The Framingham Heart Study has been a leader in the development and dissemination of multivariable statistical models to estimate the risk of coronary heart disease. These models quantify the impact of measurable and modifiable risk factors on the development of coronary heart disease and can be used to generate estimates of risk of coronary heart disease over a predetermined period, for example the next 10 years. We developed a system, which we call a points system, for making these complex statistical models useful to practitioners. The system is easy to use, it does not require a calculator or computer and it simplifies the estimation of risk based on complex statistical models. This system represents an effort to make available a tool for clinicians to aid in their decision-making process regarding treatment and to assist them in motivating patients toward healthy behaviours. The system is also readily available to patients who can easily estimate their own coronary heart disease risk and monitor this risk over time.

Likelihood Modelling: Presentation of Multivariate Data for Clinical Use: The Framingham Study Risk Score Functions

Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis - the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota.

Clostridium difficile infection.

Infections with Pseudomonas aeruginosa have become a real concern in hospital-acquired infections, especially in critically ill and immunocompromised patients. The major problem leading to high mortality lies in the appearance of drug-resistant strains. Therefore, a vast number of approaches to develop novel anti-infectives is currently pursued. Diverse strategies range from killing (new antibiotics) to disarming (antivirulence) the pathogen. In this review, selected aspects of P. aeruginosa antimicrobial resistance and infection management will be addressed. Many studies have been performed to evaluate the risk factors for resistance and the potential consequences on mortality and attributable mortality. The review also looks at the mechanisms associated with resistance - P. aeruginosa is a pathogen presenting a large genome, and it can develop a large number of factors associated with antibiotic resistance involving almost all classes of antibiotics. Clinical approaches to patients with bacteremia, ventilator-associated pneumonia, urinary tract infections and skin soft tissue infections are discussed. Antibiotic combinations are reviewed as well as an analysis of pharmacokinetic and pharmacodynamic parameters to optimize P. aeruginosa treatment. Limitations of current therapies, the potential for alternative drugs and new therapeutic options are also discussed.

https://www.drugsincontext.com/wp-content/uploads/2018/05/dic-7-212527.pdf

How to manage Pseudomonas aeruginosa infections.

Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial spectrum of activity of these antibiotics includes multidrug-resistant (MDR) gram-negative bacteria (GNB), including Pseudomonas aeruginosa. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases. However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases. Both ceftolozane/tazobactam and ceftazidime/avibactam are only available as intravenous formulations and are dosed 3 times daily in patients with normal renal function. Clinical trials showed noninferiority to comparators of both agents when used in the treatment of complicated urinary tract infections and complicated intra-abdominal infections (when used with metronidazole). Results from pneumonia studies have not yet been reported. In summary, ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations. After appropriate trials are conducted, they may prove useful in the treatment of MDR GNB infections. Antimicrobial stewardship will be essential to preserve the activity of these agents.

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Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations.

Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the t...

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The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection.

Complicated intra-abdominal infections (cIAIs) are tissue-invasive infections leading to abscess formation or generalized peritonitis. The management of cIAIs involves operative or percutaneous intervention to obtain surgical control of the source. Nonetheless, patients with cIAIs are at risk of sepsis and mortality [1–4].

Empiric antimicrobial therapy with appropriate agents is an important component of treatment [5, 6]. Initial empiric therapy that is not effective against infecting pathogens increases costs, treatment failure, and death [7–10]. Because of this, cIAIs are an important infection category for evaluation of the efficacy of investigational agents.

The well-recognized appearance of antimicrobial resistance among gram-negative bacteria has stimulated the development of novel agents [11], particularly those targeting Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs) [12], which confer resistance to most β-lactam antimicrobial agents [1].

Ceftolozane/tazobactam consists of a novel cephalosporin and an established β-lactamase inhibitor that is being developed to address antimicrobial resistance in serious infections caused by gram-negative pathogens, including cIAI, complicated urinary tract infection/pyelonephritis (cUTI), and ventilated nosocomial pneumonia. In vitro activity of ceftolozane/tazobactam has been confirmed against ESBL-producing Enterobacteriaceae, drug-resistant Pseudomonas aeruginosa [13–16], and some Streptococcus species [17]. The results from a phase 2 study with ceftolozane/tazobactam in combination with metronidazole in cIAI supported further development for this indication [18].

We now report the results from ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections), a large global phase 3 clinical program that evaluated intravenous ceftolozane/tazobactam plus metronidazole vs meropenem for the treatment of hospitalized adult patients with cIAI.

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Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI)

Background. The incidence of Clostridium difficile infection (CDI) has risen dramatically during the last decade. Although patients respond well to medical therapy such as vancomycin, 20%–30% of patients treated suffer a recurrence of CDI. Methods. We developed a simple/practical scoring rule (logistic regression model) for recurrent CDI using data from 2 large phase 3 clinical trials. Seventy-seven baseline CDI factors were classified: demographics, comorbidity, medications, vital signs, laboratory tests, severity, and symptoms. Predictors with the highest discrimination in each class (using receiver operating characteristics curve) were selected. For the final model, stepwise selection was performed. Discrimination, calibration, and internal validation were used to assess the model. Results. The final model with a simple scoring rule was developed. It includes 4 independent risk factors that are readily available when the patient makes initial contact: age (<75 vs ≥75 years), number of unformed bowel movements during previous 24 hours (<10 vs ≥10), serum creatinine leves (<1.2 mg/dL vs ≥1.2 mg/dL) and prior episode of CDI (yes vs no). In addition, the model includes choice of treatment (vancomycin or fidaxomicin). Conclusions. The prediction model for recurrence may be useful for treatment decision. Clinical Trials Registration. NCT00314951 and NCT00468728.

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Sylva H. Collins

Papers

Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI)

Risk Estimation for Recurrent Clostridium Difficile Infection Based on Clinical Factors