Pharmacodynamics of antibiotics in the therapy of meningitis: infection model observations

Detailed studies of pharmacodynamic principles relevant to the therapy of bacterial meningitis are difficult to perform in man, while the rabbit model of bacterial meningitis has proved to be extremely valuable and has led to insights that appear relevant for the treatment of humans. Most importantly in the light of the restricted penetration of antibiotics into the CSF, animal studies have shown that in meningitis there is a dose-response curve between the CSF concentrations achieved by antibiotics and their bactericidal activity. This appears to be true for all classes of antibiotics thus far examined, including the beta-lactams, which do not show such a dose-response behaviour in other infections. Only CSF concentrations that exceed the MBC of the infecting organism by at least 10-30-fold achieve consistent and rapid bactericidal activity. Such rapid bactericidal activity is a requirement for successful therapy with beta-lactams and can be impaired with certain antibiotics by the specific conditions in infected CSF (protein content; acidic pH; slow-growing bacteria). However, rapid antibiotic killing of the infecting organisms may not be without adverse effects either. Some antibiotics, particularly beta-lactams lead to the brisk liberation of bacterial cell wall components (e.g. endotoxin, in the case of Gram-negative organisms) which have an inflammatory effect on the host and can lead to a temporary deterioration of the disease. Dexamethasone, when administered with the antibiotic, can prevent some of the adverse effects of rapid bacterial lysis.

Antibacterial activity of beta-lactam antibiotics in experimental meningitis due to Streptococcus pneumoniae

In order to define the characteristics of the antibacterial activity of beta-lactam antibiotics in the treatment of bacterial meningitis, the relationship between cerebrospinal fluid (CSF) drug concentrations and the rate of bacterial killing was investigated for penicillin G and four new cephalosporins in an animal model of meningitis due to Streptococcus pneumoniae. All five drugs showed a significant correlation between increasing drug concentrations in CSF and increasing bactericidal rates. Minimal activity was observed in CSF at drug concentrations of approximately the broth minimal bactericidal concentration (MBC). Maximal activity occurred with CSF concentrations 10-30 times higher. In vitro tests did not reproduce the unique correlation of increasing drug concentrations and killing activity found in vivo. When evaluating new beta-lactam antibiotics for the treatment of bacterial meningitis, it is reasonable to establish a minimum standard of CSF drug concentrations of greater than or equal to 30 times the MBC against the infecting organism.

Pharmacodynamics of antibiotics in experimental bacterial meningitis--two sides to rapid bacterial killing in the cerebrospinal fluid

In bacterial meningitis, several pharmacodynamic factors determine therapeutic success--when defined as sterilization of the cerebrospinal fluid (CSF); (i) local host defense deficits require the use of bactericidal antibiotics; (ii) CSF antibiotic concentrations that are at least 10-fold above the MBC are necessary for maximal bactericidal activity; (iii) high CSF peak concentrations that lead to rapid bacterial killing appear more important than prolonged suprainhibitory concentrations, probably because very low residual levels in the CSF prevent bacterial regrowth even during relatively long dosing intervals; (iv) penetration of antibiotics into the CSF is significantly impaired by the blood-brain barrier, thus requiring high serum levels to achieve the CSF concentrations necessary for rapid bacterial killing. Beyond these principles, recent data suggest that rapid lytic killing of bacteria in the CSF may have harmful effects on the brain because of the release of biologically active bacterial products. The conflict between the need for rapid CSF sterilization and the harmful consequences of bacterial lysis must be addressed in the therapy of meningitis.

Prophylactic antibiotics or G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapy

BACKGROUND: Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (G-CSF) or granulocyte-macrophage colony stimulating factors (GM-CSF); and antibiotics, frequently quinolones or cotrimoxazole. Important current guidelines recommend the use of colony stimulating factors when the risk of febrile neutropenia is above 20% but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES: To compare the effectiveness of G-CSF or GM-CSF with antibiotics in cancer patients receiving myeloablative chemotherapy with respect to preventing fever, febrile neutropenia, infection, infection-related mortality, early mortality and improving quality of life. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to 2007). We planned to include both full-text and abstract publications. SELECTION CRITERIA: Randomised controlled trials comparing prophylaxis with G-CSF or GM-CSF versus antibiotics in cancer patients of all ages receiving chemotherapy or bone marrow or stem cell transplantation were included for review. Both study arms had to receive identical chemotherapy regimes and other supportive care. DATA COLLECTION AND ANALYSIS: Trial eligibility and quality assessment, data extraction and analysis were done in duplicate. Authors were contacted to obtain missing data. MAIN RESULTS: We included two eligible randomised controlled trials with 195 patients. Due to differences in the outcomes reported, the trials could not be pooled for meta-analysis. Both trials showed non-significant results favouring antibiotics for the prevention of fever or hospitalisation for febrile neutropenia. AUTHORS' CONCLUSIONS: There is no evidence for or against antibiotics compared to G(M)-CSFs for the prevention of infections in cancer patients.

Nonsurgical treatment of aggressive periodontitis with photodynamic therapy or systemic antibiotics. Three-month results of a randomized, prospective, controlled clinical study

The aim of this randomized, controlled clinical study was to compare the short-term effects of nonsurgical periodontal therapy with the additional administration of systemic antibiotics (AB) and the same therapy with additional photodynamic therapy (PDT) in the treatment of patients with aggressive periodontitis (AP). Thirty-six patients with AP received full-mouth nonsurgical periodontal treatment (SRP) and were then randomly divided into two groups of 18 subjects each. Group AB received amoxicillin and metronidazole three times a day for 7 days. Group PDT received two applications of PDT on the day of SRP as well as at follow-up after 7 days. The following clinical parameters were measured at baseline and 3 months after therapy: plaque index (PLI), bleeding on probing (BOP), probing depth (PD), gingival recession (GR), and clinical attachment level (CAL). After 3 months, PD was significantly reduced in both groups (from 5.0±0.8 mm to 3.2±0.4 mm with AB, and 5.1±0.5 mm to 4.0±0.8 mm with PDT; both p<0.001), while AB revealed significantly lower values compared to PDT (p = 0.001). In both groups, GR was not significantly changed. CAL was significantly reduced in both groups (PDT: 5.7±0.8 mm to 4.7±1.1 mm; p=0.011; AB: 5.5±1.1 mm to 3.9±1.0 mm; p<0.001) and differed significantly between the groups (p=0.025). The number of residual pockets (PD ≥4 mm) and positive BOP was reduced by AB from 961 to 377, and by PDT from 628 to 394. Pockets with PD ≥7 mm were reduced by AB from 141 to 7, and by PDT from 137 to 61. After 3 months, both treatments led to statistically significant clinical improvements. The systemic administration of antibiotics, however, resulted in significantly higher reduction of PD and a lower number of deep pockets compared to PDT.

The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomized, double-blind, placebo-controlled pilot clinical study. Part 2: mandibular fractures in 59 patients

The aim of this study was to evaluate the difference between a 5-day and a 1-day postoperative course of antibiotic on the incidence of infection after mandibular fractures involving the alveolus. Sixty-two patients with fractures of the mandible involving the dentoalveolar region were randomly assigned to 2 groups, both of which were given amoxicillin/clavulanic acid 1.2 g intravenously every 8 h from admission until 24 h postoperatively. The 5-day group were then given amoxicillin/clavulanic acid 625 mg orally every 8 h for another 4 days. The 1-day group was given an oral placebo at the same intervals. Follow-up appointments were 1, 2, 4, 6, 12 weeks and 6 months postoperatively. Development of an infection was the primary end point. Fifty-nine of the 62 patients completed this study. Six of the 30 patients in the 5-day group (20%) and 6 out of the 29 in the 1-day group (21%) developed local wound infections. Three of the 6 in the 1-day group developed purulent discharge and swelling. One patient in the 5-day group developed a rash on the trunk. There were no significant differences in the incidence of infection or side effects between the groups. In fractures of the mandible involving the alveolus, a 1-day postoperative course of antibiotic is as effective in preventing infective complications as a 5-day regimen.

The role of postoperative antibiotics in facial fractures: Comparing the efficacy of a 1-day versus a prolonged regimen

BACKGROUND The goal of this study was to evaluate the influence of the duration of postoperative antibiotics (1 day vs. ≥ 5 days) on wound infections following surgical treatment of facial fractures. METHODS Three hundred thirty-nine patient case histories with a total of 498 fractures were reviewed retrospectively with regard to infections occurring within a 6-month period following surgical management. Patients were divided into two groups based on the duration of postoperative antibiotics administered. Group A consisted of 125 patients who had 1 day of postoperative antibiotics, whereas Group B consisted of 214 patients who had five or more days of postoperative antibiotics. Statistical analysis was conducted to assess for possible differences in the rate of postoperative infections. RESULTS Five patients in Group A (4%) and seven patients in Group B (3.27%) developed infections within the follow-up period. Of these 12 patients, seven had sustained multiple facial bone fractures. Eleven infections occurred in patients with mandibular fractures and one in a midfacial fracture. Statistical analysis using Fisher's exact test showed no significant difference (p = 0.77) in the incidence of infection between Groups A and B. CONCLUSION In this retrospective study, the use of prolonged postoperative antibiotics in uncomplicated mandibular and midfacial fractures had no significant benefit in reducing the incidence of infections. LEVEL OF EVIDENCE Therapeutic study, level IV.

The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomised, double-blind, placebo-controlled pilot clinical study. Part 3: Le Fort and zygomatic fractures in 94 patients

The aim of this study was to evaluate the difference between the effect of a 5-day and a 1-day postoperative course of antibiotics on the incidence of infection after midfacial fractures. A total of 98 patients with displaced Le Fort or zygomatic fractures that required operation were randomly assigned into 2 groups, both of which were given amoxicillin/clavulanic acid 1.2g intravenously every 8h from the time of admission until 24h postoperatively. The 5-day group was then given amoxicillin/clavulanic acid 625mg orally 8-hourly for another 4 days. The 1-day group was given placebo orally at the same time points. Patients were followed up 1, 2, 4, 6, and 12 weeks, and 6 months, postoperatively. The development of an infection of the wound was the primary end point. Ninety-four of the 98 patients completed the study. Two of the 45 patients in the 5-day group (4%) and 2/49 in the 1-day group (4%) developed postoperative wound infections. One in each group had a purulent infection, while the others had only wound breakdown. Two patients of the 5-day group and one in the 1-day group developed rashes on the trunk. There were no significant differences in the incidence of infection or side effects between the groups. In midfacial fractures a 1-day course of antibiotics postoperatively is as effective in preventing infective complications as a 5-day regimen.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

[Risk factors for the oral use of antibiotics and animal treatment incidence of weaners in Switzerland].

In the present study, risk factors for the use of oral antibiotics in weaned piglets were collected on 112 pig farms by a personal questionaire. The most common indication for an antibiotic group therapy was diarrhoea, and the most frequently used antibiotic was Colistin. On average, 27.33 daily doses in the control farms and 387.21 daily doses in the problem farms per 1000 weaners were administered on a given day. The significant risk factors in the multivariate model were poor hygiene in the water supply of suckling piglets, less than two doses ofprestarter feed daily, lack of an all-in-and-all-out production system in weaners, no herd book performance data analysis, and less than two of the legally prescribed veterinary visits per year. Furthermore, the treatment incidence of weaners for oral antibiotics was calculated on the basis of the drug inventory. This study provides evidence that the use of oral antibiotics in weaners can be reduced by interventions in hygiene and management.

DNA-DAMAGING REACTIONS OF NEOCARZINOSTATIN (ANTIBIOTICS, DNA REPAIR, CYTOTOXICITY)

Sensitive assays utilizing a cell-free and an intracellular system were employed to study the molecular bases of the DNA-damaging reactions of neocarzinostatin (NCS). In the cell-free DNA system, super-helical form I DNA from the bacteriophage PM2 was used as the substrate. The three forms of DNA present after treatment with NCS were separated by agarose gel electrophoresis. When NCS-damaged DNA was assayed under neutral conditions, there was a progressive decrease in the amount of surviving form I DNA and a corresponding increase in form II (nicked, relaxed circular) DNA, but very little increase in form III (linear duplex) DNA. This indicates that NCS introduces primarily single-strand breaks. However later studies showed that there were some site-specific double-strand breaks mediated by NCS on PM2 DNA. Seven such specific sites were mapped on the PM2 genome. When the damage was assayed under nondenaturing alkaline conditions or with the apurinic/apyrimidinic endonuclease IV, there was a slightly greater decrease in the amount of surviving form I DNA compared with neutral conditions indicating the presence of some alkali-labile sites.^ NCS-mediated DNA damage and repair were examined with cultured Chinese hamster ovary (CHO) cells using either alkaline elution for analysis of single-strand breaks or neutral elution for analysis of double-strand breaks. Most of the strand breaks introduced by NCS were capable of being rejoined. However, there was a small amount of residual DNA damage remaining unrejoined at 24-hr after removal of the drug. The amount of residual DNA damage was higher in a CHO mutant cell line (EM9) having a higher sensitivity to killing by NCS than its parental strain (AA8). Other lesions, DNA-protein complexes and alkali-labile sites, were detected after NCS treatment but they constituted only a small fraction of the DNA damage.^ Based on the above information, it can be postulated that NCS introduces some very lethal DNA damage. It is likely that the lethal lesions are a subset of the total DNA lesions representing the residual DNA damage. This DNA damage may be composed of site-specific, unrejoinable double-strand breaks and are thus the primary lesion leading to NCS-mediated lethality.^

The effect of exposure to antibiotics on incidence and spontaneous clearance of childhood Helicobacter pylori infection

It is claimed often in the H. pylori literature that spontaneous clearance (infection loss without attempts to treat) is uncommon, though little evidence supports this claim. Emerging evidence suggests that spontaneous clearance may be frequent in young children; however, factors that determine persistence of untreated H. pylori infection in childhood are not well understood. The author hypothesized that antibiotics taken for common infections cause spontaneous clearance of H. pylori infection in children. The Pasitos Cohort Study (19982005) investigated predictors of acquisition and persistence of H. pylori infection in children from El Paso, Texas, and Juarez, Mexico, enrolled prenatally at maternal-child clinics. Children were screened for infection at target intervals of 6 months from 6-84 months of age by the 13C-urea breath test corrected for body-size-dependent variation in CO2 production. This dissertation aimed to estimate the risk of spontaneous clearance at the next test following an initial detected H. pylori infection (first detected clearance), estimate the effect of antibiotic exposure on the risk of first detected clearance (risk difference), and estimate the effect of antibiotic exposure on the rate of first detected infection (rate ratio). Data on infection status and medication history were available for 608 children followed for a mean of 3.5 years. Among 265 subjects with a first detected infection, 218 had a subsequent test, and among them, the risk of first detected clearance was 68% (95% CI: 61-74%). Children who took antibiotics during the interval between first detected infection and next test had an increased probability (risk difference of 10 percentage points) of a first detected clearance. However, there was also a similar effect of average antibiotic use >0 courses across all intervals preceding the next test. Average antibiotic exposure across all intervals preceding the first detected infection appeared to have a much stronger protective effect than interval/specific exposure when estimating incidence rate ratios (0.45 vs. 1.0). Incidental antibiotic exposure appears to influence the acquisition and duration of childhood H. pylori infection, however, given that many exposed children acquired the infection and many unexposed children cleared the infection, antibiotic exposure does not explain all infection events. ^