Nickel(II)-Complex of Ceftibuten Dihydrate: Synthesis, Characterization and Thermal Study

Ceftibuten dihydrate is a semisynthetic, orally administered, third generation cephalosporin antibiotic which is effective against most of the pathogens causing infections in the respiratory tract. Complexation of ceftibuten dehydrate (Ligand, L) was performed with hydrated Ni(II) salt (Metal, M) in the ratio of 2:1 (L:M) in aqueous medium at 90 oC. The metal complex was then characterized by spectral techniques and thermal analyses. The FT-IR spectral data of metal complex suggested the monodentate bonding of metal ion to carboxylate group. Spectral evidence also supported the formation of five-membered ring via coordination of metal ion to β-lactam nitrogen and carboxylate group of parent drug. Thermal behavior of ligand and complex were studied. Thus, thermoanalytical (DSC and TGA) results also supported the formation of new metal complex, indicating the successful interaction of metal ion to ligand. Dhaka Univ. J. Pharm. Sci. 20(2): 219-225, 2021 (December)

STAPHYLOCOCCUS AUREUS RESISTANCE AGAINST CEPHALOSPORIN ANTIBIOTIC IN ADEN-YEMEN

The study was carried out to determine antibacterial resistance profiles of methicillin-resistant Staphylococcus aureus (MRSA), isolated from clinical samples (n: 352) of patients during the period, from January 2019 to July 2020 in five governmental and private medical laboratories of Aden governorate, Yemen. The results showed the percentage for resistance ratio is differentiated between samples and the category of cephalosporin antibiotic groups. The highest percentage of resistance was in the wound sample for Cefadroxil, Cefuroxime, and Ceftriaxone at (100%), in addition to 100% in the pus, CSF, and sputum samples for Ceftriaxone antibiotic. Moreover, Cefadroxil has 100 % of resistance in semen, ear, and sputum samples. However, the Staphylococcus aureus isolated from the pharyngeal sample not showed any resistance to all cephalosporin antibiotic groups.

Formulation and Characterization of Dispersible Tablets of Cefpodoxime Proxetil: A Cephalosporin Antibiotic

The objective was to formulate rapid dispersible tablets of Cefpodoxime Proxetil using various types of superdisintegrants viz., Croscarmellose sodium (CCS), Sodium starch glycolate (SSG) and Crospovidone (CP) in varied concentrations (1-5%). The model drug for current investigation, Cefpodoxime Proxetil, a broad spectrum third generation Cephalosporin antibiotic belongs to BCS class IV. The preformulation studies were accomplished by determining the compatibility of model drug with respective excipients by FTIR studies. These studies, revealed no chemical interaction of excipients with the model drug. The formulation development was achieved in phases comprising of preliminary screening, pre-optimization and optimization studies. The bitter taste of model drug was masked by addition of flavors and sweeteners to make it pleasant for pediatric patients upon oral administration. The formulations (F1-F6) were prepared by direct compression method. The percent released from all formulations showed release of more than 90% of drug within 30 min with drug content of more than 95%. The study showed that formulation containing CCS as superdisintegrants furnished best results. Formulation F5 showed maximum (99.6%) drug release within 30 minutes which is prerequisite for dispersible tablets. It also possessed a rapid release of drug from the formulation. The F5 formulation showed comparative dissolution profile vis-a-vis a commercialized formulation. The study concluded that dispersible tablets of Cefpodoxime Proxetil can be an alternative to conventional dosage form for the treatment of urinary tract infection, skin infection, and upper respiratory tract infections.

Ceftraixone induced anaphylaxis and death: a case report

Ceftriaxone, a broad spectrum third generation cephalosporin antibiotic and sulbactam is a beta-lactamase inhibitor. The combination is used for pre-operative surgical prophylaxis for prevention is secondary bacterial infection. We describe a patient who developed anaphylaxis and death soon after intravenous administration of ceftriaxone and sulbactam combination and review similar cases of adverse effects to these class of drugs. The patient was a 68 year old male admitted to surgery ward for obstructed inguinal hernia. He was prescribed injection ceftriaxone and sulbactam combination along with concomitant medication injection pantoprazole and injection metronidazole. The patient was injected injection ceftriaxone and sulbactam, within 15 minutes he suddenly developed anaphylactic shock and died for fluid aspiration in lungs during resuscitation. PubMed was searched for the following terms: anaphylaxis, ceftriaxone, sulbactam. The papers containing these terms and their references were reviewed. Anaphylactic shock caused by ceftriaxone is an uncommon adverse event in patients receiving the drug. However, similar reactions have been observed in some cases in India and world-wide. Clinicians should be aware that anaphylaxis secondary to ceftriaxone and sulbactam combination is a serious death threatening side-effect.

1252. In Vitro Activity of Cefiderocol Against Metallo-β-Lactamase-Producing Gram-Negative Bacteria Collected in North America and Europe Between 2014 and 2017: SIDERO-WT-2014–2016 Studies

Background Metallo-β-lactamases (MBLs; eg, NDM, VIM, and IMP) can inactivate most commonly-used β-lactam antibiotics, including carbapenems. Infections caused by MBL producers are difficult to treat due to their resistance to many antibiotics. Cefiderocol (CFDC) is a siderophore cephalosporin antibiotic approved in the USA in 2019, with potent activity against carbapenem-resistant Gram-negative bacteria (GNB), including both serine- and metallo-carbapenemase positive strains. We evaluated the in vitro activity of CFDC and comparator agents against MBL-producing strains of GNB from North America and Europe in 3 years’ of consecutive surveillance studies (SIDERO-WT-2014–2016). Methods Susceptibility testing for CFDC, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), meropenem (MEM), cefepime (FEP), ciprofloxacin (CIP), and colistin (CST) was performed by broth microdilution according to CLSI guidance. CFDC was tested in iron-depleted medium. A total of 275 MBL-producing strains, consisting of 120 Enterobacterales (45 NDM; 75 VIM), 5 NDM-producing Acinetobacter baumannii, and 150 Pseudomonas aeruginosa (134 VIM; 16 IMP), identified among 4985 (654 Enterobacterales and 4331 non-fermenters) MEM non-susceptible (based on CLSI breakpoints) strains were used for the current analysis. Results The minimum inhibitory concentration (MIC) range and MIC90 for CFDC and comparators for each MBL-producing organism group are shown in the Table. Against NDM-producing Enterobacterales, of which 42% and 33% were isolated in Turkey and Russia, respectively, CFDC inhibited the growth of 84% of isolates tested at ≤4 µg/mL. CFDC MIC90 was 4 μg/mL for VIM-producing Enterobacterales (41% and 31% isolated in Greece and Italy, respectively), 1 μg/mL for VIM-producing P. aeruginosa (50% isolated in Russia), and 4 μg/mL for IMP-producing P. aeruginosa (88% isolated in Czech Republic). Other comparators (except for CST) were not active against these MBL producers. Table. MIC range and MIC90 (μg/mL) for CFDC and comparators of MBL-producing organisms Conclusion CFDC inhibited the growth of 100% of MBL-positive GNB at ≤8 mg/mL and showed MIC90 of 4 μg/mL against all 275 MBL producers, indicating that CFDC has high potential for treating infections caused by these difficult-to-treat strains. Disclosures Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Krystyna Kazmierczak, PhD, Shionogi & Co., Ltd. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor) Roger Echols, MD, Shionogi Inc. (Consultant) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee)

Optimal regimens based on PK/PD cutoff evaluation of ceftiofur against Actinobacillus pleuropneumoniae in swine

Background Actinobacillus pleuropneumoniae formerly known as Haemophilus pleuropneumoniae, can cause pleuropneumoniae in pigs, which lead to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals, which was effective against gram-negative and gram-positive bacterium. This study aimed to formulate a rational dosage strategy and review the preceding recommended dosage based on PK/PD modeling and Establish Clinical breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the pharmacodynamic-pharmacokinetic cutoff. Results The epidemiologic cutoff value was 0.125 μg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 μg/mL and 1 μg/mL in vitro and ex-vivo, respectively. The minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 μg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent with a partly concentration-dependent pattern. Based on the inhibitory sigmoid Emax model, the AUC24 h/MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs separately. According to the Monte Carlo simulation, the COPD was calculated as 2 μg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR respectively. Conclusions In conclusion, we reveal the EOFF and PK/PD cutoff values of ceftiofur against A. pleuropneumoniae in piglets. However, with the paucity of clinical data for ceftiofur to establish a clinical cutoff against A. pleuropneumoniae, the PK/PD cutoff value of 2 μg/mL will be recommended as surrogate. According to the PK/PD data and the MIC distribution in China, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more able to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use in piglet.

Optimal regimens regimens based on PK/PD cutoff evaluation of ceftiofur against Actinobacillus pleuropneumoniae in swine

BackgroundActinobacillus pleuropneumoniae formerly known as Haemophilus pleuropneumoniae, can cause pleuropneumoniae in pigs, which lead to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals，which was effective against gram-negative and gram-positive bacterium. This study aimed to formulate a rational dosage strategy and review the preceding recommended dosage based on PK/PD modeling and Establish Clinical breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the pharmacodynamic-pharmacokinetic cutoff. ResultsThe epidemiologic cutoff value was 0.125 μg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 μg/mL and 1 μg/mL in vitro and ex-vivo, respectively. The minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 μg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent with a partly concentration-dependent pattern. Based on the inhibitory sigmoid Emax model, the AUC24 h/MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs separately. According to the Monte Carlo simulation, the COPD was calculated as 2 μg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR respectively.ConclusionsIn conclusion, we reveal the EOFF and PK/PD cutoff values of ceftiofur against A. pleuropneumoniae in piglets. However, with the paucity of clinical data for ceftiofur to establish a clinical cutoff against A. pleuropneumoniae, the PK/PD cutoff value of 2 μg/mL will be recommended as surrogate. According to the PK/PD data and the MIC distribution in China, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more able to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use in piglet.

Optimal regimens regimens based on PK/PD cutoff evaluation of ceftiofur against Actinobacillus pleuropneumoniae in swine

Background Actinobacillus pleuropneumoniae formerly known as Haemophilus pleuropneumoniae, can cause pleuropneumoniae in pigs, which lead to significant mortality. Ceftiofur was the first cephalosporin antibiotic used in animals，which was effective against gram-negative and gram-positive bacterium. This study aimed to formulate a rational dosage strategy and review the preceding recommended dosage based on PK/PD modeling and Establish Clinical breakpoint of ceftiofur against Actinobacillus pleuropneumoniae based on the pharmacodynamic-pharmacokinetic cutoff. Results The epidemiologic cutoff value was 0.125 μg/mL. The results of the pharmacodynamic study showed that the MICs of BW39 were 0.5 μg/mL and 1 μg/mL in vitro and ex-vivo, respectively. The minimal bactericidal concentrations (MBCs) under in vitro and ex vivo conditions were both 1 μg/mL. The time-killing profiles of ceftiofur against BW39 were time-dependent with a partly concentration-dependent pattern. Based on the inhibitory sigmoid Emax model, the AUC24 h/MIC values for the bacteriostatic, bactericidal, and elimination effects in serum were 45.73, 63.83, and 69.04 h for healthy pigs separately. According to the Monte Carlo simulation, the COPD was calculated as 2 μg/mL, and the optimized dosage regimen of ceftiofur against Actinobacillus pleuropneumoniae to achieve bacteriostatic, bactericidal, and elimination effects over 24 h was 2.13, 2.97, and 3.42 mg/kg for the 50% target attainment rate (TAR) and 2.47, 3.21, and 3.70 mg/kg for the 90% TAR respectively.Conclusions In conclusion, we reveal the EOFF and PK/PD cutoff values of ceftiofur against A. pleuropneumoniae in piglets. However, with the paucity of clinical data for ceftiofur to establish a clinical cutoff against A. pleuropneumoniae, the PK/PD cutoff value of 2 μg/mL will be recommended as surrogate. According to the PK/PD data and the MIC distribution in China, the single bactericidal dose was 3.21 mg/kg for the 90% target, which would be more able to cure Actinobacillus pleuropneumoniae and avoid the emergence of resistance for clinical ceftiofur use in piglet.