Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: a proof-of-concept study.

OBJECTIVES: Pan-drug-resistant (PDR) Pseudomonas aeruginosa is one of the three top-priority pathogens identified by the WHO, and bacteriophages have been investigated as an alternative therapy. However, knowledge on the pharmacokinetics/pharmacodynamics (PK/PD) of phage therapy is sparse, limiting its clinical applications. This study aimed to evaluate the PK/PD of the antipseudomonal phage øPEV20 in vivo following intravenous administration. METHODS: Healthy Sprague-Dawley rats were given øPEV20 as a single intravenous bolus of ~6, 9 and 11-log10PFU/rat. Arterial blood was sampled over 72 h. At 72 h, the animals were killed and multiple tissues were harvested for biodistribution studies. A PK model was developed using the importance sampling algorithm and deterministic simulations with a PD model were performed. RESULTS: A three-compartment model with non-linear clearance described the exposure of øPEV20 in blood. Model evaluation indicated that the model was robust and parameter estimates were accurate. The median (standard error) values of model-predicted PK parameters for VC, VP1, VP2, Q1, Q2, Vm and Km were 111 mL/rat (8.5%), 128 mL/rat (4.97%), 180 mL/rat (4.59%), 30.4 mL/h/rat (19.2%), 538 mL/h/rat (4.97%), 4.39 × 1010 PFU/h/rat (10.2%) and 1.64 × 107 PFU/mL/rat (3.6%), respectively. The distribution of øPEV20 was not homogeneous; there was preferential accumulation in the liver and spleen. Deterministic simulations with a PD model confirmed the importance of the host immune system in facilitating phage-mediated bacterial elimination. CONCLUSIONS: We developed a robust PK model to describe the disposition of phages in healthy rats. This model may have significant potential in facilitating future preclinical and clinical PK/PD investigations.

Incidence and risk factors for healthcare utilisation among patients discharged on outpatient parenteral antimicrobial therapy.

Outpatient parenteral antimicrobial therapy (OPAT) programmes facilitate hospital discharge, but patients remain at risk of complications and consequent healthcare utilisation (HCU). Here we elucidated the incidence of and risk factors associated with HCU in OPAT patients. This was a retrospective, single-centre, case-control study of adult patients discharged on OPAT. Cases (n = 63) and controls (n = 126) were patients that did or did not utilise the healthcare system within 60 days. Characteristics associated with HCU in bivariate analysis (P ≤ 0.2) were included in a multivariable logistic regression model. Variables were retained in the final model if they were independently (P < 0.05) associated with 60-day HCU. Among all study patients, the mean age was 55 ± 16, 65% were men, and wound infection (22%) and cellulitis (14%) were common diagnoses. The cumulative incidence of 60-day unplanned HCU was 27% with a disproportionately higher incidence in the first 30 days (21%). A statin at discharge (adjusted odds ratios (aOR) 0.23, 95% confidence intervals (CIs) 0.09-0.57), number of prior admissions in past 12 months (aOR 1.48, 95% CIs 1.05-2.10), and a sepsis diagnosis (aOR 4.62, 95% CIs 1.23-17.3) were independently associated with HCU. HCU was most commonly due to non-infection related complications (44%) and worsening primary infection (31%). There are multiple risk factors for HCU in OPAT patients, and formal OPAT clinics may help to risk stratify and target the highest risk groups.

Assessment and modelling of antibacterial combination regimens.

BACKGROUND: The increasing global prevalence of multidrug-resistant bacteria is forcing clinicians to prescribe combination antibiotic regimens to treat serious infections. Currently, the joint activity of a combination is quantified by comparing the observed and expected effects using a reference model. These reference models make different assumptions and interpretations of synergy. They fail to: (i) account for multiple bacterial subpopulations with differing susceptibilities; (ii) quantify or interpret the explicit interaction (synergy/antagonism) mechanisms; and (iii) accommodate spontaneous mutations. AIMS: To develop better study designs, mathematical models, metrics and pharmacodynamic analyses to assist with the identification of highly active combinations that are translatable to the clinical context to address the mounting antibiotic resistance threat. SOURCES: PubMed, references of identified studies and reviews, and personal experience when evidence was lacking. CONTENT: We reviewed metrics and approaches for quantifying the joint activity of the combination. The first example is using experimental data from an in vitro checkerboard synergy panel to develop and illustrate a less model-dependent method for assessing combination regimens. In the second example a pharmacokinetic/pharmacodynamic model was developed using mechanism-based mathematical modelling and monotherapy and combination therapy data obtained from an in vitro hollow fibre infection model evaluating linezolid and rifampin regimens against Mycobacterium tuberculosis. IMPLICATIONS: Mechanism-based mathematical approach provides an excellent platform for describing the time course of effect while taking into account the mechanisms of different antibiotics and differing pathogen susceptibilities. This approach allows for the future integration of 'omics' data describing host-pathogen interactions, that will provide a systems-level understanding of the underlying infectious process, and enable the design of effective combination therapies.

Evaluation of activity and emergence of resistance of Polymyxin B and ZTI-01 (Fosfomycin for Injection) against KPC-Producing Klebsiella pneumoniae

ZTI-01 (fosfomycin for injection) is a broad-spectrum antibiotic with a novel mechanism of action and is currently under development in the United States for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multidrug-resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing Klebsiella pneumoniae and to assess the rate and extent of emergence of resistance to different antibiotic regimens. Two clinical isolates, BRKP26 (MIC of polymyxin B[MICPMB], 0.5 mg/liter; MIC of fosfomycin [MICFOF], 32 mg/liter) and BRKP67 (MICPMB, 8 mg/liter; MICFOF, 32 mg/liter) at an initial inoculum of 107 CFU/ml, were evaluated over 168 h in a hollow-fiber infection model simulating clinically relevant polymyxin B (2.5-mg/kg loading dose as a 2 h-infusion followed by 1.5-mg/kg dose every 12 h [q12h] as a 1-h infusion) and fosfomycin (6 g q6h as a 1-h or 3-h infusion) regimens alone and in combination. Population analysis profiles (PAPs) and MIC testing were performed to assess emergence of resistance...

Post-surgical mediastinitis due to carbapenem-resistant Enterobacteriaceae: Clinical, epidemiological and survival characteristics.

Invasive infections due to carbapenem-resistant Enterobacteriaceae (CRE), including polymyxin-resistant (PR-CRE) strains, are being increasingly reported. However, there is a lack of clinical data for several life-threatening infections. Here we describe a cohort of patients with post-surgical mediastinitis due to CRE, including PR-CRE. This study was a retrospective cohort design at a single cardiology centre. Patients with mediastinitis due to CRE were identified and were investigated for clinically relevant variables. Infecting isolates were studied using molecular techniques. Patients infected with polymyxin-susceptible CRE (PS-CRE) strains were compared with those infected with PR-CRE strains. In total, 33 patients with CRE mediastinitis were studied, including 15 patients (45%) with PR-CRE. The majority (61%) were previously colonised. All infecting isolates carried blaKPC genes. Baseline characteristics of patients with PR-CRE mediastinitis were comparable with those with PS-CRE mediastinitis. Of the patients studied, 70% received at least one agent considered active in vitro and most patients received at least three concomitant antibiotics. Carbapenem plus polymyxin B was the most common antibiotic combination (73%). Over 90% of patients underwent surgical debridement. Overall, in-hospital mortality was 33% and tended to be higher in patients infected with PR-CRE (17% vs. 53%; P=0.06). In conclusion, mediastinitis due to CRE, including PR-CRE, can become a significant challenge in centres with CRE and a high cardiac surgery volume. Despite complex antibiotic treatments and aggressive surgical procedures, these patients have a high mortality, particularly those infected with PR-CRE.

Aplastic anemia and membranous nephropathy induced by intravenous mercury.

Self-injection of mercury can be life-threatening. We report a case of attempted suicide by self-intravenous injection of elemental mercury. The patient suffered from two side effects : membranous nephropathy and aplastic anemia. She was treated and the systemic effects of mercury were reversed after 4 years. The toxicology of mercury, mechanisms of renal and systemic toxicities, and the various therapeutic measures for mercury poisoning are discussed.

Spinal stroke in older people secondary to dural arteriovenous fistula.

A 61-year-old diabetic male developed weakness of both lower limbs while walking, 1 month go. When he was examined in hospital a hour later, it was found that he had total absence of movements in both legs, sensory loss of all modalities till umbilicus and had urinary retention. MRI spine demonstrated an intramedullary longitudinal T2 hyperintensity extending from upper thoracic cord till conus medullaris. A provisional diagnosis of transverse myelitis was made and started on corticosteroids. Partial improvement was noted over a 3 week period, after which he developed urinary infection, hyponatremia and sudden worsening of weakness. Repeat MRI spine with contrast raised the possibility of dural arteriovenous malformation leading to extensive spinal cord infarction, which was confirmed by MR angiogram.

Risk factors for the spread of antibiotic-resistant bacteria.

The emergence of antibiotic resistance is primarily due to excessive and often unnecessary use of antibiotics in humans and animals. Risk factors for the spread of resistant bacteria in hospitals and the community can be summarised as over-crowding, lapses in hygiene or poor infection control practices. Increasing antibiotic resistance in bacteria has been exacerbated by the slow pace in developing newer antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and multiresistant Gram-negative bacteria are spread primarily by direct or indirect person-to-person contact. Independent risk factors for MRSA include the use of broad spectrum antibiotics, the presence of decubitus ulcers and prosthetic devices while those for VRE include prolonged hospitalisation and treatment with glycopeptides or broad spectrum antibiotics. For the spread of resistant Gram-negative bacteria risk factors include urinary catheterisation, excessive use of antibiotics and contamination of humidifiers and nebulisers. The spread of penicillin-resistant pneumococci (PRP) and drug-resistant and multidrug-resistant tuberculosis (MDRTb) is due to airborne transmission. Risk factors for the spread of PRP include overcrowding, tracheostomies and excessive use of penicillins for viral respiratory infections; for MDRTb they include poor compliance, convergence of immunosuppressed patients, delayed diagnosis or treatment, and poor or inadequate ventilation and isolation facilities. Recent developments in the genomic mapping of many bacteria and advances in combinatorial chemistry promise to usher in a new era of antibiotic development. While this may result in our regaining some of the ground lost to resistant bacteria, there will still be a continuing need to minimise the spread of antibiotic resistance through the rational use of antibiotic agents and stringent infection control practice.

Vancomycin-resistant gram-positive cocci: risk factors for faecal carriage.

This case-control study was undertaken to identify the risk factors for the gastrointestinal carriage of vancomycin-resistant, Gram-positive cocci (VRGPC) including vancomycin-resistant enterococci (VRE). Use of oral vancomycin (P = 0.003) or cephalosporins (P = 0.03) and prolonged duration of stay in the hospital (P = 0.02) were found to be the significant risk factors. Other previously suggested risk factors such as location of the patients and presence of central venous or arterial lines were not significantly associated with carriage of VRGPC. Judicious usage of glycopeptides (particularly oral vancomycin) and cephalosporins is likely to be the most effective way to prevent and control the spread of VRGPC and VRE.

Selective medium for screening for vancomycin-resistant enterococci in faeces.

Infections caused by vancomycin-resistant enterococci (VRE) are becoming increasingly prevalent throughout the world. Control measures include detection and isolation of carriers of VRE. A selective medium to detect faecal carriage of VRE is described. The medium has a high productivity ratio (90.4%) for VRE with VanA resistance phenotype, a moderate productivity ratio (79.2%) for VRE with VanB resistance phenotype, and a relatively low productivity ratio (65.5%) for VRE with VanC resistance phenotype. There was no breakthrough of vancomycin-susceptible enterococci. The medium selected the growth of all three types of VRE, which were used to spike faecal specimens. In a limited clinical trial, six faecal specimens of carriers and contacts were screened using the selective medium. Vancomycin-resistant enterococci (Enterococcus faecalis, VanA phenotype) were detected in four of the specimens. In all four specimens the growth of VRE was nearly pure and easily identifiable.

Control of outbreaks of viral diarrhoea in hospitals--a practical approach.

Outbreaks of viral diarrhoea are common in hospitals, particularly in the geriatric and children's wards. Person-to-person spread is the most frequent mode of transmission of infection. Establishment of alerting mechanisms, liaison with laboratories with electron microscopy facilities for making the diagnosis, isolation of patients, use of appropriate disinfectants and maintaining good lines of communication are all important for successful control of these outbreaks.