Bacteria producing Klebsiella pneumoniae carbapenemases (KPCs) are rapidly emerging as a cause of multidrug-resistant infections worldwide. Bacterial isolates harbouring these enzymes are capable of hydrolysing a broad spectrum of beta-lactams including the penicillins, cephalosporins, carbapenems and monobactam. Detection of isolates harbouring carbapenemases can be inconsistent using automated systems, often requiring subsequent confirmatory tests. Phenotypic methods utilizing boronic acid disc tests have demonstrated promising results and appear practical for use in clinical microbiology laboratories. Treatment of infection caused by KPC bacteria is particularly worrisome as the carbapenems are often agents of the last resort for resistant Gram-negative infections. The optimal treatment of infections caused by KPC bacteria is not well established and clinical outcome data remain sparse. We reviewed the current literature regarding clinical outcomes following KPC infections, with a specific effort to summarize the clinical data available for specific antimicrobial agents. A total of 15 papers involving 55 unique patient cases were reviewed. While the total number of patients is relatively small, some useful insights could still be gathered to guide clinicians in the management of KPC infections. Tigecycline and the aminoglycosides were associated with positive outcomes in the majority of cases. Clinical success rates were low when the polymyxins were used as monotherapy, but were much higher when they were used in combination. Studies examining combination therapy and well-controlled clinical trials are needed to ascertain the optimal treatment of infections caused by KPC bacteria.

Rates of antibiotic resistance in Pseudomonas aeruginosa are increasing worldwide. The multidrug-resistant (MDR) phenotype in P. aeruginosa could be mediated by several mechanisms including multidrug efflux systems, enzyme production, outer membrane protein (porin) loss and target mutations. Currently, no international consensus on the definition of multidrug resistance exists, making direct comparison of the literature difficult. Inappropriate empirical therapy has been associated with increased mortality in P. aeruginosa infections; delays in starting appropriate therapy may contribute to increased length of hospital stay and persistence of infection. In addition, worse clinical outcomes may be associated with MDR infections owing to limited effective antimicrobial options. This article aims to summarize the contemporary literature on patient outcomes following infections caused by drug-resistant P. aeruginosa. The impact of antimicrobial therapy on patient outcomes, mortality and morbidity; and the economic impact of MDR P. aeruginosa infections will be examined. Keywordsantipseudomonal agents; infection; morbidity; mortality; outcomes; resistance; virulence Pseudomonas aeruginosa is an important pathogen frequently implicated in healthcareassociated infections (HAIs), particularly in critically ill or immunocompromised patients [1,2]. It is a versatile pathogen with the ability to cause diverse infection types. Data from the National Nosocomial Infections Surveillance system from 1986-2003 reported P. aeruginosa as the second most common cause of pneumonia (18.1%), the third most common cause of urinary tract infection (16.3%) and the eighth most frequently isolated pathogen from the bloodstream (3.4%) [3]. While the overall proportion of infections caused by P. aeruginosa has remained stable during 1986-2003, the proportion of resistant isolates had alarming increases in 2003 compared with 1998 through 2002 [4]. Rates of resistance to imipenem, quinolones and third-generation cephalosporins increased by 15, 9 and 20%, respectively. Similarly, a national surveillance study of intensive care unit (ICU) patients from 1993 to 2002, reported a significant increase in multidrug-resistant (MDR; defined as resistance to at least three of four agents: imipenem, ceftazidime, ciprofloxacin and tobramycin) P. aeruginosa isolates [5].The true prevalence of MDR P. aeruginosa is not well established, presumably for several reasons: first, there is considerable disagreement within the medical community as to the Broad spectrum antimicrobial resistance in MDR isolates significantly limits effective therapeutic options. Commonly, the agents of last resort for MDR organisms include the aminoglycosides and polymyxins. Recent articles have highlighted that these agents may or may not be as effective as first-line agents, but may also be associated with more significant adverse effects (i.e., nephrotoxicity, ototoxicity and neurotoxicity) [9][10][11][12][13][14][15]. This contributes (at least partially) to our difficult...

c Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel ␤-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time-kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2-producing Klebsiella pneumoniae isolate (KP6339) as well as 3 Pseudomonas aeruginosa isolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations.

Since the introduction of ultrasonography and computerized tomography (CT) scanning, brain abscesses are found more frequently in cases of neonatal meningitis and septicemia, particularly when the offending pathogen is Proteus. Thirty cases of brain abscess in neonates are reported, 27 of which were caused by Proteus species infections. Twenty infants had meningitis and 13 had septicemia. Most of the abscesses were enormous, and multiple abscesses were observed in 17 cases. The frontal region was involved in 22 cases (12 unilaterally and 10 bilaterally). The ventricles were enlarged on the first CT scan in 13 cases. The abscesses were treated by aspiration and antibiotics in 25 cases, and by antibiotics alone in five. A shunt for hydrocephalus was necessary in 14 infants. Four infants died, three from the initial illness and one from a shunt complication. Sixteen children have seizures. Subsequent intelligence quotient (IQ) testing was performed in 22 children: eight (36%) have an IQ at or above 80 and eight have an IQ of less than 60. In the 17 children followed for more than 2 years, the proportion with an IQ at or above 80 fell to 24% (four cases). The absence of initial seizures, sterile cerebrospinal fluid, normal ventricles on CT scans, and early aspiration of the abscess seem to be factors portending a better prognosis in terms of epilepsy and mental sequelae.

In a comparison of duodenoscopes reprocessed by sHLD, dHLD, or HLD/ETO, we found no significant differences between groups for MDRO or bacteria contamination. Enhanced disinfection methods (dHLD or HLD/ETO) did not provide additional protection against contamination. However, insufficient events occurred to assess our primary study end-point. ClinicalTrials.gov no: NCT02611648.

Urinary tract infections (UTIs) are among the most commonly treated bacterial infections. Over the past decade, antimicrobial resistance has become an increasingly common factor in the management of outpatient UTIs. As treatment options for multidrugresistant (MDR) uropathogens are limited, clinicians need to be aware of specific clinical and epidemiological risk factors for these infections. Based on available literature, the activity of fosfomycin and nitrofurantoin remain high for most cases of MDR Escherichia coli UTIs. Trimethoprim-sulfamethoxazole retains clinical efficacy, but resistance rates are increasing internationally. Beta-lactam agents have the highest rates of resistance and lowest rates of clinical success. Fluoroquinolones have high resistance rates among MDR uropathogens and are being strongly discouraged as first-line agents for UTIs. In addition to accounting for local resistance rates, consideration of patient risk factors for resistance and pharmacological principles will help guide optimal empiric treatment of outpatient UTIs.

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