Ceftazidima/avibactam frente a otros antimicrobianos para el tratamiento de bacteriemias por Enterobacterales productores de carbapenemasa KPC: datos de la vida real en un hospital universitario de Argentina / Ceftazidime/avibactam versus other antibiotics for the treatment of KPC carbapenemase-producing Enterobacterales bacteremia: real-life data from a university hospital in Argentina

INTRODUCCIÓN: Las bacteriemias por Enterobacterales productores de carbapenemasa KPC (EPC-KPC) presentan una mortalidad elevada y opciones terapéuticas limitadas. OBJETIVOS: Describir y comparar la evolución de los pacientes con bacteriemia por EPC-KPC tratados con ceftazidima/avibactam (CA) frente a otros antimicrobianos (OA). PACIENTES Y MÉTODOS: Estudio prospectivo y retrospectivo de casos y controles. Se incluyeron pacientes adultos con bacteriemia por EPC-KPC, con una proporción entre casos tratados con CA y controles tratados con OA. de 1:2. Se analizaron variables clínicas, epidemiológicas y de evolución. RESULTADOS: Se incluyeron 48 pacientes (16 CA y 32 OA). Los casos se encontraban más frecuentemente neutropénicos (50 vs.16%, p = 0,012); asimismo, presentaron medianas de score de APACHE II más altas y de score de Pitt más bajas. El 65% de la cohorte total presentó un foco clínico y Klebsiellapneumoniae fue el microorganismo más frecuentemente aislado. Los casos recibieron una mayor proporción de tratamiento antimicrobiano empírico adecuado (81 vs. 53%, p = 0,05). La antibioterapia dirigida en casos y controles fue combinada en 38 y 91%, p = 0,009. Los casos presentaron menor mortalidad al día 7 y al día 30 relacionada a infección (0 vs. 22%, p = 0,04 y 0 vs. 34%, p = 0,008). Solo los controles desarrollaron shock, ingresaron a la unidad de cuidados intensivos y presentaron bacteriemia de brecha. CONCLUSIÓN: CA mostró beneficio clínico frente a OA para el tratamiento de pacientes con bacteriemia por EPC-KPC.

BACKGROUND: KPC-producing Enterobacterales bacteremia (KPCCPE) is associated with a high mortality rate and limited therapeutic options. AIM: To describe and compare the outcome of patients with KPC-CPE bacteremia treated with ceftazidime/avibactam (CA) versus other antibiotics (OA). METHODS: Prospective and retrospective cases and control study performed in adult patients with KPC-CPE bacteremia, with a 1:2 ratio between cases treated with CA. and controls treated with OA. Clinical, epidemiological, and outcome variables were analyzed. RESULTS: Forty-eight patients (16 CA and 32 OA) were included. Cases were more frequently neutropenic (50 vs. 16%, p = 0.012), presented higher median APACHE II score and lower Pitt score. Of the total cohort, 65% had a clinical source, and Klebsiella pneumoniae was the most frequently isolated microorganism. Cases received more adequate empirical antibiotic treatment (81 vs. 53%, p = 0.05). Targeted antibiotic therapy in cases and controls was combined in 38 and 91%, p = 0.009. Cases had a lower 7-day mortality and 30-day infection-related mortality (0 vs. 22%, p = 0.04 and 0 vs. 34%, p = 0.008). Only controls developed shock, were admitted to the intensive care unit, and had breakthrough bacteremia. CONCLUSION: CA. showed clinical benefit over OA in the treatment of patients with EPC-KPC bacteremia.

Evaluation of the post-antibiotic effect in vivo for the combination of a ß-lactam antibiotic and a ß-lactamase inhibitor: ceftazidime-avibactam in neutropenic mouse thigh and lung infections.

The post-antibiotic effect (PAE) of ceftazidime-avibactam in vivo was evaluated using models of thigh- and lung-infection with Pseudomonas aeruginosa in neutropenic mice. In thigh-infected mice, the PAE was negative (-2.18 to -0.11 h) for three of four strains: caused by a 'burst' of rapid bacterial growth after the drug concentrations had fallen below their pre-specified target values. With lung infection, PAE was positive, and longer for target drug concentrations in ELF (>2 h) than plasma (1.69-1.88 h). The time to the start of regrowth was quantified as a new parameter, PAER, which was positive (0.35-1.00 h) in both thigh- and lung-infected mice. In the context that measurements of the PAE of ß-lactam/ß-lactamase inhibitor combinations in vivo have not previously been reported, it is noted that the negative values were consistent with previous measurements of the PAE of ceftazidime-avibactam in vitro and of ceftazidime alone in vivo.

Pharmacotherapeutic advances for recurrent urinary tract infections in women.

INTRODUCTION: Treatment of recurrent Urinary tract infections (UTIs) has become challenging because of the dramatic increase in the rates of recurrent infection andof multidrug-resistant (MDR) infections. AREAS COVERED: The authors review recurrent UTIs(rUTI) management in women. EXPERT OPINION: Continuous or post-coital prophylaxis with low-dose antimicrobials or intermittent self-treatment has all been demonstrated to be effective in managing rUTIs in women. Intravaginal estrogen therapy , shows potential toward preventing rUTI. Oral vaccine Uro-Vaxom seems to reduce the number of UTIs. There is evidence that other therapies (e.g. cranberry, Methenamine hippurate, oral D-mannose) may decrease the number of symptomatic UTIs. The treatment of CRE-UTIs is focused on a colistin backbone. Carbapenems are considered first-line agents for UTIs caused by ESBL, but their use is associated with increased MDR. The usage of non-carbapenem for the treatment of ESBL UTIs is necessary. Cefepime, Piperacillin-Tazobactam, Ceftolozane-Tazobactam, and Ceftazidime-Avibactam are justified options. Oral therapy with Pivmecillinam, Fosfomycin, and Nitrofurantoin can be used against uncomplicated UTIs due to ESBL infection.

Intravenous Compatibility of Ceftazidime-Avibactam and Aztreonam Using Simulated and Actual Y-site Administration.

PURPOSE: The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration. METHODS: Ceftazidime-avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate. FINDINGS: Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime-avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments. IMPLICATIONS: Ceftazidime-avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.

Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial.

BACKGROUND: Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI. METHODS: Hospitalized children (≥3 months to <18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7-15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit. RESULTS: Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains.

Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa.

Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to ß-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a "mechanism-based approach" to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-ß-lactamases.

Population pharmacokinetics of continuous-infusion ceftazidime in febrile neutropenic children undergoing HSCT: implications for target attainment for empirical treatment against Pseudomonas aeruginosa.

OBJECTIVES: To conduct a population pharmacokinetic analysis of continuous-infusion ceftazidime in a retrospective cohort of paediatric HSCT patients who were empirically treated for febrile neutropenia (FN) and who underwent therapeutic drug monitoring of ceftazidime steady-state plasma concentrations (Css) for optimization of drug exposure. METHODS: A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed to calculate the PTA of the pharmacodynamic determinant of efficacy (Css/MIC ≥4) against Pseudomonas aeruginosa with continuous-infusion ceftazidime dosages of 1-6 g daily. The Css safety threshold was arbitrarily placed at 100 mg/L and advisable dosages were used. RESULTS: A total of 46 patients with 70 ceftazidime Css values were included. Estimated glomerular filtration rate (eGFR) and body surface area were the covariates associated with drug clearance. At the EUCAST clinical breakpoint of 8 mg/L, simulations showed that continuous-infusion ceftazidime dosages of 4-6 g daily attained optimal PTAs (>90%) across most of 16 different clinical scenarios based on four classes of eGFR (50-145, 145.1-200, 200.1-286 and 286.1-422 mL/min/1.73 m2) and body surface area (0.30-0.64, 0.65-0.88, 0.89-1.34 and 1.35-1.84 m2). In patients with body surface area 0.30-0.64 m2 and eGFR ≤200 mL/min/1.73 m2 the advisable dose of 3 g daily allowed only suboptimal PTAs (<75%). The cumulative fraction of response against MIC distribution of P. aeruginosa was >87%. CONCLUSIONS: Continuous-infusion ceftazidime dosages ranging from 3 to 6 g daily according to different classes of eGFR and body surface area may allow optimized empirical treatment of P. aeruginosa infections in paediatric HSCT patients with FN.

Vitamin E Increases Antimicrobial Sensitivity by Inhibiting Bacterial Lipocalin Antibiotic Binding.

Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes serious respiratory infections in patients with cystic fibrosis. Recently, we discovered that B. cenocepacia produces the extracellular bacterial lipocalin protein BcnA upon exposure to sublethal concentrations of bactericidal antibiotics. BcnA captures a range of antibiotics outside bacterial cells, providing a global extracellular mechanism of antimicrobial resistance. In this study, we investigated water-soluble and liposoluble forms of vitamin E as inhibitors of antibiotic binding by BcnA. Our results demonstrate that in vitro, both vitamin E forms bind strongly to BcnA and contribute to reduce the MICs of norfloxacin (a fluoroquinolone) and ceftazidime (a ß-lactam), both of them used as model molecules representing two different chemical classes of antibiotics. Expression of BcnA was required for the adjuvant effect of vitamin E. These results were replicated in vivo using the Galleria mellonella larva infection model whereby vitamin E treatment, in combination with norfloxacin, significantly increased larva survival upon infection in a BcnA-dependent manner. Together, our data suggest that vitamin E can be used to increase killing by bactericidal antibiotics through interference with lipocalin binding.IMPORTANCE Bacteria exposed to stress mediated by sublethal antibiotic concentrations respond by adaptive mechanisms leading to an overall increase of antibiotic resistance. One of these mechanisms involves the release of bacterial proteins called lipocalins, which have the ability to sequester antibiotics in the extracellular space before they reach bacterial cells. We speculated that interfering with lipocalin-mediated antibiotic binding could enhance the efficacy of antibiotics to kill bacteria. In this work, we report that when combined with bactericidal antibiotics, vitamin E contributes to enhance bacterial killing both in vitro and in vivo. This adjuvant effect of vitamin E requires the presence of BcnA, a bacterial lipocalin produced by the cystic fibrosis pathogen Burkholderia cenocepacia Since most bacteria produce lipocalins like BcnA, we propose that our findings could be translated into making novel antibiotic adjuvants to potentiate bacterial killing by existing antibiotics.

Antibiotic Dosing in Continuous Renal Replacement Therapy.

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

An assessment of the performance of the Baxter elastomeric (LV10) Infusor™ pump under hyperbaric conditions.

INTRODUCTION: There are limited data on the use of elastomeric infusion pumps during hyperbaric oxygen treatment. AIM: This study evaluated the flow rate of the Baxter elastomeric LV10 Infusor™ pump under normobaric (101.3 kPa) and three hyperbaric conditions of 203 kPa, 243 kPa and 284 kPa. METHODS: Elastomeric pumps were secured to participants in the same manner as for a typical patient, except that a container collected the delivered antibiotic solution. Pumps and tubing were weighed before and after the test period to determine volume delivered and to calculate flow rates at sea level and the three commonly used hyperbaric treatment pressures at two different time periods, 0-2 hours (h) and 19-21 h into the infusion. RESULTS: The mean flow rates in ml·h⁻¹ (SD) were: 9.5 (0.4), 10.3 (0.6), 10.4 (0.6), 10.4 (0.5) at 0-2 h and 10.5 (1.0), 12.2 (0.6), 9.4 (0.5), 10.3 (0.9) at 19-21 h for the normobaric, 203 kPa, 243 kPa and 284 kPa conditions respectively. There was no significant association between flow rate and time period (P = 0.166) but the 203 kPa flow rates were significantly faster than the other flow rates (P = 0.008). In retrospect, the 203 kPa experiments had all been conducted with the same antibiotic solution (ceftazidime 6 g). Repeating that experimental arm using flucloxacillin 8 g produced flow rates of 10.4 (0.8) ml·h⁻¹, with no significant associations between flow rate and time period (P = 0.652) or pressure (P = 0.705). CONCLUSION: In this study, the flow rate of the Baxter LV10 Infusor™ device was not significantly affected by increases in ambient pressure across the pressure range of 101.3 kPa to 284 kPa, and flow rates were generally within a clinically acceptable range of 9-12 ml·h⁻¹. However, there was evidence that the specific antibiotic solution might affect flow rates and this requires further study.

Severe skull base osteomyelitis caused by Pseudomonas aeruginosa with successful outcome after prolonged outpatient therapy with continuous infusion of ceftazidime and oral ciprofloxacin: a case report.

BACKGROUND: Skull base osteomyelitis is an uncommon disease that usually complicates a malignant external otitis with temporal bone involvement. It affects predominantly diabetic and immunocompromised males and has a high mortality rate. Pseudomonas aeruginosa is the most common causative organism. Currently, there is no consensus about the best therapeutic option. Here we describe a case of severe skull base osteomyelitis caused by Pseudomonas aeruginosa with progressive palsy of cranial nerves that was successfully managed with prolonged outpatient continuous infusion of ceftazidime plus oral ciprofloxacin. CASE PRESENTATION: A 69-year-old Caucasian man presented with dysphagia, headache, and weight loss. He complained of left earache and purulent otorrhea. Over the following weeks he developed progressive palsy of IX, X, VI, and XII cranial nerves and papilledema. A petrous bone computed tomography scan showed a mass in the left jugular foramen with a strong lytic component that expanded to the cavum. A biopsy was then performed and microbiological cultures grew Pseudomonas aeruginosa. After 6 weeks of parenteral antibiotic treatment, our patient was discharged and treatment was continued with a domiciliary continuous infusion of a beta-lactam through a peripherally inserted central catheter, along with an oral fluoroquinolone for 10 months. Both radiological and clinical responses were excellent. CONCLUSIONS: Skull base osteomyelitis is a life-threating condition; clinical suspicion and correct microbiological identification are key to achieve an accurate and timely diagnosis. Due to the poor outcome of Pseudomonas aeruginosa skull base osteomyelitis, prolonged outpatient parenteral antibiotic therapy administered by continuous infusion could be a valuable option for these patients.

Intraperitoneal Vancomycin Plus Either Oral Moxifloxacin or Intraperitoneal Ceftazidime for the Treatment of Peritoneal Dialysis-Related Peritonitis: A Randomized Controlled Pilot Study.

BACKGROUND: Intraperitoneal administration of antibiotics is recommended as a first treatment for managing peritoneal dialysis (PD)-related peritonitis. However, the efficacy of oral administration of quinolones has not been well studied. STUDY DESIGN: Randomized controlled pilot study. SETTING & PARTICIPANTS: 80 eligible patients with PD-related peritonitis from Peking University First Hospital (40 in each arm). INTERVENTION: Intraperitoneal vancomycin, 1g, every 5 days plus oral moxifloxacin, 400mg, every day (treatment group) versus intraperitoneal vancomycin, 1g, every 5 days plus intraperitoneal ceftazidime, 1g, every day (control group). OUTCOMES: The primary end point was complete resolution of peritonitis, and secondary end points were primary or secondary treatment failure. MEASUREMENTS: PD effluent white blood cell count. RESULTS: Baseline demographic and clinical characteristics of the 2 groups were comparable. There were 24 and 22 Gram-positive organisms, 6 and 7 Gram-negative organisms, 9 and 10 culture-negative samples, and 1 and 1 fungal sample in the treatment and control groups, respectively. Complete resolution of peritonitis was achieved in 78% and 80% of cases in the treatment and control groups, respectively (OR, 0.86; 95% CI, 0.30-2.52; P=0.8). There were 3 and 1 cases of relapse in the treatment and control groups, respectively. Primary and secondary treatment failure rates were not significantly different (33% vs 20% and 10% vs 13%, respectively). In each group, there was 1 peritonitis-related death and 6 transfers to hemodialysis therapy. During the 3-month follow-up period, 7 and 3 successive episodes of peritonitis occurred in the treatment and control groups, respectively. Only 2 adverse drug reactions (mild nausea and mild rash, respectively) were observed in the 2 groups. LIMITATIONS: Sample size was relatively small and the eligibility ratio was low. Also, the number of peritonitis episodes was low, limiting the power to detect a difference between groups. CONCLUSIONS: This pilot study suggests that intraperitoneal vancomycin with oral moxifloxacin is a safe, well-tolerated, practical, and effective first-line treatment for PD-related peritonitis. Larger adequately powered clinical trials are warranted.

Spotlight on ceftazidime/avibactam: a new option for MDR Gram-negative infections.

During the last decade infections caused by MDR Gram-negative bacteria (GNB) have become increasingly prevalent. Because of their high morbidity and mortality rates, these infections constitute a serious threat to public health worldwide. Ceftazidime/avibactam is a new approved agent combining ceftazidime and a novel ß-lactamase inhibitor with activity against various ß-lactamases produced by MDR GNB. Avibactam has a spectrum of inhibition of class A and C ß-lactamases, including ESBLs, AmpC and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Thus, combination with this inhibitor expands ceftazidime's spectrum of activity to MDR Enterobacteriaceae and Pseudomonas aeruginosa strains. In Phase II clinical trials of patients with complicated intra-abdominal infections and complicated urinary tract infections ceftazidime/avibactam exhibited clinical efficacy comparable to those of meropenem and imipenem/cilastatin, respectively. A Phase III clinical trial confirmed the efficacy of ceftazidime/avibactam in patients with MDR Enterobacteriaceae and P. aeruginosa infections. Microbiological surveillance studies, in vivo animal models of infection and pharmacokinetic/pharmacodynamic target attainment analyses are also discussed, to assess the potential role of this new drug in the treatment of infections caused by MDR GNB.

Increased therapeutic efficacy of combination of azithromycin and ceftazidime on Pseudomonas aeruginosa biofilm in an animal model of ureteral stent infection.

BACKGROUND: Infection caused by ureteral stent indwelling is one of the most difficult medical problems, since once bacteria reside in biofilms they are extremely resistant to antibiotics as well as to the host immune defences. In this study we assessed the in vitro and in vivo efficacy of azithromycin and ceftazidime in preventing ureteral stent infection by Pseudomonas aeruginosa. RESULTS: The susceptibility testing with adherent bacteria showed that the biofilm was strongly inhibited by azithromycin treatment, ceftazidime against adherent bacteria in the presence of azithromycin showed the minimum inhibitory concentrations (MICs) and minimum bacteriocidal concentrations (MBCs) dramatically lower than those obtained in the absence of azithromycin. Moreover, ceftazidime plus azithromycin reduced twitching motility and production of rhamnolipid. For the single-treatment groups, in vivo intravenous injection of ceftazidime showed the highest inhibitory effect on bacterial load. Azithromycin prophylactic injection combined with ceftazidime showed increased inhibitory effect on bacterial load than that of each single antibiotic. CONCLUSIONS: Combination of azithromycin and ceftazidime effectively prevent the formation of biofilm and reduced bacteria load of Pseudomonas aeruginosa compared to separate treatment of either of these two antibiotics. This combined treatment option have the potential to contribute to the success of Pseudomonas biofilm elimination in the clinical environment.

Two case reports of the successful eradication of new isolates of Burkholderia cepacia complex in children with cystic fibrosis.

BACKGROUND: Chronic infection with Burkholderia cepacia complex (BCC) has a detrimental effect on morbidity and mortality for patients with cystic fibrosis (CF). It is therefore logical to attempt to eradicate new isolates however there is a paucity of information to guide treatment. We report the successful eradication of new isolates of BCC in two children with CF. CASE PRESENTATION: Burkholderia cepacia was successfully eradicated in a 14 year old boy with CF and Burkholderia gladioli was successfully eradicated in a six year old girl with CF. In both children two weeks of intravenous (IV) tobramycin, ceftazidime and temocillin were used followed by three months of inhaled tobramycin. Bronchoalveolar lavage samples taken during flexible bronchoscopy were used prior to treatment to exclude spontaneous clearance as well as after treatment to confirm eradication. CONCLUSIONS: New isolates of BCC can be successfully eradicated in children with CF. More research is urgently required in this area to identify the best treatment regimen for BCC eradication.

Empirical treatment in patients with acute obstructive pyelonephritis.

Acute obstructive pyelonephritis (AOP) is a urological life-threatening inflammatory condition that initially requires immediate urinary drainage and simultaneous prescribing of highly effective targeted antibacterial treatment. The empirical antibacterial therapy is always prescribed before urine culture and susceptibility testing are done. Percutaneous nephrostomy (PNS) and ureteral stenting (US) are the two options for urinary drainage in obstructed kidneys, while fluoroquinolones and 3(rd) generation cephalosporins are the main groups of antibacterial drugs that are recommended and are available for empirical AOP therapy. In our study we aimed to compare efficacy of fluoroquinolone ciprofloxacin vs 3(rd) generation cephalosporin ceftazidime in empirical antibacterial treatment of patients with acute obstructive pyelonephritis. We also tried to analyze the impact of urinary drainage option on cure rates. 241 AOP patients were randomized into two groups: Group 1, n=124 pts in whom percutaneous nephrostomy was performed urinary drainage and Group 2, n=117 pts, in whom ureteral stenting was made. Then each abovementioned group was also randomized into equal two subgroups (ciprofloxacin vs ceftazidime) depending on the empiric antibacterial treatment which was chosen. Our results revealed that cure rates in patients treated by ceftazidime were higher than those who were treated by ciprofloxacin. At late follow-up, the clinical cure rate in PNS group treated by ceftazidime was 95.2% vs 83.6% in ciprofloxacin arm, while the microbiological cure rates were 92.9% vs 80.0% correspondingly (p<0.05). At late follow-up, the clinical cure rate in US group treated by ceftazidime was 86.4% vs 74.1% in ciprofloxacin arm while the microbiological cure rates were 82.4% vs 69.4% correspondingly (p<0.05). We also concluded that percutaneous nephrostomy ensures a better clinical cure than ureteral stenting at early and late follow-ups regardless of the drug regimes which were chosen. Thus, in our opinion, percutaneous nephrostomy combined with ceftazidime treatment can be considered as the most effective option in patients with acute obstructive pyelonephritis.

Efficacies of ceftazidime-avibactam and ceftazidime against Pseudomonas aeruginosa in a murine lung infection model.

This study aimed to determine the efficacy of human-simulated plasma exposures of 2 g ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28 Pseudomonas aeruginosa isolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. The fT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28 P. aeruginosa strains used, the ceftazidime-avibactam MICs were 4 to 64 µg/ml, and those of ceftazidime were 8 to >128 µg/ml. The change in log10 CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using ceftazidime-avibactam in infected and uninfected mice. Humanized ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log10 CFU against P. aeruginosa with ceftazidime-avibactam MICs of ≤32 µg/ml (ELF upper 95% confidence limit for fT>MIC [ELF fT>MIC] of ≥19%), except for one isolate with a ceftazidime-avibactam MIC of 16 µg/ml. No efficacy was observed against the isolate with a ceftazidime-avibactam MIC of 64 µg/ml (ELF fT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 µg/ml (ELF fT>MIC of ≥12%), variable efficacy at ceftazidime MICs of 64 µg/ml (ELF fT>MIC of ≥0%), and no activity at a ceftazidime MIC of 128 µg/ml, where the ELF fT>MIC was 0%. ELF fT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective against P. aeruginosa, with MICs of up to 32 µg/ml with an ELF fT>MIC of ≥19%. The data suggest the potential utility of ceftazidime-avibactam for treatment of lung infections caused by P. aeruginosa.

Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection.

IMPORTANCE: Treatment with intravitreal (IVT) injections has increased during the last several years as evidence has accumulated demonstrating the efficacy of anti-vascular endothelial growth factor agents in the treatment of neovascular age-related macular degeneration (AMD) and various retinal vascular diseases. Although IVT injections are generally safe, infectious endophthalmitis is a rare but devastating complication, and the risk of morbidity and vision loss from endophthalmitis is high. OBJECTIVE: To examine the change in antibiotic resistance of ocular surface flora with repeated prophylactic use of antibiotics after IVT injection for AMD. DESIGN AND SETTING: Prospective, nonrandomized cohort study in 2 tertiary academic hospitals. PARTICIPANTS: Patients 65 years and older with newly diagnosed AMD were recruited by 7 retinal specialists from July 1, 2010, through December 31, 2011. INTERVENTION: The study group received topical moxifloxacin hydrochloride for 3 days after each monthly IVT injection. MAIN OUTCOME MEASURE: Resistance to moxifloxacin and ceftazidime in cultured isolates at baseline and monthly for 3 months by change in minimal inhibitory concentration (MIC) of culture isolates was studied. RESULTS: The study group consisted of 84 patients, and the control group had 94 patients. In the study group, the baseline adjusted MIC increased (from 1.04 to 1.25 µg/mL; P = .01) as did the MIC for 50% of isolates (MIC50) (from 0.64 to 1.00 µg/mL) and the MIC for 90% of isolates (MIC90) (from 0.94 to 4.00 µg/mL). In both groups, the culture-positive rate did not change significantly when adjusted for baseline. No significant change was found in the MIC level, culture-positive rate, MIC50 level, and MIC90 level in the control group. Subgroup analysis found diabetes mellitus to be noncontributory to both the MIC and culture-positive rate. No endophthalmitis or adverse events were reported. CONCLUSIONS AND RELEVANCE: Repeated use of topical moxifloxacin after IVT injection significantly increases antibiotic resistance of ocular surface flora. We recommend that routine use of prophylactic antibiotics after IVT injection be discouraged. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01181713.

Effects of infection control measures on acquisition of five antimicrobial drug-resistant microorganisms in a tetanus intensive care unit in Vietnam.

PURPOSE: To quantify the effects of barrier precautions and antibiotic mixing on prevalence and acquisition of five drug-resistant microorganisms within a single tetanus intensive care unit at a tertiary referral hospital in Ho Chi Minh City, Vietnam. METHODS: All patients admitted within the study period were included. After a 1-year baseline period, barrier precautions were implemented and the single empirical treatment ceftazidime was changed to mixing (per consecutive patient) of three different regimens (ceftazidime, ciprofloxacin, piperacillin-tazobactam). Markov chain modeling and genotyping were used to determine the effects of interventions on prevalence levels and the relative importance of cross-transmission and antibiotic-associated selection. RESULTS: A total of 190 patients were included in year 1 (2,708 patient days, 17,260 cultures) and 167 patients in year 2 (3,384 patient days, 20,580 cultures). In year 1, average daily prevalence rates for methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (excluding Klebsiella pneumoniae), Pseudomonas aeruginosa, gentamicin-resistant K. pneumoniae, and amikacin-resistant Acinetobacter species were 34.0, 61.3, 53.4, 65.7 and 57.1 %. After intervention, ceftazidime usage decreased by 53 %; the use of piperacillin-tazobactam and ciprofloxacin increased 7.2-fold and 4.5-fold, respectively. Adherence to hand hygiene after patient contact was 54 %. These measures were associated with a reduction of MRSA prevalence by 69.8 % (to 10.3 %), mainly because of less cross-transmission (88 % reduction), and of ESBL-producing Enterobacteriaceae prevalence by 10.3 % (non-significantly). In contrast, prevalence levels of the other three pathogens remained unaffected. CONCLUSION: The combination of simple infection control measures and antibiotic mixing was highly effective in reducing the prevalence of MRSA, but not of Gram-negative microorganisms.