Intravenous Β-lactam Antibiotics Research Articles

Oral quinolones versus intravenous β-lactam for the treatment of acute focal bacterial nephritis: a retrospective cohort study

BackgroundEvidence regarding the best antibiotic regimen and the route of administration to treat acute focal bacterial nephritis (AFBN) is scarce. The aim of the present study was to compare the effectiveness of intravenous (IV) β-lactam antibiotics versus oral quinolones.MethodsThis is a retrospective single centre study of patients diagnosed with AFBN between January 2017 and December 2018 in Hospital Universitari Vall d’Hebron, Barcelona (Spain). Patients were identified from the diagnostic codifications database. Patients treated with oral quinolones were compared with those treated with IV β-lactam antibiotics. Therapeutic failure was defined as death, relapse, or evolution to abscess within the first 30 days.ResultsA total of 264 patients fulfilled the inclusion criteria. Of those, 103 patients (39%) received oral ciprofloxacin, and 70 (26.5%) IV β-lactam. The most common isolated microorganism was Escherichia coli (149, 73.8%) followed by Klebsiella pneumoniae (26, 12.9%). Mean duration of treatment was 21.3 days (SD 7.9). There were no statistical differences regarding therapeutic failure between oral quinolones and IV β-lactam treatment (6.6% vs. 8.7%, p = 0.6). Out of the 66 patients treated with intravenous antibiotics, 4 (6.1%) experienced an episode of phlebitis and 1 patient (1.5%) an episode of catheter-related bacteraemia.ConclusionsWhen susceptible, treatment of AFBN with oral quinolones is as effective as IV β-lactam treatment with fewer adverse events.

International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists.

Intravenous β-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. β-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PIs) can be applied during the administration of intravenous β-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of PI β-lactams developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug-monitoring considerations, and the use of PI β-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of β-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).

International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists: An executive summary.

Intravenous β-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. β-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PI) can be applied during the administration of intravenous β-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of β-lactam PI developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug monitoring considerations, and the use of PI β-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of β-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).

Antibiotic susceptibility of clinical Burkholderia pseudomallei isolates in northeast Thailand during 2015-2018 and the genomic characterization of β-lactam-resistant isolates.

Melioidosis is an often fatal infection in tropical regions caused by an environmental bacterium, Burkholderia pseudomallei Current recommended melioidosis treatment requires intravenous β-lactam antibiotics such as ceftazidime (CAZ), meropenem (MEM) or amoxicillin-clavulanic acid (AMC) and oral trimethoprim-sulfamethoxazole. Emerging antibiotic resistance could lead to therapy failure and high mortality. We performed a prospective multicentre study in northeast Thailand during 2015-2018 to evaluate antibiotic susceptibility and characterize β-lactam resistance in clinical B. pseudomallei isolates. Collection of 1,317 B. pseudomallei isolates from patients with primary and relapse infections were evaluated for susceptibility to CAZ, imipenem (IPM), MEM and AMC. β-lactam resistant isolates were confirmed by broth microdilution method and characterized by whole genome sequence analysis, penA expression and β-lactamase activity. The resistant phenotype was verified via penA mutagenesis. All primary isolates were IPM-susceptible but we observed two CAZ-resistant and one CAZ-intermediate resistant isolates, two MEM-less susceptible isolates, one AMC-resistant and two AMC-intermediate resistant isolates. One of 13 relapse isolates was resistant to both CAZ and AMC. Two isolates were MEM-less susceptible. Strains DR10212A (primary) and DR50054E (relapse) were multi-drug resistant. Genomic and mutagenesis analyses supplemented with gene expression and β-lactamase analyses demonstrated that CAZ-resistant phenotype was caused by PenA variants: P167S (N=2) and penA amplification (N=1). Despite the high mortality rate in melioidosis, our study revealed that B. pseudomallei isolates had a low frequency of β-lactam resistance caused by penA alterations. Clinical data suggest that resistant variants may emerge in patients during antibiotic therapy and be associated with poor response to treatment.

Ribaxamase, an Orally Administered β-Lactamase, Diminishes Changes to Acquired Antimicrobial Resistance of the Gut Resistome in Patients Treated with Ceftriaxone.

IntroductionIntravenous (IV) β-lactam antibiotics, excreted through bile into the gastrointestinal (GI) tract, may disrupt the gut microbiome by eliminating the colonization resistance from beneficial bacteria. This increases the risk for Clostridium difficile infection (CDI) and can promote antimicrobial resistance by selecting resistant organisms and eliminating competition by non-resistant organisms. Ribaxamase is an orally administered β-lactamase for use with IV β-lactam antibiotics (penicillins and cephalosporins) and is intended to degrade excess antibiotics in the upper GI before they can disrupt the gut microbiome and alter the resistome.MethodsLongitudinal fecal samples (349) were collected from patients who participated in a previous Phase 2b clinical study with ribaxamase for prevention of CDI. In that previous study, patients were treated with ceftriaxone for a lower respiratory tract infection and received concurrent ribaxamase or placebo. Extracted fecal DNA from the samples was subjected to whole-genome shotgun sequencing and analyzed for the presence of antimicrobial resistance (AMR) genes by alignment of sequences against the Comprehensive Antibiotic Resistance Database. A qPCR assay was also used to confirm some of the results.ResultsDatabase alignment identified ~1300 acquired AMR genes and gene variants, including those encoding β-lactamases and vancomycin resistance which were significantly increased in placebo vs ribaxamase-treated patients following antibiotic exposure. qPCR corroborated the presence of these genes and supported both new acquisition and expansion of existing gene pools based on no detectable copy number or a low copy number in pre-antibiotic samples which increased post-antibiotics. Additional statistical analyses demonstrated significant correlations between changes in the gut resistome and clinical study parameters including study drug assignment and β-lactamase and vancomycin resistance gene frequency.DiscussionThese findings demonstrated that ribaxamase reduced changes to the gut resistome subsequent to ceftriaxone administration and may help limit the emergence of AMR.

Use of ribaxamase (SYN-004), a β-lactamase, to prevent Clostridium difficile infection in β-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial

Infections with Clostridium difficile are a health threat, yet no products are currently licensed for prevention of primary C difficile infections. Intravenous β-lactam antibiotics are considered to confer a high risk of C difficile infection because of their biliary excretion into the gastrointestinal tract and disruption of the gut microbiome. ribaxamase (SYN-004) is an orally administered β-lactamase that was designed to be given with intravenous β-lactam antibiotics to degrade excess antibiotics in the upper gastrointestinal tract before they disrupt the gut microbiome and lead to C difficile infection. We therefore aimed to determine whether administration of ribaxamase could prevent C difficile infection in patients being treated with intravenous ceftriaxone for a lower respiratory tract infection, thereby supporting continued clinical development. In this parallel-group, double-blind, multicentre, phase 2b, randomised placebo-controlled trial, we recruited patients who had been admitted to a hospital with a lower respiratory tract infection with a pneumonia index score of 90-130 and who were expected to be treated with ceftriaxone for at least 5 days. Patients were recruited from 54 clinical sites in the USA, Canada, Bulgaria, Hungary, Poland, Romania, and Serbia. We randomly assigned patients older than 50 years to groups (1:1) in blocks of four by use of an interactive web portal; these groups were assigned to receive either 150 mg ribaxamase or placebo four times per day during, and for 72 h after, treatment with ceftriaxone. All patients, clinical investigators, study staff, and sponsor personnel were masked to the study drug assignments. The primary endpoint was the incidence of C difficile infection, as diagnosed by the local laboratory, in patients who received at least one treatment dose, and this outcome was assessed during treatment and for 4 weeks after treatment. This study is registered with ClinicalTrials.gov, number NCT02563106. Between Nov 16, 2015, and Nov 10, 2016, we screened 433 patients for inclusion in the study. Of these patients, 20 (5%) patients were excluded from the study (16 [4%] patients did not meet inclusion criteria; four [1%] patients because of dosing restrictions). We enrolled and randomly assigned 413 patients to groups, of whom 207 patients were assigned to receive ceftriaxone plus ribaxamase and 206 patients were assigned to receive ceftriaxone plus placebo. However, one (<1%) patient in the ribaxamase group withdrew consent and was not treated with ribaxamase. During the study and within the 4 weeks after antibiotic treatment, two (1·0%) patients in the ribaxamase group and seven (3·4%) patients in the placebo group were diagnosed with an infection with C difficile (risk reduction 2·4%, 95% CI -0·6 to 5·9; one-sided p=0·045). Adverse events were similar between groups but more deaths were reported in the ribaxamase group (11 deaths vs five deaths in the placebo group). This disparity was due to the higher incidence of deaths attributed to cardiac-associated causes in the ribaxamase group (six deaths vs one death in the placebo group). In patients treated with intravenous ceftriaxone for lower respiratory tract infections, oral ribaxamase reduced the incidence of C difficile infections compared with placebo. The imbalance in deaths between the groups appeared to be related to the underlying health of the patients. Ribaxamase has the potential to prevent C difficile infection in patients treated with intravenous β-lactam antibiotics, and our findings support continued clinical development of ribaxamase to prevent C difficile infection. Synthetic Biologics.

SYN-004 (Ribaxamase), an Orally Administered β-Lactamase for Prevention of Clostridium Difficile Infection in Patients Treated with Intravenous β-Lactam Antibiotics: A Randomized, Double-Blind, Placebo-Controlled Phase 2b Study

Background: Clostridium difficile infection (CDI) is an urgent public health threat, yet there is no product currently licensed for its prevention. The use of intravenous β-lactam antibiotics are considered high risk for the development of CDI due to their biliary excretion into the GI tract and disruption of the gut microbiome. SYN-004 (ribaxamase) is an orally-administered β-lactamase, designed to be given with IV β-lactam antibiotics to degrade excess antibiotics in the upper GI tract before they can disrupt the gut microbiome leading to CDI. Methods: A parallel-group, double-blind, placebo-controlled, multi-center, study evaluating the effectiveness of ribaxamase for prevention of CDI was conducted in 412 hospitalized patients > 50 years of age who received intravenous ceftriaxone for a lower respiratory tract infection (LRTI). Patients were randomized 1:1 to receive either 150 mg of ribaxamase or placebo four times per day during and for 72 hours after ceftriaxone treatment. The primary endpoint was the incidence of CDI through 4 weeks post-treatment in the ribaxamase vs. the placebo group. Secondary endpoints included resolution of the LRTI, new colonization by certain opportunistic pathogens, and microbiome-focused exploratory endpoints. Findings: Of 412 patients (mean age ~69·5), 206 each received ceftriaxone plus ribaxamase or ceftriaxone plus placebo. By 4 weeks post-antibiotics, the incidence of CDI in the placebo group was 3·4% while the incidence of C. difficile infection in the ribaxamase group was only 1·0% which corresponds to a 71% reduction in the incidence of C. difficile infection (one-sided, P=0·045). Patients who received ribaxamase also had a lower incidence of new fecal colonization with C. difficile and vancomycin resistant enterococci. Interpretation: In patients being treated with intravenous ceftriaxone for a LRTI, oral ribaxamase significantly reduced the incidence of CDI as compared with placebo. Ribaxamase has the potential to become the first product licensed for prevention of CDI. Trial registration number: The trial was registered at clinicaltrials.gov: NCT02563106. Funding: Synthetic Biologics, Inc. Declaration of Interest: All authors are employees or paid consultants of Synthetic Biologics, Inc. Ethical Approval: The study protocol was approved by the appropriate institutional review boards or ethics committees at the corresponding institutions or countries. All study patients provided written informed consent to participate in the study.

Epidemiological Features and Antibiotic Resistance Patterns of Haemophilus influenzae Originating from Respiratory Tract and Vaginal Specimens in Pediatric Patients

Study ObjectiveHaemophilus influenzae (H. influenzae) is a common pathogen of respiratory tract infections in children, however, as a possible cause of vulvovaginitis in prepubertal girls, its epidemiological features, antibiotic-resistance patterns, and treatment are seldom noted. Design, Setting, Participants, Interventions, and Main Outcome MeasuresSpecimens obtained from patients were inoculated on Haemophilus selective medium; and drug-sensitivities tests were determined using the disk diffusion method. A cefinase disk was used to detect β-lactamase. ResultsA total of 610 H. influenzae strains, 81.6% (498/610) from the respiratory tract and 18.0% (110/610) from the vagina, were identified in the Children's Hospital in 2015. The age of the children with respiratory tract strains were significantly younger than those with vaginal strains (P < .001). The H. influenzae isolation rate in May was the highest. The β-lactamase positive rate was 51.5% (314/610), and 52.5% (320/610) were resistant to ampicillin. The susceptibilities rates to cefuroxime, ampicillin/sulbactam, cefotaxime, clarithromycin, and sulfamethoxazole-trimethoprim were 72.1% (440/610), 95.9%, 96.4% (588/610), 81.8% (499/610), and 36.4% (222/610), respectively. Higher resistance to ampicillin, cefuroxime, clarithromycin, and sulfamethoxazole-trimethoprim were found in respiratory tract strains, compared with vaginal strains (P < .05). All of the patients with H. influenzae in the respiratory tract were cured with oral or intravenous β-lactam antibiotics. Of all patients with vaginal strains, 50% (55/110) were cured with topical ofloxacin gel, and 44.5% (49/110) were cured with oral β-lactam antibiotics. ConclusionThe drug-resistance rates of H. influenzae isolated from vagina were lower than those from the respiratory tract. Topical ofloxacin gel or oral β-lactam antibiotics are effective treatments to eliminate the H. influenza causing infection in the vagina.

Nonclinical Safety Assessment of SYN-004: An Oral β-lactamase for the Protection of the Gut Microbiome From Disruption by Biliary-Excreted, Intravenously Administered Antibiotics.

SYN-004 is a first in class, recombinant β-lactamase that degrades β-lactam antibiotics and has been formulated to be administered orally to patients receiving intravenous β-lactam antibiotics including cephalosporins. SYN-004 is intended to degrade unmetabolized antibiotics excreted into the intestines and thus has the potential to protect the gut microbiome from disruption by these antibiotics. Protection of the gut microbiome is expected to protect against opportunistic enteric infections such as Clostridium difficile infection as well as antibiotic-associated diarrhea. In order to demonstrate that oral SYN-004 is safe for human clinical trials, 2 Good Laboratory Practice-compliant toxicity studies were conducted in Beagle dogs. In both studies, SYN-004 was administered orally 3 times per day up to the maximum tolerated dose of the formulation. In the first study, doses of SYN-004 administered over 28 days were safe and well tolerated in dogs with the no-observed-adverse-effect level at the high dose of 57 mg/kg/day. Systemic absorption of SYN-004 was minimal and sporadic and showed no accumulation during the study. In the second study, doses up to 57 mg/kg/day were administered to dogs in combination with an intravenous dose of ceftriaxone (300 mg/kg) given once per day for 14 days. Coadministration of oral SYN-004 with intravenous ceftriaxone was safe and well tolerated, with SYN-004 having no noticeable effect on the plasma pharmacokinetics of ceftriaxone. These preclinical studies demonstrate that SYN-004 is well tolerated and, when coadministered with ceftriaxone, does not interfere with its systemic pharmacokinetics. These data supported advancing SYN-004 into human clinical trials.

Characterization of anti‐drug antibodies and drug‐responsive B‐lymphocytes in piperacillin hypersensitive patients with cystic fibrosis

Cystic fibrosis is the most common autosomal recessive condition in Caucasians and recurrent infections lead to a plethora of complications. Repeated courses of high dose intravenous β-lactam antibiotics, such as piperacillin, are employed for the treatment of respiratory exacerbations. Unfortunately, delayed-type hypersensitivity reactions develop in between 26-50% of treated patients. We have recently described the cellular immunological processes that underlie drug-specific response in hypersensitive patients; however, the involvement of the humoral immune system has not been studied. The aim of this study was to quantify piperacillin-specific antibodies in plasma of hypersensitive and tolerant patients and investigate whether B-cells can be stimulated to secrete antibodies in vitro following drug stimulation. Drug-specific antibodies were quantified by ELISA using piperacillin-modified BSA as an antigen. Adducts generated using different drug-protein ratios were used to measure the degree of conjugation that elicits an antibody response. BSA was modified with different β-lactam antibiotics to define structural specificity. Specificity for the piperacillin BSA adduct was confirmed by hapten inhibition. Mass spectrometry was used to characterize the Lys residues modified with piperacillin. B-cells isolated from PBMC were cultured with piperacillin for 5 days and IgG secretion and B-cell activation was measured using ELISpot and flow cytometry (CD19, CD27), respectively. A significantly higher level of anti-piperacillin IgG antibody was detected in plasma of hypersensitive patients when hypersensitive and tolerant patients were compared. Hapten inhibition ELISA confirmed specificity for the piperacillin antigenic determinant. Antibody binding was detected with adducts generated at piperacillin:BSA ratios between 1:1 and 100:1. In contrast, antibody binding was not detectable with penicillin G, amoxicillin or aztreonam BSA conjugates. IgG antibody secretion was also detected from purified B-cells from hypersensitive patients cultured with soluble piperacillin. Drug treatment was associated with increased expression of the B-cell activation marker CD27. These data begin to describe the drug-specific humoral immune response in piperacillin hypersensitive patients with cystic fibrosis. Further work is needed to define the role different antibody subtypes play in the disease pathogenesis.

Continuous intravenous β-lactam antibiotics in cystic fibrosis patients with severe drug hypersensitivity

Continuous intravenous β-lactam antibiotics in cystic fibrosis patients with severe drug hypersensitivity

Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams

IntroductionSeveral reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.MethodsWe performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded.ResultsA total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock.ConclusionsThe PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.