Addition Of Tobramycin Research Articles

Antibacterial effect of seven days exposure to ceftolozane-tazobactam as monotherapy and in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa with ceftolozane-tazobactam MICs at or above 4 mg/l in an in vitro pharmacokinetic model.

To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L). An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h. Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.5-4.5 log reductions in count by 6 h post drug exposure for strains with MIC ≤32 mg/L. The antibacterial effect over the first 24 h was related to ceftolozane/tazobactam MIC. There was subsequent regrowth with most strains to bacterial densities of >106 CFU/mL. Addition of either fosfomycin or tobramycin resulted in suppression of regrowth and in the case of tobramycin more rapid initial bacterial killing up to 6 h. These effects could not be related to either fosfomycin or tobramycin MICs. Changes in population profiles were noted with ceftolozane/tazobactam alone often after 96 h exposure but such changes were suppressed by fosfomycin and almost abolished by the addition of tobramycin. The addition of either fosfomycin or tobramycin to ceftolozane/tazobactam at simulated human clinically observed concentrations reduced P. aeruginosa bacterial loads and the risk of resistance to ceftolozane/tazobactam when strains had ceftolozane/tazobactam MIC values at or above the clinical breakpoint.

Sensitive determination of tobramycin using homocystine capped gold nanoclusters as probe by second-order scattering

A novel photoluminescent Hcy-AuNCs has been developed through one-pot reduction method, to establish a tobramycin sensing by second-order scattering (SOS). Hcy-AuNCs could spontaneously assemble to small-scaled aggregation, resulting in remarkable intensity enhancement of scattered luminescence signals. The luminescence of Hcy-AuNCs could be clearly observed under ultraviolet lamp, when excited at 365 nm, a significant luminescent intensity at 741 nm was monitored in SOS spectra. The introduction of AuNPs would cause large-scaled aggregation of Hcy-AuNCs that was rapidly settled in the solution, resulting in the decrease of SOS intensity. Besides, the non-radiative energy transfer between AuNPs and Hcy-AuNCs would also reduce the luminescent intensity. However, the addition of tobramycin would cause the aggregation of AuNPs due to the electrostatic and covalent bonding between AuNPs and tobramycin, thus eliminating the interference of AuNPs. The luminescence of Hcy-AuNCs reappeared, exhibiting an optical response toward tobramycin. The good linearity was obtained in a wide range from 4 nM to 300 nM with a low detection limit of 0.27 nM. The selectivity was acceptable toward different types of antibiotics. Finally, the proposed method was successfully applied to the widely used tobramycin eye drops.

Mode of bacterial killing affects the inflammatory response and associated organ dysfunctions in a porcine E. coli intensive care sepsis model

BackgroundSepsis is often treated with penicillin-binding protein 3 (PBP-3) acting β-lactam antibiotics, such as piperacillin-tazobactam, cefotaxime, and meropenem. They cause considerable bacterial structural changes and have in vitro been associated with an increased inflammatory response. In a clinically relevant large animal sepsis model, our primary aim was to investigate whether bacteria killed by a PBP-3-active antibiotic has a greater effect on the early inflammatory response and organ dysfunction compared with corresponding amounts of live or heat-killed bacteria. A secondary aim was to determine whether the addition of an aminoglycoside could mitigate the cefuroxime-induced response.MethodKilled or live Escherichia coli were administrated as a 3-h infusion to 16 healthy pigs in a prospective, randomized controlled interventional experimental study. Cefuroxime was chosen as the PBP-3-active antibiotic and tobramycin represented the aminoglycosides. The animals were randomized to receive (I) bacteria killed by cefuroxime, (II) live bacteria, (III) bacteria killed by heat, or (IV) bacteria killed by the combination of cefuroxime and tobramycin. Plasma endotoxin, tumor necrosis factor alpha, interleukin-6, interleukin-10, leukocytes, and organ function were recorded at the start of the experiment and then hourly for 6 h.ResultsDifferences in dynamics of concentration over time between the four treatment groups were found for the three cytokines (p < 0.001). Animals receiving cefuroxime-killed bacteria demonstrated higher responses than those receiving live (p < 0.05) or heat-killed bacteria (p < 0.01). The addition of tobramycin reduced the cefuroxime-induced responses (p < 0.001). The cytokine responses were associated with leucocyte activation that was further associated with pulmonary dysfunction and increases in lactate (p < 0.01).ConclusionsIn comparison with live or heat-killed bacteria, bacteria killed by a PBP-3-active antibiotic induced an increased inflammatory response that appears to be associated with deteriorated organ and cellular function. The addition of an aminoglycoside to the PBP-3-active antibiotic reduced that response.

Evaluation of Guideline Recommendations for Dual Antipseudomonal Therapy in Hospitalized Adults with Pneumonia Using Combination Antibiograms.

Guidelines for pneumonia recommend empiric dual antipseudomonal therapy in patients with specific risk factors. However, there is lack of consensus on when to use dual antipseudomonal therapy as the recommendations are rated as weak, based on low-quality evidence. The objectives of this study were to develop combination antibiograms to assess the susceptibility of Pseudomonas aeruginosa (P. aeruginosa) in respiratory cultures to combinations of empiric antibiotics and to use combination antibiograms to delineate the impact of specific risk factors for which guidelines recommend dual antipseudomonal therapy. A retrospective cohort study was conducted of adults hospitalized with pneumonia with positive respiratory cultures for P. aeruginosa between September 2014 and September 2018. Data collected included demographics, antimicrobial susceptibility results, and risk factors for which guidelines recommend dual antipseudomonal therapy. Combination antibiograms were developed and logistic regression was performed to identify risk factors for nonsusceptibility to beta-lactams. Eight hundred nineteen patients were included and 72% received antibiotics. Beta-lactam susceptibility ranged from 58% to 69% and addition of a fluoroquinolone or aminoglycoside resulted in statistically significant increases in susceptibility. However, only addition of tobramycin or amikacin provided susceptibility rates approaching or exceeding 90% stratified by pneumonia type and risk factors. Presence of guideline-based risk factors generally resulted in reduced susceptibility rates. Logistic regression identified three risk factors associated with nonsusceptibility to beta-lactams: intravenous antibiotics in the previous 90 days, nursing home residence, and mechanical ventilation at onset. The cumulative presence of each additional risk factor affected beta-lactam susceptibility rates, which were 93% in the absence of any risk factors and 39% when all three risk factors co-existed. Risk factors necessitating dual antipseudomonal therapy for pneumonia should be locally validated. When dual antipseudomonal therapy is indicated, tobramycin or amikacin have the best likelihood of providing adequate in vitro activity.

Daptomycin-Tobramycin Cement Beads have Lethal Local Antibacterial Effect in Resistant Periprosthetic Joint Infections.

BackgroundResistant periprosthetic joint infection (PJI) can be a devastating complication of surgery and is difficult to treat. We attempted to identify the utility of Daptomycin/Tobramycin-impregnated polymethylmethacrylate (PMMA) beads in resistant PJIs.MethodsCharts of patients with hip or knee PJI at a single academic medical center, with surgeries performed from May 2008 through May 2018, were reviewed retrospectively. The diagnosis of PJI was consistent with the Musculoskeletal Infection Society recommendations. Prosthetic joints underwent radical anterior-posterior synovectomy and placement of antibiotic cement beads in the infected joint. Clinical cure rate and local intraarticular antibiotic concentration were measured.ResultsForty-four patients experienced 53 episodes of PJI, requiring 88 surgeries. There was a fairly even split between hip and knee PJI. The cure rate was 92% (11/12) for patients who had any infection with methicillin-resistant staphylococci during the evaluation period, compared with 62% (13/21) for patients with methicillin-susceptible Staphylococci. On days one and seven, the addition of tobramycin increased daptomycin concentrations by 47% and 3374%, respectively, for beads made onsite compared to elution of daptomycin alone. Elution increased by 44% and 8394%, respectively, for commercial beads compared to beads fabricated onsite.ConclusionsDaptomycin-Tobramycin-loaded PMMA beads are safe and powerful bactericidal agents in prosthetic joint infections.

Gold nanoparticle based photometric determination of tobramycin by using new specific DNA aptamers.

A magnetic bead-based SELEX was applied to identify 37 single-stranded DNA aptamers specific for tobramycin after ten rounds of selection. The aptamers were classified into nine families according to sequence analysis. Among them, several aptamers with typical sequences were selected and their dissociation constants (Kds) were determined by a fluorescent method. An aptamer termed "Ap 32", with a Kd value of 56.8 ± 4.6nM, possesses the highest affinity and satisfactory specificity. Theoretical modeling showed that nucleotides 14-18 and 26-29 play a most significant role in the interaction between aptamer and tobramycin. Subsequently, the sequence of Ap 32 was optimized through rationally designed truncation. The truncated aptamer Ap 32-2 consists of 34 nucleotides and has a Kd that is similar to the original one. It was chosen as the optimal aptamer for use in the assay and was immobilized on gold nanoparticles. On addition of tobramycin, the color turns from red to purple. The findings were used to design a photometric assay (best performed at 520nm) that has a linear response in the 100nM to 1.4μM concentration range, with a 37.9nM detection limit. The method was successfully applied to the determination of tobramycin in (spiked) honey samples. Graphical abstract A 34-nucleotide aptamer specific for tobramycin was obtained through magnetic beads-based systematic evolution of ligands by exponential enrichment (SELEX) and structural analysis-based rational post-SELEX truncation, and then applied to the determination of tobramycin using a gold nanoparticle-based photometric assay.

RpoN Promotes Pseudomonas aeruginosa Survival in the Presence of Tobramycin.

Pseudomonas aeruginosa has developed diverse strategies to respond and adapt to antibiotic stress. Among the factors that modulate survival in the presence of antibiotics, alternative sigma factors play an important role. Here, we demonstrate that the alternative sigma factor RpoN (σ54) promotes survival in the presence of tobramycin. The tobramycin-sensitive phenotype of logarithmic phase ΔrpoN mutant cells is suppressed by the loss of the alternative sigma factor RpoS. Transcriptional analysis indicated that RpoN positively regulates the expression of RsmA, an RNA-binding protein, in the P. aeruginosa stationary growth phase in a nutrient-rich medium. The loss of RpoS led to the upregulation of gacA expression in the nutrient-limited medium-grown stationary phase cells. Conversely, in the logarithmic growth phase, the ΔrpoS mutant demonstrated lower expression of gacA, underscoring a regulatory role of RpoS for GacA. Supplementation of tobramycin to stationary phase ΔrpoN mutant cells grown in nutrient-rich medium resulted in decreased expression of gacA, relA, and rpoS without altering the expression of rsmA relative to wild-type PAO1. The observed downregulation of gacA and relA in the ΔrpoN mutant in the presence of tobramycin could be reversed through the mutation of rpoS in the ΔrpoN mutant background. The tobramycin-tolerant phenotype of the ΔrpoNΔrpoS mutant logarithmic phase cells may be associated with the expression of relA, which remained unresponsive upon addition of tobramycin. The logarithmic phase ΔrpoS and ΔrpoNΔrpoS mutant cells demonstrated increased expression of gacA in response to tobramycin. Together, these results suggest that a complex regulatory interaction between RpoN, RpoS, the Gac/Rsm pathway, and RelA modulates the P. aeruginosa response to tobramycin.

Potency of parenteral antimicrobials including ceftolozane/tazobactam against nosocomial respiratory tract pathogens: considerations for empiric and directed therapy.

Empiric therapy decisions are predicated on knowledge of both the epidemiology and antimicrobial susceptibility of the probable infecting pathogen(s). The objective of this study was to evaluate the microbial distribution and phenotypic profiles of nosocomial respiratory isolates collected from multiple US hospitals and assess the clinical utility of various monotherapy and combination regimens. Hospitals provided consecutive non-duplicate adult inpatients Gram-negative nosocomial respiratory isolates from cultures received ≥48 h after hospital admission. Minimum inhibitory concentrations (MICs) for 12 antimicrobials were determined using broth microdilution methods. An antibiogram was constructed for monotherapy regimens as well as combinations inclusive of either tobramycin (TOB) or ciprofloxacin (CIP). Six hospitals provided 518 nosocomial respiratory isolates. P. aeruginosa (PSA) comprised 28% of the population followed by Klebsiella pneumoniae (13%), Enterobacter spp. (13%), S. maltophilia (9%), S. marcesens (6%), A. baumannii (6%), and others (18%). When considering monotherapy for the Enterobacteriaceae & PSA ceftolozane/tazobactam (C/T) provided the highest (87%) percent susceptibility (%S) followed by meropenem (MEM), CIP, cefepime (FEP), ceftazidime (CAZ) and piperacillin-tazobactam (TZP) at 71-85%S. The addition of TOB > CIP improved the probability that the antimicrobial combination would provide ≥1 active agent. PSA was the predominant nosocomial respiratory pathogen; however, the Enterobacteriaceae comprised an additional 53% in this survey. When considering empiric β-lactam monotherapy therapy for the entire spectrum of pathogens C/T provided the highest (78%) %S followed by MEM, FEP and TZP. The addition of either TOB > CIP to these β-lactams enhances the likelihood that an active agent would be selected when considering empirical therapy choices for nosocomial respiratory tract infections.

In vitro Activity of Ceftolozane/Tazobactam Alone or with an Aminoglycoside Against Multi-Drug-Resistant Pseudomonas aeruginosa from Pediatric Cystic Fibrosis Patients.

IntroductionGram-negative multi-drug resistance is an emerging threat among pediatric patients with cystic fibrosis (CF). Ceftolozane/tazobactam (C/T) is an extended-spectrum cephalosporin/beta-lactamase inhibitor combination that has been shown to maintain activity against MDR P. aeruginosa isolates. The understanding of C/T effectiveness in pediatric patients is extremely limited. Minimum inhibitory concentration (MIC) testing and time-kill analyses were performed to better understand the antimicrobial susceptibility and potential role of C/T.MethodsNon-duplicate clinical respiratory MDR P. aeruginosa isolates (n = 5) from four pediatric CF patients were identified. MICs were determined for these isolates using CLSI broth microdilution methods. Time-kill analyses were performed using multiples of C/T alone, and combinations of C/T 2× and 8× the MIC with 30 mg/L tobramycin or 80 mg/L amikacin for all isolates. Cell counts were determined by serial dilution plating.ResultsIsolates had variable susceptibilities to C/T (range 0.5–8 mg/L), tobramycin (range 2 to >64 mg/L) and amikacin (range 8 to >256 mg/L). Time-kill analyses revealed an average of 0.71 (range −0.6 to 4.4), 1.50 (range 0.8–2.0) and 2.1 (range 1.2–3.4) log-kill at 4×, 8× and 16× the C/T MIC, respectively. At a tobramycin MIC of 32 mg/L, combination therapy showed synergistic benefit when the isolate was C/T susceptible. C/T and amikacin combination therapy showed synergistic activity at an amikacin MIC >256 mg/L when C/T MIC was 2 mg/L (4.7 log-kill at 2× C/T MIC and 4.0 log-kill at 8× C/T MIC).ConclusionC/T appears to be a promising treatment option for treatment of MDR P. aeruginosa in pediatric CF patients, both alone and in combination with tobramycin or amikacin. Interestingly, the benefit of C/T combination therapy with amikacin may be more pronounced than with the addition of tobramycin. Further evaluation of such combination regimens in pediatric CF patients is warranted.

Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System.

Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing in vitro model of Pseudomonas aeruginosa biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between P. aeruginosa, a bacterium associated with declining lung function and worsening disease, and Streptococcus constellatus, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of S. constellatus 7155 and P. aeruginosa PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of S. constellatus 7155 and P. aeruginosa PA14 resulted in enhanced S. constellatus biofilm formation. Through a candidate genetic approach, we showed that P. aeruginosa rhamnolipids were reduced upon tobramycin exposure, allowing for S. constellatus 7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce S. constellatus 7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of S. constellatus 7155 and P. aeruginosa PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways. Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions, we have the potential to select the best therapy for a given bacterial community and reveal potential opportunities for novel therapeutic interventions. Using an in vitro model of bacterial infection on CF airway cells, we tested how a particular polymicrobial community grows, damages human cells, and responds to antibiotics in single and mixed infections. We describe here the mechanism of an interspecies interaction between two pathogens in the CF lung, P. aeruginosa and S. constellatus, which is potentiated by a commonly prescribed antibiotic, tobramycin.

Pulmonary Mucormycosis - A Disease Against Time

Abstract SESSION TYPE: Infectious Disease Case Report Posters IIPRESENTED ON: Tuesday, October 23, 2012 at 01:30 PM - 02:30 PMINTRODUCTION: Pulmonary mucormycosis, a rare fungal infection with a high mortality rate, has been reported in patients with diabetic ketoacidosis, diabetes mellitus, and immunosupression due to chemotherapy, steroids, and hematological malignancies. Without early recognition and management, it can be ultimately fatal. We report a rare case of isolated pulmonary mucormycosis.CASE PRESENTATION: 65-year-old Caucasian male presented with shortness of breath for 2 days associated with chills, nonproductive cough, right upper pleuritic chest pain, and 4 days of polyuria and polydipsia. Patient was recently admitted and discharged on tapering prednisone for COPD exacerbation. Patient had 30 pack year smoking history. On presentation he was febrile, tachycardic, tachypneic and normotensive with physical findings consistent with right upper lobe (RUL) infiltrate. Lab investigations showed leukocytosis. Serum chemistry showed acute kidney injury (AKI) and hyperglycemia with a normal anion gap. Chest x-ray demonstrated RUL infiltrate. Patient was started on IV fluids, insulin drip, and piperacillin-tazobactam, vancomycin and ciprofloxacin. In ICU, patient's vitals deteriorated requiring mechanical ventilation. Initially all cultures showed no growth. Ciprofloxacin and vancomycin were changed to moxifloxacin and linezolid with addition of tobramycin. RUL infiltrate steadily worsened with suspicion of cavitation or abscess formation. CT chest showed necrotizing RUL infiltrate. Patient developed multi-organ failure and DIC requiring aggressive management. Bronchoscopy and BAL of the RUL showed mucosal edema and dark brown secretions . Few weeks later BAL results yielded a mold with cultures positive for Rhizopus species. Posaconazole and amphoterocin B were used to treat Rhizopus. Surgery for lobectomy could not be performed due to multilobar involvement. Gradually necrotizing pneumonia resulted in right sided pneumothorax. Chest tube was placed with non-resolving severe air leak. Repeat bronchoscopy showed bronchopleural fistula and necrotizing tissue. After multiple family meetings, comfort care decision was made, after which patient passed away.DISCUSSION: Rhizopus is genus of class Zygomycetes. It can cause tissue infarctions ranging from cutaneous, rhinocerebral, and sinopulmonary to disseminated and frequently fatal infections, especially in immunocompromised hosts. Ischemic necrosis of tissues can prevent delivery of antifungal agents to the foci of infection. Surgical debridement is critical for treatment but is only possible if disease is localized. Combination of posaconazole, amphotericin B and capsofungin is used for medical management.CONCLUSIONS: Pulmonary mucormycosis is a rapidly progressive rare disease that carries a high mortality over a short period of time. Dissemination, multiorgan failure and invariably death follows, if not recognized early.1) Francis Y. Pulmonary Mucormycosis Arch Intern Med. 1999;159:1301-1309DISCLOSURE: The following authors have nothing to disclose: Muhammad Ali, Hasan Zaidi, Aasiya Haroon, Nader Mahmood, Mourad IsmailNo Product/Research Disclosure InformationSt. Josephs's Regional Medical Center/Seton Hall Universtiy, Paterson, NJ.

Effect of a single dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour porcine model*

To evaluate whether the addition of tobramycin further compromises renal function in inflammatory response-induced acute kidney injury. Effective antibiotic treatment in septic shock is crucial for the outcome. The combination of aminoglycosides with different beta-lactam antibiotics offers a broad antimicrobial coverage, rapid bacterial killing, synergistic effects, and low antibiotic-induced endotoxin release. However, aminoglycosides have nephrotoxic effects that may aggravate sepsis-induced acute kidney injury. Prospective, randomized, placebo-controlled experimental study. University research unit. Twenty-four healthy pigs. The animals were anesthetized and randomized to four groups. Groups I (n = 8) and II (n = 8) received endotoxin infusion for 6 hrs, whereas groups III (n = 4) and IV (n = 4) received saline. Groups I and III received 7 mg/kg of tobramycin 20 mins after the initiation of the protocol, whereas groups II and IV received saline. The renal elimination rate of a bolus dose of cefuroxime was chosen as the primary end point. Renal function was also evaluated by urine output, creatinine clearance, plasma cystatin C, plasma urea, and urine NAG (N-acetyl-beta-D-glucoaminidase). After 3 hrs, there were significantly lower cefuroxime elimination rates in the two endotoxin groups than in the nonendotoxin groups. No difference in cefuroxime elimination rates between groups I and II could be detected at any time point. Similarly, there were changes indicating acute kidney injury in urine output, creatinine clearance, and plasma cystatin C in the endotoxin groups with no differences between groups I and II. Plasma urea and urine NAG did not differ between any of the groups. The result of this study does not lend any support to the hypothesis that a single dose of tobramycin enhances the risk of acute renal failure in cases with systemic inflammatory response-induced acute kidney injury.

Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: higher release after the second dose

To study endotoxin release from two strains of Escherichia coli after exposure to two repeated doses of cefuroxime in an in vitro kinetic model. Cefuroxime in concentrations simulating human pharmacokinetics was added to the bacterial solution with a repeated dose after 12 h. In another experiment, tobramycin was given concomitantly with the second dose of cefuroxime. Samples for viable counts and endotoxin analyses were drawn before the addition of antibiotics and at 2 and 4 h after each dose. The propensity to release endotoxin, expressed as log10 endotoxin release (EU)/log10 killed bacteria, was higher after the second than after the first dose, 0.80+/-0.04 and 0.65+/-0.01, respectively, in the ATCC strain and 0.80+/-0.04 and 0.65+/-0.02, respectively, in the clinical strain (P<0.001). Endotoxin was released earlier after the second dose (P<0.001). Addition of tobramycin at the second dose reduced the endotoxin release in comparison with that of cefuroxime alone (P<0.001). The propensity to liberate endotoxin is higher after the second dose of cefuroxime than after the first, resulting in a higher release of endotoxin than expected from bacterial count. The release after the second dose can be reduced by the addition of tobramycin.

Listeria meningitis in transplant recipients

Meningitis is a rare complication following organ and stem-cell transplantation and can be caused by a variety of microorganisms. To retrospectively review the clinical course and outcome of five cases of listeriosis in four organ recipients and one stem-cell recipient during a seven-year period. Patient records for more than 3500 patients undergoing organ or stem-cell transplantation at the university hospital of Innsbruck during a 27-year period were evaluated. Standard immunosuppression consisted of calcineurin inhibitor-based triple drug therapy with or without ATG or IL2 receptor antagonist induction. The first case affected a 35-year-old woman who received an allogenic bone marrow transplant for advanced breast cancer. Cases two and three related to two male heart recipients. Cases four and five were diagnosed in one male and one female renal recipient. Listeria monocytogenes was isolated from blood in two cases and from cerebrospinal fluid in three. Treatment consisted of ampicillin in all cases with the addition of tobramycin (1), TMPS (1), meropenem (2) or imipenem/cilastatin (1). The deaths of two patients were directly related to L. monocytogenes. Although listeriosis is a rare complication following transplantation, this infection should be ruled out in individuals presenting with neurological symptoms and fever.

Liquid Gentamicin in Bone Cement

Liquid gentamicin is approved by the Food and Drug Administration, is readily available, and is much less costly than tobramycin, the more commonly used antibiotic in cement spacers. The purpose of the present study was to test the mechanical properties, elution characteristics, and antibacterial activity of liquid gentamicin in an acrylic bone cement spacer. Standardized specimens consisting of Palacos cement combined with liquid gentamicin, powdered tobramycin, or no antibiotic were fashioned, and the three groups were tested with regard to compressive and tensile strength, elution characteristics (with use of radioimmunoassays), and antibacterial activity (with use of bioassays). The ultimate compression strength decreased by 49% (from 64.65 +/- 3.89 MPa to 32.96 +/- 3.33 MPa) and the ultimate tension strength decreased by 46% (from 35.85 +/- 2.97 MPa to 19.20 +/- 0.36 MPa) when the specimens containing 480 mg of liquid gentamicin were compared with the controls. The addition of tobramycin had no significant effect compared with the controls. The majority of gentamicin was released from the cement during the initial twenty-four hours (mean concentration, 26.4 mcg/mL). The mean concentrations at three and six weeks were 4.15 and 0.65 mcg/mL, respectively. The bioassays confirmed the bactericidal activity of the gentamicin released from the cement. Liquid gentamicin in bone cement is potent and bactericidal. Although the mechanical properties of the cement are significantly diminished by the addition of liquid gentamicin, the temporary nature of the cement spacer makes its use potentially worthwhile given the substantial cost savings to the hospital and the patient.

Variation in the propensity to release endotoxin after cefuroxime exposure in different gram-negative bacteria: uniform and dose-dependent reduction by the addition of tobramycin.

An aminoglycoside in combination with a beta-lactam antibiotic is often recommended for the treatment of severe infections. The aim of the present study was to study whether cefuroxime-induced endotoxin release could be reduced by addition of tobramycin in different Gram-negative bacteria and how endotoxin release was affected by bacterial killing rate and number of killed bacteria. Three Escherichia coli strains, 1 Klebsiella, 1 Salmonella and 1 Neisseria strain were exposed in vitro to 2, 10 and 50 x minimum inhibitory concentration of cefuroxime, tobramycin or a combination of both. The cefuroxime-induced endotoxin release in the 6 strains varied from 0.1 to 9.9 x 10(-3) EU/killed bacterium. By adding tobramycin, highly significant reductions of 96%, 93%, 97%, 86% and 85% were seen in the 3 E. coli strains and in the Klebsiella and the Salmonella strain, respectively. In the Neisseria strain, the reduction was less. Increasing doses of tobramycin or the combination led to significant endotoxin release reduction in 4/6 strains. In conclusion, addition of tobramycin reduced penicillin-binding protein-3-beta-lactam binding-induced endotoxin release in all tested Gram-negative strains, despite a large interspecies variation in the propensity to release endotoxin. Besides broadening the spectrum and increasing the killing rate, this might be of benefit in the most severe forms of sepsis.

Endotoxin-neutralising effect and anti-inflammatory properites of tobramycin and ceftazidime in porcine endotoxic shock

Administration of antibiotics represents a cornerstone in the treatment of severe bacterial infections. In addition to their antibacterial effect, antibiotics have been shown to cause other effects on the inflammatory response. Aminoglycosides have been considered to neutralise endotoxin and ceftazidime to modulate the inflammatory response by an antioxidative effect. The primary aim of this study was to investigate whether endotoxin given as an infusion in a porcine model could be neutralised by the addition of tobramycin. The secondary endpoint was to study whether ceftazidime could affect the inflammatory response by modifying the cytokine release during the end of the study period.

Treatment of Chronic Rhinosinusitis Refractory to Other Treatments with Topical Antibiotic Therapy Delivered by Means of a Large‐Particle Nebulizer: Results of a Controlled Trial

To study the efficacy of nebulized topical saline-tobramycin solution in patients with chronic rhinosinusitis refractory to medical and surgical therapy. Twenty patients in whom endoscopic sinus surgery failed to relieve symptoms entered a randomized, double-blind trial of tobramycin-saline solution or saline-only solution administered thrice daily to the nasal passages by means of a large-particle nebulizer apparatus for 4 weeks, followed by a 4-week observation period. Outcome measures of symptoms, quality of life, and endoscopic aspect of sinus mucosa were assessed. Both treatments were well tolerated and produced equivalent improvement in symptoms, quality of life, and mucosal aspect. Treatment with the tobramycin-saline solution gave more rapid improvement of pain, but led to the development of nasal congestion. Therapy with a 4-week course of large-particle nebulized aerosol therapy improves symptomatology and objective parameters of rhinosinusitis in patients refractory to surgical and medical therapies. Addition of tobramycin appears of minimal benefit. The mechanism of this effect is unexplained. Large-particle nebulized aerosol therapy may offer a safe and effective management alternative for patients with refractory rhinosinusitis.

The release of endotoxin from antibiotic-treated Escherichia coli and the production of tumour necrosis factor by human monocytes.

The influence of antibiotic-induced release of endotoxin from in-vitro grown Escherichia coli on the production of tumour necrosis factor-alpha (TNF) by human monocytes was studied. Antibiotics tested were: cefuroxime (7.5 and 75 mg/L); ceftazidime (10 and 100 mg/L); aztreonam (10 and 100 mg/L); imipenem (10 and 100 mg/L); and tobramycin (8 mg/L). The effect of the combination of cefuroxime plus tobramycin, and the effect of taurolidine, an endotoxin-binding agent, on TNF production was also tested. After incubation for 4 h, all antibiotic-treated cultures (high-dose) induced a similar rise in extracellular TNF production when compared to the controls. However, after incubation for 24 h, a significant rise in TNF production was noticed in the cefuroxime and aztreonam-treated cultures (6440 and 5969 ng/L, respectively) compared to the ceftazidime and imipenem-treated cultures (846 and 381 ng/L, respectively). The cefuroxime-induced release of TNF could be reduced by addition of tobramycin (from 6440 to 1615 ng/L). Similar differences in TNF production were noticed in cell-associated TNF. Dose-response curves did not demonstrate differences in TNF production in aztreonam or imipenem-treated cultures. However, for both cefuroxime and ceftazidime-treated cultures, low-dose treatment resulted in significantly higher production of TNF. The differences in TNF production between these antibiotics could be explained by the production of filaments following treatment with cefuroxime, aztreonam and low-dose ceftazidime, resulting in late bacterial lysis with high levels of endotoxin, whereas treatment with imipenem or high-dose ceftazidime resulted in the formation of spheroplasts, resulting in early lysis of the bacteria and much lower levels of endotoxin. The addition of taurolidine to either imipenem or aztreonam-treated cultures prevented a rise in TNF production as a result of nearly complete neutralization of the released endotoxin. It was concluded that the observed differences in TNF production by human monocytes in vitro were related to differences in the mechanisms and amount of antibiotic-induced release of endotoxin.

Effect of hand mixing tobramycin on the fatigue strength of Simplex P

In a recent study, we showed that the presence of gentamicin in Palacos R or erythromycin plus colistin in Simplex P bone cement did not significantly decrease the fatigue strength of the cement. [J.P. Davies, D.O. O'Connor, D.W. Burke, and W.H. Harris, "Influence of antibiotic impregnation on the fatigue life of Simplex P and Palacos R acrylic bone cements, with and without centrifugation," J. Biomed. Mater. Res., 23, 379-397 (1989)] However, the commercially prepared Palacos R with Gentamicin and AKZ (Simplex P with colistin and erythromycin) which were tested are not approved by the FDA for use in the United States. Because of this, many surgeons in the United States hand mix tobramycin with the cement in the operating room if a case calls for the use of antibiotic-impregnated cement. In this study, we determined the effect of adding 1.2 g of tobramycin to one pack (40 g) of Simplex P powder on the fatigue strength of the cement. The effect of centrifugation on the fatigue strength of Simplex P with the tobramycin added was also assessed. Simplex P was prepared according to the manufacturer's instructions with and without the addition of 1.2 g tobramycin per 40-g pack and with and without centrifugation. Fifteen specimens of each of the four cement preparations were tested in fully reversed tension-compression fatigue at +/- 15 MPa, 2 Hz. The fatigue strength of the uncentrifuged and centrifuged Simplex P was not significantly reduced by the tobramycin. Centrifugation significantly increased the fatigue life of Simplex P both with and without the addition of tobramycin. The fatigue life of the Simplex P with tobramycin was increased by a factor of 8 by centrifugation.