Combination Of Ceftazidime Research Articles

Concentrations of ceftazidime and avibactam in bile fluid-a prospective phase IIb study.

The rise in carbapenem-resistant bacteria and the limited number of effective antibiotics pose a major health-care threat. The combination of ceftazidime (CAZ) and avibactam (AVI) represents an approved treatment option for carbapenem-resistant intra-abdominal infections. However, data on the pharmacokinetic profile of AVI in the hepatobiliary compartment is lacking. To provide clinical in vivo data on the concentration of AVI in bile fluid as a surrogate for hepatobiliary excretion. A single dose of 2000/500 mg CAZ/AVI was administered prolonged over 2 h to 10 patients prior to abdominal surgery, with bile samples available in nine patients in this phase IIb study (DRKS-ID: DRKS00023533). Antibiotic concentrations in plasma (0-8 h), bile (after resection) and pharmacodynamic parameters were determined. The mean concentration across individuals in bile was 33.5 mg/L (±20.5 mg/L) for CAZ and 7.1 mg/L (±3.5 mg/L) for AVI, resulting in bile/plasma ratios of 0.58 (±0.26) and 0.61 (±0.18). The Cmax in plasma was 87.2 mg/L (±25.0 mg/L) for CAZ and 18.6 mg/L (±6.29 mg/L) for AVI, with AUC0-∞ values of 351 h·mg/L (±104 h·mg/L) and 72.1 h·mg/L (±32.1 h·mg/L), respectively. Plasma concentrations of both CAZ and AVI remained more than 50% of the dosing interval above the minimum inhibitory concentrations (T>MIC > 50%; MICCAZ = 8 mg/L, MICAVI = 1 mg/L) in all patients. No antibiotic-associated side effects were reported during the 30-day follow-up. The concentrations of CAZ and AVI in bile suggest their potential as a valuable therapeutic option for multi-resistant biliary infections.

Infectious keratitis in pediatric population aged less than two years: a tertiary eye institute experience

BackgroundInfectious keratitis is a serious ocular condition, which can lead to corneal scarring, vision loss, and even blindness. Pediatric infectious keratitis accounts for about 13% of all cases, although there is a lack of comprehensive data regarding keratitis in less than two years of age population group. This study was aimed to determine predisposing factors, clinical characteristics, microbial profile, and management of infectious keratitis in a population of children aged less than two years.Materials and methodsA retrospective study was carried out in a tertiary eye institute over a period of 18 years from July 2005 to December 2022. Collected data was analyzed for demographics, predisposing factors, clinical features, and treatment methods.ResultsFifty-seven cases of keratitis were identified. Age of the patients ranged from 1 to 24 months (Median: 6, interquartile range: 2–10). Thirty cases were male (52.6%). Predisposing factors were identified in 39 cases (68.4%): consisting of prior ocular trauma (n = 15), previous intraocular surgery (n = 11), ocular surface disease (n = 10), nasolacrimal duct obstruction (n = 4), prematurity (n = 3), developmental delay (n = 2), TORCH infection (n = 1), and contact lens (n = 1). Corneal thinning was observed in 29 eyes (50.9%), which progressed to perforation in 13 eyes (22.8%). Three patients developed endophthalmitis (95% CI, 1.5–13.4%). Most eyes had negative smear (60.4%) and culture (59.6%) results. Pseudomonas aeruginosa was the most common microorganism (11 of 21). Candida albicans was isolated in one case. In vitro susceptibility results showed good coverage of the combined ceftazidime and vancomycin regimen (100%). Surgical procedures were carried out in 35 eyes (61.4%) and 15 eyes required tectonic procedures (26.3%).ConclusionDespite good coverage of medical treatment over cultured isolates, surgical tectonic intervention was required in nearly a quarter of cases to resolve the corneal infection. This finding indicates the necessity of prompt patient referring, corneal sampling and initiation of the treatment.

A SUCCESSFUL TREATMENT OF INTRAVITREAL MOXIFLOXACIN INJECTION IN ACUTE POST-CATARACT SURGERY ENDOPHTHALMITIS: A CASE REPORT

Introduction : Endophthalmitis is a severe form of ocular inflammation and one of the most dreaded cataract surgery complications which may lead to loss of vision. Post-cataract surgery endophthalmitis is a serious complication that occurs when infecting organisms invade the posterior segment of the eye during the time of surgery. Currently, intravitreal injection of vancomycin along with ceftazidime is the first-line treatment, but another study showed a good result of intravitreal moxifloxacin injection in patients with Postoperative endophthalmitis.
 Case Illustration : We reported a 59-year-old woman presented with blurred vision, redness, and pain in the left eye 4 days after phacoemulsification. Visual acuity of LE was hand movement and anterior segment examination found that there was a conjunctival and pericorneal injection, corneal edema, cells, and anterior chamber fibrin formation. Ultrasonography examination showed severe levels of debris in the vitreous humor. Patient was diagnosed with acute post-cataract surgery endophthalmitis and received an intravitreal moxifloxacin injection. Fortunately, one week after that injection, there wasa good result in the patient’s eye condition. Visual acuity of LE improved to 0,1 and the patient planned to receive the second moxifloxacin injection to get the best possible results.
 Discussion : Moxifloxacin expresses broad-spectrum microbial coverage with a very good diffusion and low adverse effects. Moxifloxacin also has a better penetration ability into inflamed ocular tissue than all other antibiotics. Based on that, other studies said that intravitreal moxifloxacin can replace vancomycin and ceftazidime combinations for the treatment of ocular infections.
 Conclusion : Intravitreal moxifloxacin injections have a good result in acute post-cataract surgery endophthalmitis.

Synergistic Antimicrobial Effects of Ibuprofen Combined with Standard-of-Care Antibiotics against Cystic Fibrosis Pathogens.

Cystic fibrosis (CF) is a common life-shortening genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lungs of CF patients are often colonized or infected with microorganisms requiring frequent courses of antibiotics. Antibiotic-resistant bacterial infections have been a growing concern in CF patients. Chronic bacterial infections and concomitant airway inflammation damage the lungs, ultimately leading to respiratory failure. Several clinical trials have demonstrated that high-dose ibuprofen reduces the rate of pulmonary function decline in CF patients. This beneficial effect has been attributed to the anti-inflammatory properties of ibuprofen. Previously, we have confirmed that high-dose ibuprofen demonstrates antimicrobial activity against P. aeruginosa both in vitro and in vivo. However, no study has examined the antimicrobial effect of combining ibuprofen with standard-of-care antimicrobials. Here, we evaluated the possible synergistic activity of combinations of common nonsteroidal anti-inflammatory drugs (NSAIDs), namely, ibuprofen, naproxen, and aspirin, with commonly used antibiotics for CF patients. The drug combinations were screened against different CF clinical isolates. Antibiotics that demonstrated increased efficacy in the presence of ibuprofen were further tested for potential synergistic effects between these NSAIDS and antimicrobials. Finally, a survival analysis of a P. aeruginosa murine infection model was used to demonstrate the efficacy of the most potent combination identified in in vitro screening. Our results suggest that combinations of ibuprofen with commonly used antibiotics demonstrate synergistic antimicrobial activity against drug-resistant, clinical bacterial strains in vitro. The efficacy of the combination of ceftazidime and ibuprofen against resistant P. aeruginosa was demonstrated in an in vivo pneumonia model.

A nested cohort 5-year Canadian surveillance of Gram-negative antimicrobial resistance for optimized antimicrobial therapy

We analyzed 5 years (2016–2020) of nested Canadian data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) to identify pathogen predominance and antimicrobial resistance (AMR) patterns of adult Gram-negative infections in Canadian health care and to complement other public surveillance programs and studies in Canada. A total of 6853 isolates were analyzed from medical (44%), surgical (18%), intensive care (22%) and emergency units (15%) and from respiratory tract (36%), intra-abdominal (25%), urinary tract (24%) and bloodstream (15%) infections. Overall, E. coli (36%), P. aeruginosa (18%) and K. pneumoniae (12%) were the most frequent isolates and P. aeruginosa was the most common respiratory pathogen. 18% of Enterobacterales species were ESBL positive. Collective susceptibility profiles showed that P. aeruginosa isolates were highly susceptible (> 95%) to ceftolozane/tazobactam and colistin, though markedly less susceptible (58–74%) to other antimicrobials tested. Multi-drug resistance (MDR) was present in 10% of P. aeruginosa isolates and was more frequent in those from respiratory infections and from ICU than non-ICU locations. Of P. aeruginosa isolates that were resistant to combinations of ceftazidime, piperacillin/tazobactam and meropenem, 73–96% were susceptible to ceftolozane/tazobactam over the period of the study. These national data can now be combined with clinical prediction rules and genomic data to enable expert antimicrobial stewardship applications and guide treatment policies to optimize adult patient care.

Development of a Polymicrobial Checkerboard Assay as a Tool for Determining Combinatorial Antibiotic Effectiveness in Polymicrobial Communities.

The checkerboard assay is a well-established tool used to determine the antimicrobial effects of two compounds in combination. Usually, data collected from the checkerboard assay use visible turbidity and optical density as a readout. While helpful in traditional checkerboard assays, these measurements become less useful in a polymicrobial context as they do not enable assessment of the drug effects on the individual members of the community. The methodology described herein allows for the determination of cell viability through selective and differential plating of each individual species in a community while retaining much of the high-throughput nature of a turbidity-based analysis and requiring no specialized equipment. This methodology further improves turbidity-based measurements by providing a distinction between bacteriostatic versus bactericidal concentrations of antibiotics. Herein, we use this method to demonstrate that the clinically used antibiotic combination of ceftazidime and gentamicin works synergistically against Pseudomonas aeruginosa in monoculture but antagonistically in a polymicrobial culture also containing Acinetobacter baumannii, Staphylococcus aureus, and Enterococcus faecalis, highlighting the fundamental importance of this methodology in improving clinical practices. We propose that this method could be implemented in clinical microbiology laboratories with minimal impact on the overall time for diagnosis.

Neutropenic Sepsis and Challenges to Combat

Neutropenic sepsis (NS) is a common and predictable complication of bone marrow disorders and cytotoxic chemotherapy. After intensive chemotherapy, the incidence of NS is about 70–100% during the neutropenic phase. Patients with neutropenia are vulnerable to invasive infections, which can be rapidly overwhelming, causing septic shock and death. The epidemiology of sepsis in industrialized countries is mainly influenced by the age of the population and the increasing prevalence of comorbidities, such as chronic organ dysfunctions, non-cancer-related immunosuppressive diseases, or cancer itself. Patients with cancer are at more than 10 times higher risk for sepsis than the general population, with some variability according to the cancer types. There is frequent frustration among physicians caring for patients with neutropenic sepsis. Infections are a frequent complication in leukopenic patients, affecting an estimated 24% of patients after chemotherapy for hematologic diseases or solid organ tumors. Bloodstream infections (BSIs) are the most frequent infection in febrile neutropenic, onco-hematological patients, with incidence rates spanning from 10% to 38%. Septic shock is the most severe clinical presentation form of such infections. This is becoming a cause for growing concern due to several factors. Rates of Gram-negative bacilli (GNB) in oncohematological patients are progressively increasing. It is shown that ~50% of bacteremia in cancer patients was caused by GNB, among which almost 14% were MDR GNB. This could impact a greater percentage of patients presenting with septic shock. The widespread emergence and dissemination of multidrug-resistant Gram-negative bacilli, which are a common cause of infection and sepsis in patients with cancer, is of great concern. Several investigators have reported high rates of bacteremia due to extended-spectrum â-lactamase (ESBL)-producing Enterobacterales, MDR Pseudomonas aeruginosa (MDR-PA), and carbapenem-resistant Enterobacterales. Additionally, empirical antibiotic therapy is challenging in the era of emerging multidrug-resistant (MDR) GNB. Indeed, inappropriate empirical antibiotic therapy (IEAT) has been associated with increased mortality in patients with febrile neutropenia and BSI. Neutropenic sepsis is a medical emergency in which broad-spectrum antibiotics must be given without delay. Delaying treatment in neutropenic sepsis may increase the risk of death. â-Lactam/â-lactamase inhibitors (BL/ BLIs) and carbapenems are often considered for the treatment of sepsis when the main suspected pathogens are Gram-negative bacteria, because of their broad spectrum of coverage. Ceftazidime avibactam is a new molecule available against these bugs. It is a novel combination of ceftazidime (thirdgeneration cephalosporin) and avibactam (novel, nonâ- lactam â-lactamase inhibitor) which covers ESBL isolates like E Coli & K. Pneumoniae, MDR Pseudomonas aeruginosa, and CRE. Ceftazidime and avibactam are now playing a crucial role in combating MDR gram-negative infections in sepsis patients. Many international guidelines recommend using early ceftazidime and avibactam in sepsis patients to achieve better outcomes and reduce volatility. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 197-198

Ceftazidime-avibactam resistance in Klebsiella pneumoniae sequence type 37: a decade of persistence and concealed evolution.

The first reports of carbapenem-resistant Enterobacterales in our hospital date back to 2006. In that period, few ertapenem-resistant but meropenem-susceptible Klebsiella pneumoniae isolates belonging to sequence type (ST) 37 were retrieved from clinical samples. These strains produced the CTX-M-15 extended spectrum β-lactamase, OmpK35 was depleted due to a nonsense mutation, and a novel OmpK36 variant was identified. Yet, starting from 2010, Klebsiella pneumoniae carbapenemase (KPC)-producing ST512 isolates started prevailing and ST37 vanished from sight. Since 2018 the clinical use of the combination of ceftazidime-avibactam (CZA) has been introduced in clinical practice for the treatment of bacteria producing serine-β-lactamases, but KPC-producing, CZA-resistant K. pneumoniae are emerging. In 2021, four CZA-resistant ST37 isolates producing KPC variants were isolated from the same number of patients. blaKPC gene cloning in Escherichia coli was used to define the role of those KPC variants on CZA resistance, and whole genome sequencing was performed on these isolates and on three ST37 historical isolates from 2011. CZA resistance was due to mutations in the blaKPC genes carried on related pKpQIL-type plasmids, and three variants of the KPC enzyme have been identified in the four ST37 strains. The four ST37 isolates were closely related to each other and to the historical isolates, suggesting that ST37 survived without notice in our hospital for 10 years, waiting to re-emerge as a CZA-resistant K. pneumoniae clone. The ancestor of these contemporary isolates derives from ST37 wild-type porin strains, with no other mutations in chromosomal genes involved in conferring antibiotic resistance (parC, gyrA, ramR, mgrB, pmrB).

665. Modified Superposition in vitro Susceptibility of Aztreonam and Ceftazidime/Avibactam for an NDM-5 Metallo-β-Lactamase-Producing Klebsiella pneumoniae Isolate

Abstract Background We describe a novel in vitro susceptibility testing approach of aztreonam and ceftazidime/avibactam using a superposition method paired with confirmatory testing and molecular sequencing of a New Delhi metallo-β-lactamase (NDM)-5-producing Klebsiella pneumoniae. Methods A modified strip superposition method with Epsilometer test (Etest) strips and Kirby Bauer disks was utilized to test the in vitro activity of aztreonam and ceftazidime/avibactam against the NDM-producing K. pneumoniae. The isolate was also sent for whole genome sequencing and tested for the in vitro activity of aztreonam and ceftazidime in combination with avibactam using a broth microdilution checkerboard assay. Aztreonam and ceftazidime/avibactam in vitro testing with modified superposition method Results All zones of inhibition from the Etest superposition method were measured to be 22 mm in diameter (Clinical and Laboratory Standards Institute [CLSI] zone of inhibition for aztreonam susceptibility is ≥ 21 mm for Enterobacterales). The results of whole genome sequencing showed the K. pneumoniae isolate carried a metallo-β-lactamase (blaNDM-5), extended-spectrum β-lactamase (blaCTX-M-15), and other β-lactamases (blaSHV-11, blaTEM-1). Through the broth microdilution checkerboard method, the isolate demonstrated inhibition by aztreonam/avibactam (fixed concentration of 4mg/L) at a minimum inhibitory concentration (MIC) of 0.25 mg/L but was resistant to ceftazidime/avibactam (MIC > 16 mg/L) and aztreonam alone (MIC > 16 mg/L) according to CLSI breakpoints. Conclusion The in vitro activity of aztreonam and ceftazidime/avibactam against an NDM-5-producing K. pneumoniae was demonstrated with a modified superposition method. This may serve as a simplistic and readily available technique for rapidly determining antimicrobial activity in these difficult to treat pathogens. Disclosures Justin Schmetterer, PharmD, PhC, BCIDP, AbbVie Speaker Bureau: Honoraria Yao Lin, MS, Abbvie Inc: employee|Abbvie Inc: Stocks/Bonds.

In Vitro Assessment of the Combination of Antibiotics against Some Integron-Harbouring Enterobacteriaceae from Environmental Sources.

One strategy for combating antimicrobial resistance in many infections is to combine antibacterial compounds to create combinations that outperform each molecule alone. In this study, we examine and study the inhibitory effect of combining two drugs belonging to different antibiotic classes to obtain a possible potentiating effect against some Enterobacteriaceae isolates harbouring integrons recovered from rivers and effluents of hospital and wastewater treatment plants in Eastern Cape Province, South Africa. These integrons could easily enable the isolates to acquire genes that confer additional resistance against conventional antibiotics. The minimum inhibitory concentration of the various antibiotics was determined using the broth microdilution, while the checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs). A total of 26.3% (10/38) of the interactions were categorised as synergistic, while 73.7% (28/38) were indifferent. None of the combinations were antagonistic. The time–kill assays revealed all the synergistic interactions as bactericidal. Therefore, the combinations of gentamicin with tetracycline, ciprofloxacin, and ceftazidime against multidrug-resistant (MDR) Klebsiella pneumoniae, tetracycline–ceftazidime combination against MDR Escherichia coli, colistin combinations with ceftazidime and gentamicin, and tetracycline–gentamicin combinations against MDR Citrobacter freundii may be future therapeutic alternatives. Hence, the synergistic combinations reported in this study must be assessed further in vivo before their clinical applications.

Molecular mechanisms underlying bacterial resistance to ceftazidime/avibactam.

Ceftazidime/avibactam (CAZ/AVI), a combination of ceftazidime and a novel β-lactamase inhibitor (avibactam) that has been approved by the U.S. Food and Drug Administration, the European Union, and the National Regulatory Administration in China. CAZ/AVI is used mainly to treat complicated urinary tract infections and complicated intra-abdominal infections in adults, as well as to treat patients infected with Carbapenem-resistant Enterobacteriaceae (CRE) susceptible to CAZ/AVI. However, increased clinical application of CAZ/AVI has resulted in the development of resistant strains. Mechanisms of resistance in most of these strains have been attributed to blaKPC mutations, which lead to amino acid substitutions in β-lactamase and changes in gene expression. Resistance to CAZ/AVI is also associated with reduced expression and loss of outer membrane proteins or overexpression of efflux pumps. In this review, the prevalence of CAZ/AVI-resistance bacteria, resistance mechanisms, and selection of detection methods of CAZ/AVI are demonstrated, aiming to provide scientific evidence for the clinical prevention and treatment of CAZ/AVI resistant strains, and provide guidance for the development of new drugs. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.

Ceftazidime/Avibactam and Other Commonly Used Antibiotics Activity Against Enterobacterales and Pseudomonas aeruginosa Isolated in Poland in 2015-2019.

PurposeInfections caused by resistant Gram-negative bacteria are becoming increasingly common and now pose a serious public health threat worldwide, because they are difficult to treat due to few treatment options and they are associated with high morbidity and mortality. The combination of ceftazidime with the beta-lactamase inhibitor avibactam – seems to be the right choice in this situation. The aim of the study was to evaluate the activity of ceftazidime/avibactam and other commonly used antibiotics against Enterobacterales and Pseudomonas aeruginosa strains isolated within last years in Poland.Patients and MethodsThis study analyzed the antibiotic susceptibility of 1607 Enterobacterales isolates and 543 nonfermenting P. aeruginosa strains collected between 2015 and 2019 in 4 medical laboratories participating in the ATLAS (Antimicrobial Testing Leadership And Surveillance) program in Poland. Unduplicated clinically significant Enterobacterales and P. aeruginosa strains were collected from patients with respiratory, skin and musculoskeletal, genitourinary, abdominal, bloodstream or other infections (ear, eye).ResultsThe ceftazidime/avibactam combination demonstrates the highest activity against Enterobacterales (98.9%), in both adults and children, including strains presenting MDR (multidrug-resistant) (97.5%) and ESBL (extended spectrum β-lactamase) (96.3%) phenotypes. The activity of ceftazidime/avibactam increased to 100% when only MBL (metallo-β-lactamase)-negative subset of Enterobacterales was considered. This combination also achieved the second highest activity result (89.3%) after colistin in P. aeruginosa, including isolates of MDR (65.9%) and carbapenem-resistant (CR) phenotypes (54.8%). When MBL-positive isolates were excluded, susceptibility rate of P. aeruginosa increased to 94.7%. It is worth to note that susceptibility of the examined P. aeruginosa strains to ceftazidime/avibactam was very high in children (93.3%), especially in a pediatric intensive care unit (94.2%).ConclusionEnterobacterales and P. aeruginosa included in this analysis presented high susceptibility rates to ceftazidime/avibactam. Ceftazidime/avibactam showed the highest activity against Enterobacterales strains among all antibiotics studied, both for the total population as well as for MDR phenotype and ESBL phenotype. Ceftazidime/avibactam also achieved the second highest activity result against P. aeruginosa strains (including MDR and CR phenotypes). These results are much higher when excluding MBL-positive isolates that exhibit intrinsic resistance to ceftazidime/avibactam.

Uji In Vitro Beberapa Kombinasi Antibiotik Antipseudomonas terhadap Pseudomonas aeruginosa yang Resisten terhadap Karbapenem

Lower respiratory tract, sepsis, or urinary tract infection caused by the multidrug resistance Pseudomonas aeruginosa is common in the hospital, especially in the ICU wards. The treatment against this bacteria requires combination of antibiotics with different mechanism of actions. In this study, several combinations of antibiotics were evaluated in vitro against carbapenem-resistant P. aeruginosa isolated from the ICU of Cipto Mangunkusumo Hospital. The combination of antibiotics tested were ceftazidime-amikacin, ceftazidime-ciprofloxacin, and ciprofloxacin-amikacin. Checkerboard assay to the combination of antibiotics was conducted to assess the in vitro synergistic activity. A total of 22 P. aeruginosa isolates were collected, 16 of them were resistant to ceftazidime, ciprofloxacin, amikacin, as well as carbapenem. The result revealed that the combination of ceftazidime and amikacin showed promising synergistic activity. Conversely, no synergitic activities were shown by the combination of ceftazidime-ciprofloxacin and ciprofloxacin-amikacin. The combination of ceftazidime-amikacin may has potential effect againsts carbapenem-resistant P. aeruginosa in vitro.

1263. In Vitro Activity of Ceftazidime-avibactam and Comparator Agents against Enterobacterales and Pseudomonas aeruginosa Collected from Patients with Bloodstream Infections as Part of the ATLAS Global Surveillance Program, 2017-2019

Abstract Background Avibactam (AVI) is a β-lactamase inhibitor with potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. The combination of ceftazidime (CAZ) with AVI has been approved in Europe and in the United States for several indications. This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacterales (Eba) and Pseudomonas aeruginosa (Pae) isolates collected from patients with bloodstream infections as part of the ATLAS surveillance program in 2017-2019. Methods A total of 48193 Eba and 15376 Pae non-duplicate clinically significant isolates, including 9224 Eba and 1808 Pae isolated from bloodstream infections, were collected in 53 countries in Europe, Latin America, Asia/Pacific (excluding mainland China), and the Middle East/Africa region. Susceptibility testing was performed by CLSI broth microdilution. CAZ-AVI was tested at a fixed concentration of 4 µg/ml AVI. Meropenem-nonsusceptible (MEM-NS) Eba and Pae isolates were screened for the presence of β-lactamase genes. Results Susceptibility data are shown in the Table. Percentages of susceptibility (% S) to the tested agents were 0.4-3.4% lower among Eba and Pae from bloodstream infections compared to isolates from combined sources in most cases. CAZ-AVI showed potent in vitro activity against all Eba bloodstream isolates and the CAZ-NS subset (MIC90, 0.5-4 µg/ml, 91.7-97.4% S). Reduced activity against MEM-NS Eba was attributable to carriage of class B metallo-β-lactamases (MBLs) as 98.1% of MEM-NS MBL-negative isolates were susceptible to CAZ-AVI. None of the tested comparators exceeded the activity of CAZ-AVI. CAZ-AVI also showed good in vitro activity against the majority of Pae bloodstream isolates (MIC90, 16 µg/ml, 89.7% S). Activity was reduced against CAZ-NS and MEM-NS subsets (55.9-63.0% S), which included isolates carrying MBLs, but exceeded the activity of CAZ against MEM-NS and MEM against CAZ-NS by 26-28 percentage points. Amikacin was the only tested comparator that demonstrated comparable activity against Pae bloodstream isolates. Results Table Conclusion CAZ-AVI provides a valuable therapeutic option for treating bloodstream infections caused by MBL-negative Eba and Pae isolates. Disclosures Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Gregory Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

Econazole as adjuvant to conventional antibiotics is able to eradicate starvation-induced tolerant bacteria by causing proton motive force dissipation.

Bacterial antibiotic tolerance is responsible for the recalcitrance of chronic infections. This study aims to investigate a potential drug that can effectively kill antibiotic-tolerant bacteria and evaluate the ability of this drug on the eradication of tolerant cells both in vitro and in vivo. The in vitro effect of econazole on eradicating starvation-induced tolerant bacterial populations was studied by testing the amount of survival bacteria in the presence of econazole combining conventional antibiotics. Proton motive force (PMF) was determined after econazole treatment by DiOC2(3). Finally, mouse infection models were used to detect the ability of econazole on killing the tolerant populations in vivo. Econazole eradicated starvation-induced tolerant cells of various bacterial species within 24 or 96 h when used in combination with conventional antibiotics. Moreover, mouse survival rate drastically increased along with the decrease of in vivo bacterial count after treatment of infected mice with the econazole and ceftazidime combination for 72 h. PMF was found to have dissipated almost completely in econazole-treated cells. Econazole could act in combination with conventional antibiotics to effectively eradicate bacterial tolerant cells. The combined use of econazole and ceftazidime was shown to be effective for eradicating tolerant cells in a mouse infection model. The ability of econazole to eradicate tolerant cells was due to its ability to cause dissipation of bacterial transmembrane PMF. Econazole-mediated PMF disruption is a feasible strategy for the treatment of chronic and recurrent bacterial infections.

Prevalence of Ventriculostomy Related Infections and Associated Factors in Low Income Setup.

Ventriculostomy, a lifesaving and emergency procedure, is used to address raised intracranial pressure. In resource limited set-up like Tikur Annbessa Specialized Referral Hospital, properly designed closed system for ventriculostomy is not available; a device made with sterile pediatric nasogastric tube connected to urine bag is used. Institutional based retrospective cross-sectional study conducted on 93 patients with ventriculostomy from January 1, 2009 to June 30, 2018. Ventriculostomy related infection risk described in descriptive statistics and Binary Logistic Regression analysis. The prevalence rate of Ventriculostomy related infection is 25.8% at Tikur Annbessa Specialized Referral Hospital. Identified risk factors: Ventriculostomy stay for five or more days (AOR=7.676, 95% CI: 1.424, 41.367) and cerbro-spinal fluid leak (AOR=4.592, 95% CI: 1.279, 16.488). Ventriculostomy manipulation showed association on bivariate analysis. K.Pneumoniae (34.6%) and Acinetobacter spp. (30.8%) identified as the main organisms. They were sensitive to combined ceftazidime and vancomycin in 19.2% and meropenem in 42.3%. Based on Tängdén's criteria, 11.8% of patients died of Ventriculostomy related infection while 43% of the patients died in total. Mortality from Ventriculostomy related infection is 45.8% once diagnosed. The prevalence rate of Ventriculostomy related infection is 25.8% at Tikur Annbessa Specialized Referral Hospital. The duration of external ventricular drain and Cerebrospinal fluid leak are identified risk factors. Ventriculostomy related infection is responsible for one third of mortality related with external ventricular drain. The remaining two third exact causes are not known.

Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived Multidrug-Resistant Pseudomonas aeruginosa.

The need for synergy testing is driven by the necessity to extend the antimicrobial spectrum, reducing drug dosage/toxicity and the development of resistance. Despite the abundance of synergy testing methods, there is the absence of a gold standard and a lack of synergy correlation among methods. The most popular method (checkerboard) is labor-intensive and is not practical for clinical use. Most clinical laboratories use several gradient synergy methods which are quicker/easier to use. This study sought to evaluate three gradient synergy methods (direct overlay, cross, MIC:MIC ratio) with the checkerboard, and compare two interpretative criteria (the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI)) regarding these methods. We tested 70 multidrug-resistant Pseudomonas aeruginosa, using a tobramycin and ceftazidime combination. The agreement between the checkerboard and gradient methods was 60 to 77% for FICI, while agreements for SBPI that ranged between 67 and 82.86% were statistically significant (p ≤ 0.001). High kappa agreements were observed using SBPI (Ƙ > 0.356) compared to FICI (Ƙ < 0.291) criteria, and the MIC:MIC method demonstrated the highest, albeit moderate, intraclass correlation coefficient (ICC = 0.542) estimate. Isolate resistance profiles suggest method-dependent synergism for isolates, with ceftazidime susceptibility after increased exposure. The results show that when interpretative criteria are considered, gradient diffusion (especially MIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa.

A Review on Ceftazidime and Avibactum

Ceftazidime is a semi synthetic, broad-spectrum, beta-lactam, third-generation cephalosporin antibiotic useful for the treatment of many bacterial infections like joint infections, meningitis, pneumonia, sepsis, urinary tract infections, malignant otitis externa, and vibrio infection. It is synthesized chemically using ethyl acetoacetate, sodium nitrite and hydrochloric acid. The Structural analogues of Ceftazidime are better in terms of activity, potency and stability. Cefmenoxime has increased stability to beta-lactamases, the syn isomer of Ceftizoxime is more potent, Moxalactam has enhanced activity against Pseudomonas, Ceftriaxone has higher serum peak level and a prolonged half-life. Ceftazidime acts by inhibiting bacterial transpeptidases and preventing the synthesis of bacterial cell wall. It is assayed by Infrared spectroscopy. Stability studies showed that the drug degrades extensively on reconstitution in aqueous solution on exposures to heating at 45ºC and UV/Visible radiation, while the drug in solid state is stable. The drug is identified by carbonate or sodium tests and tested for its pH, clarity of solution, loss on drying and bacterial endotoxins. In 2015, USFDA approved a combination of Ceftazidime with Avibactam, a non-β-lactam β-lactamase inhibitor which protects ceftazidime from hydrolysis by a wide range of serine β-lactamases and expands its spectrum of activity to Enterobacteriaceae resistant to ceftazidime, and is used for the treatment of complicated urinary tract infections and intra-abdominal infections. Five new ceftazidime derivatives have improved acid stability and increased spectrum of ceftazidime. All the Schiff bases showed good antimicrobial activity especially against G(+) bacteria. Compounds 2 and 3 showed broader antibacterial spectrum against both G(+) and G(-) bacteria.

Synergistic Killing and Re-Sensitization of Pseudomonas aeruginosa to Antibiotics by Phage-Antibiotic Combination Treatment.

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections pose a serious health threat. Bacteriophage–antibiotic combination therapy is a promising candidate for combating these infections. A 5-phage P. aeruginosa cocktail, PAM2H, was tested in combination with antibiotics (ceftazidime, ciprofloxacin, gentamicin, meropenem) to determine if PAM2H enhances antibiotic activity. Combination treatment in vitro resulted in a significant increase in susceptibility of MDR strains to antibiotics. Treatment with ceftazidime (CAZ), meropenem, gentamicin, or ciprofloxacin in the presence of the phage increased the number of P. aeruginosa strains susceptible to these antibiotics by 63%, 56%, 31%, and 81%, respectively. Additionally, in a mouse dorsal wound model, seven of eight mice treated with a combination of CAZ and PAM2H for three days had no detectable bacteria remaining in their wounds on day 4, while all mice treated with CAZ or PAM2H alone had ~107 colony forming units (CFU) remaining in their wounds. P. aeruginosa recovered from mouse wounds post-treatment showed decreased virulence in a wax worm model, and DNA sequencing indicated that the combination treatment prevented mutations in genes encoding known phage receptors. Treatment with PAM2H in combination with antibiotics resulted in the re-sensitization of P. aeruginosa to antibiotics in vitro and a synergistic reduction in bacterial burden in vivo.

1569. In Vitro Activity of Ceftazidime-avibactam and Comparator Agents against Enterobacterales and Pseudomonas aeruginosa Collected from Patients with Bloodstream Infections as Part of the ATLAS Global Surveillance Program, 2015-2018

BackgroundAvibactam (AVI) is a β-lactamase inhibitor with potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. The combination of ceftazidime (CAZ) with AVI has been approved in Europe and in the United States for several indications. This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacterales (Eba) and Pseudomonas aeruginosa (Pae) isolates collected from patients with bloodstream infections as part of the ATLAS surveillance program in 2015-2018.MethodsA total of 57048 Eba and 15813 Pae non-duplicate clinically significant isolates, including 7720 Eba and 1286 Pae isolated from bloodstream infections, were collected in 52 countries in Europe, Latin America, Asia/Pacific (excluding mainland China), and the Middle East/Africa region. Susceptibility testing was performed by CLSI broth microdilution. CAZ-AVI was tested at a fixed concentration of 4 µg/ml AVI. Meropenem-nonsusceptible (MEM-NS) Eba and Pae isolates were screened for the presence of β-lactamase genes.ResultsSusceptibility data are shown in the Table. Percentages of susceptibility (% S) to the tested agents were 0.3-2.9% lower among Eba and Pae from bloodstream infections compared to isolates from combined sources in most cases. CAZ-AVI showed potent in vitro activity against all Eba bloodstream isolates and the CAZ-NS subset (MIC90, 0.5-2 µg/ml, 93.4-98.1% S). Reduced activity against MEM-NS Eba was attributable to carriage of class B metallo-β-lactamases (MBLs) because 99% of MEM-NS MBL-negative isolates were susceptible to CAZ-AVI. None of the tested comparators exceeded the activity of CAZ-AVI. CAZ-AVI also showed good in vitro activity against the majority of Pae bloodstream isolates (MIC90, 16 µg/ml, 89.4% S). Activity was reduced against CAZ-NS and MEM-NS subsets (54.2-63.8% S), which included isolates carrying MBLs, but exceeded the activity of CAZ and MEM against these subsets by 26-31 percentage points. Amikacin was the only tested comparator that demonstrated comparable activity against Pae bloodstream isolates.Table ConclusionCAZ-AVI provides a valuable therapeutic option for treating bloodstream infections caused by MBL-negative Eba and Pae isolates.DisclosuresKrystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Greg Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)