mately 60% to 90% (2–5). This is in contrast to studies showing inferior outcomes with PTZ use where the minority (roughly 15% to 30%) of bloodstream infections were from low-inoculum sources (13, 14). It seems intuitive that, for infections where relieving an obstruction is arguably the most important component of infection management (i.e., biliary sources) or sites where antibiotic concentrations are expected to be particularly high (i.e., urine), antibiotic therapy may not need to be as “aggressive.” These sites of infection are likely more amenable to pathogen eradication than pneumonia, intra- abdominal collections, deep wound infections, or endovascular infections. Second, ⱕ 15% of patients in ESBL-GNR bloodstream studies supporting PTZ use were critically ill (2–5), whereas one-third to over half of patients in studies suggesting suboptimal outcomes with PTZ required intensive care unit (ICU) care (13, 14). Furthermore, studies favoring PTZ generally included isolates with relatively low piperacillin MICs ( ⬃ 2 g/ml) (2–5). In contrast, the median piperacillin MICs approached susceptibility breakpoints in studies indicating inferior outcomes with PTZ (13, 14).
Our research has several limitations. The first is that it is a retrospective study where none of the authors were able to prospectively follow patient treatment and out- come. However, of the nearly 80 patients assessed, most had non-UTI infections and those with UTI nearly all (6 of 7) experienced complicated infections (renal function impairment), which limits concentration of β-lactam agents in the urinary collecting system. The majority of infec- tions were from the respiratory tract and even when di- rectly caring for a patient it can be challenging to know if the isolation of P. aeruginosa from respiratory secre- tions represents infection or colonization. However, the patients were all treated for pneumonia by their primary physician. From the perspective of our patients, 30 of the 42 patients (71%) who responded were cared for in the ICU as were 7 of 9 (78%) who failed therapy, indicating a high level of seriously ill persons. All were considered likely enough to have pneumonia from P. aeruginosa to be treated for this disease. Also, in this type of analysis, it is possible that the results from one enrollment site can dominate those from the other reporting centers. We do not believe this was the case in this report as 53% of cases were derived from one site, 30% from the second site, and 17% from the third. The distribution of infections, suc- cessful (or partially successful) outcome, and failures were not different between the three sites submitting cases. Our investigation found a relatively small number of evaluable patients (78) to determine our conclusions. However, this is the only study to date that has investi- gated the role of in vitro susceptibility plus actual drug exposure compared to clinical outcome of P. aeruginosa infection treated with piperacillin-tazobactam. The fact that the majority of cases (55%) received monotherapy further strengthens our findings. Also, we did not collect information on serum albumin concentrations that can affect drug protein binding and distribution of free piper- acillin. However, at the low level of piperacillin binding to serum albumin the impact is practically minimal since free drug equilibrates between the intravascular and ex- travascular free body water. Because the free water ex- travascular space is nearly 10-fold that of the intravascu- lar water, raising a given drug’s binding to serum proteins from 0% to 90% reduces the concentration of free drug in serum and tissue by only one-half . Finally, our meas- urements reflect both the initial dosing as well as more drug exposure that occurred as treatment time lengthened. Importantly, this does not negate our findings of what is needed for starting therapy with piperacillin-tazobactam are the pharmacodynamic parameters that predict success or failure based on treatment with this agent.
To preserve and extend the utility of ␤ -lactams, some have been used in combina- tion with ␤ -lactmase inhibitors. For example, amoxicillin, ampicillin, and piperacillin are used in combination with the ␤ -lactamase inhibitors clavulanate, sulbactam, and tazobactam, respectively. These classical inhibitors render most organisms that express class A serine ␤ -lactamases susceptible to ␤ -lactams, excluding a few enzymes that are inhibitor resistant, such as Klebsiella pneumoniae carbapenemases (KPCs) (1). However, intensive use of ␤ -lactamase inhibitors has caused the emergence of inhibitor-resistant variants within the TEM and SHV ␤ -lactamase families. In addition, overexpression of inhibitor-sensitive enzymes, such as Bla TEM-1 , has led to clavulanate, sulbactam, and/or
12 Read more
and the incidence of KDIGO events are greater in the pediatric patient population, while differences between the drug groups appear less pronounced. Several factors may contribute to this effect: children were exposed to higher doses of vancomycin, piperacillin, and imipenem when normalized to body weight, which may have caused in- creased renal damage in itself; the significantly greater severity of injury and associated systemic critical illness, as well as dilution effects of creatinine due to the more aggressive resuscitation measures taken in this group, may have obscured the differences in creatinine in- creases. Notwithstanding these potentially confounding variables, the relationship between administration of vanco- mycin/piperacillin and creatinine increase remains signifi- cant and robust, indicating that the observed effect is not exclusive to adults.
10 Read more
17. Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, Alenazi TH, Arabi Y, Falcone M, Bassetti M, Righi E, Rogers BA, Kanj S, Bhally H, Iredell J, Mendelson M, Boyles TH, Looke D, Miyakis S, Walls G, Al Khamis M, Zikri A, Crowe A, Ingram P, Daneman N, Grifﬁn P, Athan E, Lorenc P, Baker P, Roberts L, Beatson SA, Peleg AY, Harris-Brown T, Paterson DL, for the MERINO Trial Investigators and the Australasian Society for Infec- tious Disease Clinical Research Network (ASID-CRN). 2018. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriax- one resistance: a randomized clinical trial. JAMA 320:984 –994. https:// doi.org/10.1001/jama.2018.12163.
Piperacillin is hydrolyzed by plasmid-mediated ␤ -lactamases of gram-positive and gram-negative bacteria as well as by Bush group 1 chromosomal ␤ -lactamases of gram-negative bacteria (AmpC) (2). Tazobactam inhibits most ␤ -lactamases produced by Escherichia coli, Klebsiella species, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, and Citro- bacter koseri but not isolates of Enterobacter species, Serratia species, Citrobacter freundii, and Pseudomonas aeruginosa ex- pressing stably derepressed AmpC ␤ -lactamases (2, 12). Pip- eracillin-tazobactam demonstrates in vitro activity against isolates of Enterobacteriaceae harboring TEM or SHV ␤ -lac- tamases and their derivatives, extended-spectrum ␤ -lactamases (2, 9, 12). Piperacillin (15, 16) and tazobactam (4, 8, 9, 11, 12, 20) do not induce chromosomal AmpC ␤ -lactamases at clini- cally relevant concentrations; piperacillin is also a poor selec- tor for stably derepressed mutants (6, 11).
Although the present evidence suggests ertapenem had similar efficacy and safety profile with piperacillin/tazo- bactam in the treatment of complicated infections such as cIAIs, APIs and cSSSIs, several unique characteristics make it as an alternative to piperacillin/tazobactam. Firstly, ertapenem may mitigate the emergence of resistant strains. Previous studies indicated that there were fewer instances of emergence of resistant Enterobacteriaceae and extended-spectrum β-lactamase producing Entero- bacteriaceae in the colonizing bowel flora of ertapenem- treated patients with cIAIs than receiving piperacillin/ tazobactam or ceftriaxone plus metronidazole, and there were no differences between groups in the prevalence of imipenem-resistant Pseudomonas in the colonizing bowel flora after completion of therapy [30,31]. This may be attributed to the limited development of microbial resist- ance to carbapenems and the targeted spectrum of ertap- enem . Secondly, once-daily dosing of ertapenem may offer benefits compared with agents that require multiple dosing or combination therapy, including patient conven- ience and comfort, and a lower risk of medication errors . Thirdly, compared with piperacillin/tazobactam given four times daily i.v., ertapenem given once daily i.v. was associated with lower drug and supply costs and less time and labor devoted to the preparation and adminis- tration of i.v. therapy.
11 Read more
Risk factors of vancomycin-associated nephrotoxicity have been extensively studied. Higher vancomycin daily dosage, longer duration of therapy, and elevated plasma concentrations of vancomycin are widely known predis- posing factors. 4 – 7 The most recent guidelines recom- mended that clinicians should monitor vancomycin nephrotoxicity by calculating the AUC/MIC ratio. 8 Some other conditions have also been proposed as risk factors, like renal dysfunction, admission to ICU and concomitant nephrotoxic agents. 6 For instance, ICU residence increased the incidence of AKI from 9.3% to 13.3%. 6,9 Concurrent piperacillin/tazobactam signi ﬁ cantly added the risk of AKI with a hazard ratio of 4.27. 10
12 Read more
Methods/Design: The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.
The isolates were tested for susceptibility to ceftazi- dime (30 µg), imipenem (10 µg) piperacillin–tazobactam (30 µg), amoxicillin–clavulanic acid (30 µg), tetracycline, TMP–SMX (1.25/23.75 µg), gentamicin (10 µg) and ami- kacin (30 µg) by disc diffusion technique . Briefly, a 0.5 McFarland suspension of each bacterial isolate was made in normal saline and inoculated onto Mueller–Hin- ton agar (Oxoid Ltd, UK) to prepare a uniform lawn. The disks were applied at a specific distance from each other and the zone of inhibition around the antibiotic disc was
CLSI: Clinical and Laboratory Standards Institute; cUTI: Complicated urinary tract infection; ESBL: Extended-spectrum β -lactamase; GDP: Gross Domestic Product; HCUP: Healthcare Cost and Utilization Project; IAAT: Initial appropriate antibiotic therapy; ICD-9: International Classification of Diseases, Ninth Edition; ICER: Incremental cost-effectivness ratio; IIAT: Initial inappropriate antibiotic therapy; LOS: Length of stay; NMB: Net monetary benefit; OWSA: One-way sensitivity analyses; PACTS: Program to Assess Ceftolozane/Tazobactam Susceptibility; PSA: Probabilistic sensitivity analysis; QALYs: Quality-adjusted life years; US: United States
10 Read more
The development of resistance to antimicrobial agents has been an ongoing and evolving process since antibiotics were introduced a half-century ago. Antimicrobial-resist- ant pathogens are becoming a prevalent cause of hospital- acquired infections, particularly in intensive care units (ICU) . Members of the family Enterobacteriaceae are the most frequent organisms isolated in clinical microbio- logical laboratories. Escherichia coli is responsible of both community and nosocomial infection. It is frequently involved in sepsis in critically ill patients . It is becom- ing increasingly resistant to commonly used antibiotics such as fluoroquinolones or amoxicillin-clavulanic acid . The widespread presence of resistant bacteria in ICU has led to the common practice of using broad-spectrum antimicrobial coverage in case of suspected gram-negative sepsis. Piperacillin/tazobactam is an injectable antibiotic mixture consisting of the semisynthetic antibiotic pipera- cillin-sodium (PIP) and the betalactamase inhibitor tazo- bactam-sodium (TAZ). PIP-TAZ antimicrobial spectrum includes both Gram-positive cocci and Gram-negative bacilli, especially enterobacteriaceae and Pseudomonas aer- uginosa. Clinical use of PIP-TAZ is wide, especially in ICU. It is notably proposed for the treatment of severe intra- abdominal infections, febrile neutropenic patients at high risk, late-onset ventilator-associated pneumonia [4-6]. Recent reports pointed out the increase in the prevalence of PIP-TAZ resistant strains of E. coli isolated from clinical relevant specimens in ICU [7,8]. Data regarding the impact of antimicrobial-resistant pathogens on clinical outcome demonstrated deleterious effects with higher length of stay and mortality rate [9,10]. This impact was demonstrated in case of infections due to various patho- gens including E. coli. Previous studies focusing on the impact of E. coli resistance concerned essentially ESBL- producing strains and more recently resistance to fluoro- quinolones [11,12]. We conducted a retrospective cohort study to specially investigate the incidence of PIP-TAZ resistance and its impact on clinical outcome of infections with E. coli in critically ill patients.
Methods: A retrospective cohort study including all adult patients discharged from hospital with a diagnosis of IAI between 1st of January and 31st of October, 2016. All variables potentially associated with pre-defined outcomes: infection by a pathogen sensitive to non-pseudomonal cephalosporin or ciprofloxacin plus metronidazole (ATB 1, primary outcome), sensitive to piperacillin-tazobactam (ATB 2) and hospital mortality (secondary outcomes) were studied through logistic regression. Accuracy of the models was assessed by area under receiver operating characteristics (AUROC) curve and calibration was tested using the Hosmer-Lemeshow goodness-of-fit test.
consumed; the quantitative interaction is achieved within a time of more than 1 min (observation time). The method on initial rates (tangent method) was used to collect kinetic data (usually at 280 nm) by following the appearance product of perhydrolysis reaction of Piperacillin. A solution of sodium hydroxide was thermostated in the cell compartment, and then mixtures of solutions of Piperacillin / Tazobactam with solutions Caro’s acid (time incubation of 1 min) were added to the cell. The resulting solution was mixed thoroughly and put into the spectrophotometer. The precision of rate determination was usually ± 1-3%. The results were obtained by the recommended procedure for seven replicate titrations of mixtures containing the three species at various concentrations. RSD = 1.4%. The obtained results have good agreement with the Parmacopoeia one δ = 1.0%.
Several studies suggested that ESBL-PE were susceptible to non-carbapenem beta-lactams. However, the preva- lence of susceptibility depends on the species concerned, the antibiotic class and local epidemiology. ESBL-pro- ducing E. coli is usually regarded as more susceptible to all beta-lactams than ESBL-producing K. pneumo- niae, piperacillin–tazobactam (Pip–Taz) being the most effective antibiotic . North American data from the 2010–2014 SMART programs find that 4, 10 and 46% of ESBL-producing E. coli were susceptible to ceftriax- one, cefepime and ceftazidime, respectively , whereas 96–98 and 69% of ESBL-producing E. coli isolates from urinary tract  and from patients with pneumonia  were found susceptible in vitro to Pip–Taz, respectively. Conversely, only 26.9% of ESBL-producing Klebsiella spp. isolates from patients with pneumonia were suscep- tible to Pip–Taz . Asian data on ESBL-producing E. coli find similar susceptibilities, with 1.6, 9.5, 33.4 and 84.5% isolates susceptible to cefotaxime, cefepime, cef- tazidime and Pip–Taz, respectively . It is noteworthy that in silico PK/PD studies aiming to evaluate the use of alternatives to carbapenems for treatment of ESBL-PE infections suggest that ESBL-Kp susceptibility is over- estimated by conventional methods in comparison with E-test susceptibility testing.
17 Read more
To tackle this alarming situation pertaining to the antibiotic resistance due to improper prescription of antibiotics, there is a desperate need of conducting surveillance study in hospitals. Thus in view of these aspects, the present work was aimed to study the susceptibility pattern of nosocomial gram negative microbes towards meropenem, piperacillin+tazobactam, amikacin and ceftriaxone+sulbactam+EDTA (Elores) in Fortis Memorial Research Institute, Gurgaon, India. This study will bring into focus the efficiency of drugs which are routinely used to treat the infections caused by MDR strains in Fortis hospitals.
Results: During this period, 610 prescriptions were ordered for 596 patients. The main indication for initiation of Tazocin was sepsis (207/610; 34%). The overall rate of appropriateness of empirical therapy was 348/610 (57%). Most of the inappropriate prescriptions were in cases of aspiration pneumonia and abdominal infections, with inappropriate prescriptions found mostly in surgical wards (86%) and the surgical intensive care unit (66.7%). Septic work-up results showed positive cultures in 57% (345/610) of cases. There were 198/254 prescriptions (78%) where antibiotics were changed according to the sensitivity data to narrow-spectrum antimicrobials. In 56/254 (22%) cases, pathogens were susceptible to narrow-spectrum antibiotics even though piperacillin/tazobactam was continued.
The choice of piperacillin/tazobactam was determined by review of our local Antibiogram, and consultation with local infectious disease specialist prior to proceeding. Over the preceding 2 years all patients admitted to our local hos- pitals with febrile infections after PUS/Bx were started on piperacillin/tazobactam while urine and blood culture results were pending. From review of all our local antibiogram, imipenem, 99%, and piperacillin/tazobactam provided the highest coverage for E. coli, 98%. There is a theoretical poten- tial benefit of ceftriaxone with a longer half-life compared with piperacillin/tazobactam. Of the ten group 1 patients who developed serious infections after prostate ultrasound and biopsy we noticed that three had E. coli resistant to cef- triaxone. For this reason, we choose iv infusion, rather than im injection, to reliably achieve peak plasma concentrations immediately prior to performing PUS/Bx. Our hypothesis was that many of the serious infectious complications occur- ring after prostate ultrasound and biopsy results from the iv access of bacteria to the bloodstream at the time of biopsy. This was our rationale for iv infusion of piperacillin/tazobac- tam rather than im to reliably achieve peak serum levels at the time of prostate ultrasound and biopsy.
aspirates were brown. Her coagulation param- eters did not respond to targeted therapy. Fresh frozen plasma transfusion, etamsylate and vitamin K1 injection were initiated and contin- ued for three days. On the third day, blood and sputum cultures revealed P. aeruginosa sensi- tive to piperacillin, ceftazidime, cefoperazone/ sulbactam and meropenem. Based on the sus- ceptibility test results, treatment with vancomy- cin was discontinued and cefoperazone/sul- bactam treatment was continued as definitive therapy. On the fourth day, bloody frothy spu- tum decreased. BNP and PCT declined signifi- cantly. Investigations of PCT, CRP and white blood cell (WBC) in the following days are shown in Table 2.
Abstract: Doripenem is the latest carbapenem on the market to date. Although not an antibiotic in a new class, it offers a glimmer of hope in combating serious infections secondary to multidrug-resistant Gram-negative bacteria when we have not seen a new class of antibacterial, particularly for Gram-negative bacteria, for more than 10 years. In vitro, doripenem exhibits a broad spectrum of activity against Gram-positive and Gram-negative bacteria, including extended-spectrum β-lactamase (ESBL) and Amp-C β-lactamase producing Enterobacteriaceae and anaerobes. Doripenem also exhibits better in vitro activity against Pseudomonas aeruginosa compared to other anti-pseudomonal carbapenems. It combines the desirable activities of both imipenem and meropenem. It has similar activity to imipenem against Gram-positive pathogens and has the antimicrobial spectrum of meropenem against Gram-negative organisms. Several randomized clinical trials have demonstrated that doripenem is non-inferior to meropenem, imipenem, piperacillin/tazobactam, or levofloxacin in its efficacy and safety profile in treating a wide range of serious bacterial infections including intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia. Due to its wide spectrum of activity and good safety profile it is susceptible to misuse leading to increasing rates of resistance. Judicious use should be considered when using doripenem as a first-line agent or drug of choice for serious infections. Doripenem is a well-tolerated drug with common adverse effects includ- ing headache, nausea and diarrhea. Caution should be used in patients with hypersensitivity to carbapenems and adverse reactions to β-lactam agents. Dosage adjustment is needed for patients with renal impairment. Doripenem has demonstrated economic and clinical benefits. It has been shown to reduce hospital length of stay and duration of mechanical ventilation for intensive care unit (ICU) patients. Therefore, doripenem is a welcome addition to our limited armamentarium of antibiotics available to treat serious bacterial infections in hospitalized patients.