen. Their CSF features were compared with HIV-negative patients and native HIV-positive individuals without CNS involvement. 14.3.3 protein was found in bacterial and HSV infections while T-tau and neopterin were abnormally high in the herpesvirus group. P-tau, instead, was elevated in enterovirus meningitis. S-100ß was found to be high in patients with HSV-1 and HSV-2 infections but not in those with Varicella Zoster Virus (VZV). Thirty-day mortality was unexpectedly low (2.7%): patients who died had higher levels of T-tau and, significantly, lower levels of Aß1-42. CONCLUSION: This work demonstrates that CSF biomarkers of neuronal damage or inflammation may vary during CNS infections according to different causative agents. The prognostic value of these biomarkers needs to be assessed in prospective studies.

Laboratory findings in Zika infection: The experience of a reference centre in North-West Italy.

BACKGROUND: Zika virus (ZIKV) remains a public health concern due to its association with fetal malformation and neurologic disease. OBJECTIVE: To report a reference centre experience on ZIKA virus (ZIKV) infection in travelers from epidemic countries from January 1 to September, 30, 2016 in Italy North-West (a geographic area covering 4.424 million inhabitants, corresponding to almost 73% of Italy North-West area). STUDY DESIGN: One hundred and twelve febrile travelers were studied to rule out a tropical fever [e.g. malaria, dengue (DENV), chikungunya (CHIKV), West Nile (WNV) and ZIKV]. Molecular tests for detecting ZIKV RNA were applied on serum or urine as well as IgG and IgM specific serology. RESULTS: ZIKV was the most frequent "tropical infection (11.6%) with 12 infected travelers and one sexual partner of an infected traveler. At the time of the diagnosis, ZIKV RNA was detected in the blood from 9 patients (69%) within 7 days from symptom onset; afterwards, the virus was detected only in urine (5 patients) and ZIKV IgM was reactive in 9 patients (69%). Travelers with ZIKV infection tested negative for DENV, CHIKV, WNV and malaria and completely recovered. Other infections identified in travelers were DENV (5 patients, 4.5%), CHIKV (1, 0.9%), malaria (Plasmodium vivax, 1, 0.9%), measles (1, 0.9%) and tuberculosis (1, 0.9%). CONCLUSIONS: The etiologic diagnosis of a febrile illness in travelers where ZIKV is endemic is highly desirable as they are sentinel of a challenging epidemiology including the risk of autochthonous transmission in non endemic countries where the competent or carrier vector is present.

High Incidence of Infections in HIV-positive Patients Treated for Lymphoproliferative Disorders.

BACKGROUND: Lymphoproliferative disorders are frequently diagnosed in HIV-positive patients and severe infections may occur during antineoplastic treatments: the incidence and impact of such events are not well-characterized. OBJECTIVE: To describe the occurrence and mortality of incident infections in HIV-positive individuals treated for lymphoproliferative disorders. METHODS: A retrospective study in HIV-positive adults with lymphoproliferative disorders (2000- 2012) who were hospitalised to receive antineoplastic chemotherapy; antimicrobial prophylaxis with alternate day co-trimoxazole (800/160 mg) was administered to all individuals. RESULTS: 103 patients were included: mostly males (81, 78.6%), Caucasians (101, 98.1%), with a median age of 43 years (39-51). Fifty-eight (56.3%) patients had non-Hodgkin's lymphoma (NHL), thirty-two (29.1%) had Hodgkin's lymphoma (HL) and ten patients (9.7%) had Burkitt's lymphoma (BL). Five year survival was 63.1%: the best survival rates were reported in HL (78.1%), followed by NHL (58.6%) and BL (50%). Forty-four patients (42.7%) developed 82 infections during follow up: identified causative agents were bacteria (35, 42.7%), viruses (28, 34.1%), mycobacteria (7, 8.5%), protozoa (7, 8.5%) and fungi (5, 6.1%). Cytomegalovirus infections (n=17, including 5 endorgan diseases) emerged 53 days after the diagnosis: multivariate analysis showed CD4+ cell count <100/uL as the only independently associated factor (p<0.001, aOR=23.5). Two factors were associated with mortality risk: an IPI/IPS-score of >2 (p=0.004, aOR=6.55) and the presence of CMV disease (p=0.032, aOR=2.73). CONCLUSION: HIV positive patients receiving treatment for lymphoproliferative disorders suffer from a high incidence of infections and associated mortality risk. Tailored prophylactic strategies need to be considered in this setting.

Louseborne Relapsing Fever among East African Refugees, Italy, 2015.

During June 9-September 30, 2015, five cases of louseborne relapsing fever were identified in Turin, Italy. All 5 cases were in young refugees from Somalia, 2 of whom had lived in Italy since 2011. Our report seems to confirm the possibility of local transmission of louse-borne relapsing fever.

Recent outbreak of aseptic meningitis in Italy due to Echovirus 30 and phylogenetic relationship with other European circulating strains.

BACKGROUND: Enteroviruses (EVs) are common human viral pathogens, causing a variety of diseases, including aseptic meningitis. Recently, EV aseptic meningitis outbreaks have been reported across Europe, but, in Italy, knowledge of recent EV molecular epidemiology is very limited. OBJECTIVES: We report an outbreak of EV aseptic meningitis in 10 adults in North-Western Italy, from October to November 2012. Patients were parents or close relatives of children <5 years old attending the same class of a nursery school, suffering from a mild febrile upper respiratory disease. Phylogenetic relationship with other European circulating strains was analyzed updating E30 circulation in Italy in recent years. STUDY DESIGN: EVs were detected from cerebrospinal fluid (CSF) specimens with a real-time reverse transcription polymerase chain reaction and virus isolation was achieved from rectal and pharyngeal swabs. For cluster definition and phylogenetic studies, viral VP1 region was directly amplified and sequenced from CSF. RESULTS: EVs were identified in CSF from all patients and from rectal and pharyngeal swabs in 7 of them. Direct sequencing of CSF revealed the presence of the same Echovirus 30 (E30) in all patients and phylogenetic analysis identified it as a diverging clade within E30 genotype VII, the most recent strain circulating in UK, Finland and Denmark since 2006. CONCLUSION: Molecular techniques allowed the rapid identification and typing of E30 from CSF. Phylogenetic analysis revealed that the cluster might be due to a new E30 variant within the genotype VII currently circulating in Europe, thus updating the epidemiology of EV circulation in Italy.

Diagnosis of dengue fever in North West Italy in travelers from endemic areas: a retrospective study.

BACKGROUND: Domestic outbreaks of Dengue (DENV) fever from imported cases have to be considered a possible risk in non-endemic countries where Dengue vectors are present, such as in Italy. OBJECTIVE: To review imported acute/recent DENV infections in a one-year survey in a North West Italy region where the presence of Aedes albopictus is documented. STUDY DESIGN: We retrospectively reviewed laboratory and clinical records of Italian febrile travelers from Dengue endemic areas referring to the local reference Centre for Infectious Disease, covering a population of about 4 million people. RESULTS: Acute/recent DENV infection was identified in 15 out of 91 travelers from endemic areas (16.5%) including 12 primary and 3 secondary infections; in 6 patients the virus was detectable in blood according to molecular real-time Polymerase Chain Reaction-based assays: in 9 patients the diagnosis of DENV infection was accomplished by the combination of specific IgM reactivity, high IgG titers, IgG seroconversion from negative to positive and increasing (four-fold) IgG titers in paired serum samples. Two cases of DENV infections were imported from South Egypt in patients travelling together, confirming the importance of returning travelers as sentinels of a rapidly changing epidemiology in specific geographic areas. CONCLUSIONS: Our findings outline the high rate of imported Dengue infection in North West Italy and emphasize the need for a continued Dengue surveillance in non-endemic countries as well as a careful evaluation and follow-up of febrile patients returning from Dengue endemic countries.

Echovirus-4 meningitis outbreak imported from India.

We describe seven cases of meningitis in a group of young Italian travelers coming back from India. Virologic studies identified echovirus-4 as the cause of this cluster of cases, the first imported echovirus outbreak in Italy. Enteroviruses may play an important role in undiagnosed fevers in travelers.

[Primary soft tissue and tenosynovial tuberculosis after needlestick injury in a surgeon]. / Tubercolosi primaria tenosinoviale e dei tessuti molli da inoculazione in un chirurgo.

We describe the case of a surgeon, who pricked himself with a needle used to drain a paravertebral abscess in a patient from Sudan. He lost this patient at follow up. Six weeks later, the surgeon developed oedema of his left hand and wrist. He started antibiotics, amoxicillin/clavulanate plus ciprofloxacin 2 weeks, without any improvement. He came to our centre for examination, and by chance his patient had been admitted to our ward the day before, and had died during the night of disseminated tuberculosis. The surgeon was treated with rifampin, isoniazid and pyrazinamide (3 drugs 2 months, followed by rifampin plus isoniazid for further 7 months) with rapid improvement. He could start his job again after 5 months. To our knowledge, this is the first case of inoculation tuberculosis transmitted to a surgeon, while other cases in health care workers (internists, pathologists, nurses...) have already been well described.

Klebsiella pneumoniae meningitis in a 38-year-old Chinese traveller with impaired glucose tolerance: a new emerging syndrome?

Early diagnosis and appropriate empirical treatment of bacterial meningitis reduce morbidity and mortality. Prevalence rates of different causative pathogens associated with bacterial meningitis can depend on age, the underlying medical condition, way of infection and geographical distribution. Klebsiella pneumoniae represents an infrequent cause of community-acquired meningitis in South-East Asia and North-East Asia, where it accounts for 20% of all bacterial meningitis, frequently associated with septic metastatic complications. We describe a case of K. pneumoniae meningitis, diplopia and chemosis in a recently immigrated patient with impaired glucose tolerance. The reason for the high prevalence of metastatic septic infections caused by K. pneumoniae in Taiwan and South-East Asia remains unclear: high prevalence in this area of serotype K1 and K2 and the expression of a novel locus called magA conferring to bacterium an elevated phagocytosis resistance and an active proliferation ability have been suggested. A high degree of suspicion for this etiology must be taken into account in immigrants from China and Taiwan. Due to a very high lethality, guidelines on empiric treatment should be considered in the management of bacterial meningitis, with the patients geographical origin and the clinical syndrome (meningitis and endophtalmitis) as potential risk factors for K. pneumoniae infection.

Infective endocarditis in drug addicts: role of HIV infection and the diagnostic accuracy of Duke criteria.

BACKGROUND: Intravenous drug users (IVDUs) are at increased risk of infective endocarditis. Moreover, HIV infection is common in IVDUs, with a reported prevalence of 40-90%. The clinical features of IVDUs with infective endocarditis and HIV infection may be peculiar. Few data have been reported on the diagnostic accuracy of Duke criteria in IVDUs with or without HIV infection, and a comparison of these two populations is lacking. METHODS: The present study aimed to compare prospectively the clinical features of patients with infective endocarditis with or without HIV infection and to evaluate the diagnostic accuracy of Duke criteria in these patients. The study population consisted of 201 consecutive adult IVDUs with a suspected infective endocarditis (102 patients with HIV infection and 99 patients without HIV infection). RESULTS: Infective endocarditis was the final diagnosis in 40 of 102 patients (38.2%) with HIV infection and in 55 of 99 HIV-negative patients (55.6%). Despite similar baseline features, longer vegetations were recorded in infective endocarditis without HIV infection (23.7 +/- 7.1 mm versus 13.6 +/- 6.8 mm; P = 0.001). Patients with infective endocarditis and HIV infection had a higher total mortality at 2 months (respectively 12.5% versus 1.8%; P = 0.09); almost all the deaths were recorded in patients with AIDS or a CD4 cell count below 200 per microl, and no deaths were recorded in patients with HIV infection and a CD4 cell count > 500 per microl. CONCLUSIONS: Despite no identical clinical features, Duke criteria had a similar sensitivity, specificity and diagnostic accuracy in IVDUs with and without HIV infection.