Sleep quality and quantity determined by polysomnography in mechanically ventilated critically ill patients randomized to dexmedetomidine or placebo.

BACKGROUND: Abnormal sleep is commonly observed in the ICU and is associated with delirium and increased mortality. If sedation is necessary, it is often performed with gamma-aminobutyric acid agonists such as propofol or midazolam leading to an absence of restorative sleep. We aim to evaluate the effect of dexmedetomidine on sleep quality and quantity. METHODS: Thirty consecutive patients were included. The study was conducted as a double-blinded, randomized, placebo-controlled trial with two parallel groups: 20 patients were treated with dexmedetomidine, and 10 with placebo. Two 16 h of polysomnography recordings were done for each patient on two consecutive nights. Patients were randomized to dexmedetomidine or placebo after the first recording, thus providing a control recording for all patients. Dexmedetomidine was administered during the second recording (6 p.m.-6 a.m.). OBJECTIVE: To compare the effect of dexmedetomidine versus. placebo on sleep - quality and quantity. PRIMARY OUTCOME: Sleep quality, total sleep time (TST), Sleep efficiency (SE), and Rapid Eye Movement (REM) sleep determined by Polysomnography (PSG). SECONDARY OUTCOME: Delirium and daytime function determined by Confusion Assessment Method of the Intensive Care Unit and physical activity. Alertness and wakefulness were determined by RASS (Richmond Agitation and Sedation Scale). RESULTS: SE were increased in the dexmedetomidine group by; 37.6% (29.7;45.6 95% CI) versus 3.7% (-11.4;18.8 95% CI) (p < .001) and TST were prolonged by 271 min. (210;324 95% CI) versus 27 min. (-82;135 95% CI), (p < .001). No significant difference in REM sleep, delirium physical activity, or RASS score was found except for RASS night two. CONCLUSION: Total sleep time and sleep efficiency were significantly increased, without elimination of REM sleep, in mechanically ventilated ICU patients randomized to dexmedetomidine, when compared to a control PSG recording performed during non-sedation/standard care.

Dexmedetomidine and sleep quality in mechanically ventilated critically ill patients: study protocol for a randomised placebo-controlled trial.

INTRODUCTION: Sleep deprivation, which is a common complication in the intensive care unit (ICU), is associated with delirium and increased mortality. Sedation with gamma-aminobutyric acid agonists (propofol, benzodiazepine) results in significant disturbance of the sleep architecture. Dexmedetomidine is a lipophilic imidazole with an affinity for α2-adrenoceptors and it has sedative and analgesic properties. It has been reported to enhance sleep efficiency, thus sedate while preserving sleep architecture. METHODS AND ANALYSIS: Thirty consecutive patients are planned to be included, at the Department of Anesthesia and Intensive Care at the Hospital of Southwest Jutland, Denmark. The study is a double-blinded, randomised, controlled trial with two parallel groups (2:1 allocation ratio). Screening and inclusion will be done on day 1 from 8:00 to 16:00. Two 16 hours PSG (polysomnography) recording will be done starting at 16:00 on day 1 and day 2. Randomisation is performed if the first recording is of acceptable quality, otherwise the patient is excluded before randomisation. Dexmedetomidine/placebo will be administered during the second recording from 18:00 on day 2 to 6:00 on day 3. PRIMARY ENDPOINT: Improvement of total sleep time and sleep quality of clinical significance determined by PSG. SECONDARY ENDPOINTS: Sleep phases determined by PSG. Daytime function and delirium determined by Confusion Assessment Method-ICU. Alertness and wakefulness determined by Richmonde Agitation Sedation Scale. The objective is to compare the effect of dexmedetomidine versus placebo on sleep quality in critical ill mechanically ventilated patients. ETHICS AND DISSEMINATION: The trial investigate the potential benefit of dexmedetomidine on clinically relevant endpoints. If a beneficial effect is shown, this would have a large impact on future treatment of mechanically ventilated critically ill patients. Publication in peer-reviewed journal are plannedand the study has been approved by the National Committee on Health Research Ethics (ID:S-20180214). TRIAL REGISTRATION NUMBER: EudraCT (2017-001612-11DK) and Danish National Committee on Health Research Ethics (ID:S-20180214). The study related to pre-results.

Correction to: A Multicenter, Observational, Prospective Study of the Effectiveness of Switching from Budesonide/Formoterol Turbuhaler® to Budesonide/Formoterol Easyhaler®.

Unfortunately, the mean difference in change from baseline ACT was incorrectly reported in the abstract as 19.0 vs. 20.8 instead of 18.9 vs. 20.7.

A Multicenter, Observational, Prospective Study of the Effectiveness of Switching from Budesonide/Formoterol Turbuhaler® to Budesonide/Formoterol Easyhaler®.

INTRODUCTION: In real-life practice, asthma remains poorly controlled, with a considerable burden on patients' quality of life. Budesonide/formoterol (B/F) Easyhaler® has demonstrated similar dose consistency, therapeutic equivalence, and equivalent bronchodilator efficacy to B/F Turbuhaler®, but no real-life comparisons are yet available in patients switching from B/F Turbuhaler® to B/F Easyhaler®. METHODS: The primary objective of this real-life, non-interventional, observational study was to show non-inferiority of asthma control when adult patients in Swedish primary care with persistent asthma switched from B/F Turbuhaler® to B/F Easyhaler®. At visit 1, baseline demographic and endpoint data were recorded, and eligible patients switched to B/F Easyhaler®. The study comprised a control visit (visit 2) and a concluding examination (visit 3) after 12 weeks. Asthma control was assessed using the Asthma Control Test (ACT). The mini-Asthma Quality of Life Questionnaire (AQLQ) and lung function test were performed, and participants and investigators answered questionnaires about ease-of-use and teaching. RESULTS: A total of 117 patients were enrolled in the on-treatment population; 81 (64.8%) were female. At visit 3, B/F Easyhaler® demonstrated non-inferiority to B/F Turbuhaler®; the mean difference in change from baseline ACT was statistically significant (18.9 vs. 20.7, respectively; p < 0.0001) and met the non-inferiority criteria of B/F Easyhaler® being greater than - 1.5 points versus the reference product. Asthma was well controlled in 62 (53.0%) patients at baseline, increasing to 83 patients (70.9%) at visit 3. Patients experienced statistically significant improvements in mini-AQLQ score after B/F Easyhaler® treatment and lung function remained stable across the treatment period. B/F Easyhaler® was easy to learn and prepare for use. CONCLUSION: This real-life, non-interventional, non-inferiority study in adults with persist asthma demonstrates equivalent or better disease control when patients switch from B/F Turbuhaler® to B/F Easyhaler®. A further study with direct comparison between treatments could add to the understanding of inhaler switch. FUNDING: Orion Corporation, Orion Pharma.

Effect of Sedation Regimen on Weaning from Mechanical Ventilation in the Intensive Care Unit.

BACKGROUND: Intensive care unit patients undergoing mechanical ventilation have traditionally been sedated to make them comfortable and to avoid pain and anxiety. However, this may lead to prolonged mechanical ventilation and a longer length of stay. OBJECTIVE: The aim of this retrospective study was to explore whether different sedation regimens influence the course and duration of the weaning process. PATIENTS AND METHODS: Intubated adult patients (n = 152) from 15 general intensive care units in Sweden were mechanically ventilated for ≥ 24 h. Patients were divided into three groups according to the sedative(s) received during the weaning period (i.e. from being assessed as 'fit for weaning' until extubation): dexmedetomidine alone (DEX group, n = 32); standard of care with midazolam and/or propofol (SOC group, n = 67); or SOC plus dexmedetomidine (SOCDEX group, n = 53). RESULTS: Patients receiving dexmedetomidine alone were weaned more rapidly than those in the other groups despite spending longer time on mechanical ventilation prior to weaning. Anxiety during weaning was present in 0, 9 and 24% patients in the DEX, SOC and SOCDEX groups, respectively. Anxiety after extubation was present in 41, 20 and 34% in the DEX, SOC and SOCDEX groups, respectively. Delirium during weaning was present in 1, 2 and 1 patient in the DEX, SOC and SOCDEX groups, respectively. Delirium at ICU discharge was present in 1, 0 and 3 patients in the DEX, SOC and SOCDEX groups, respectively. Few patients fulfilled criteria for post-traumatic stress disorder. CONCLUSION: Dexmedetomidine, used as a single sedative, may have contributed to a shorter weaning period than SOC or SOCDEX. Patients who received dexmedetomidine-only sedation tended to report better health-related quality of life than those receiving other forms of sedation.

Age as risk factor for Helicobacter pylori recurrence in children in Vietnam.

BACKGROUND: The determinants for acquisition of Helicobacter pylori infection remain incompletely understood. The study aim was to investigate risk factors for recurrence in children in Vietnam during 1 year immediately following successful H. pylori eradication. MATERIALS AND METHODS: In a prospective longitudinal study, 136 children, 3-15 years of age, were seen every 3 months for a total of four visits. Helicobacter pylori infection status was determined by an antigen-in-stool test (Premier Platinum HpSA PLUS) on samples obtained at each visit. A questionnaire was filled out at the start of the study. RESULTS: After 1 year, 30 children had become H. pylori positive, while 17 were lost to follow-up. Low age was the most prominent independent risk factor for recurrence: adjusted hazard ratio (HR) among children aged 3-4, 5-6, and 7-8 years, relative to those aged 9-15 years, were, respectively, 14.3 [95% CI 3.8-53.7], 5.4 [1.8-16.3] and 2.6 [0.7-10.4]. Surprisingly, female sex tended to be associated with increased risk (adjusted HR among girls relative to boys 2.5 [95% CI 1.1-5.9]). No other factors such as sibship size, birth order, bed sharing, sanitary standards, or factual antibiotic dose per kilo bodyweight in the eradication trial were found to be significant risk factors for re-infection. CONCLUSIONS: The main risk factor for recurrence with H. pylori was found to be age, with the youngest children running the greatest risk. The finding lends support to the observation that early childhood may be the main age of acquisition of H. pylori infection and for postponing attempts of eradication in high-prevalence areas unless motivated for medical reasons.

Eradication of Helicobacter pylori in children in Vietnam in relation to antibiotic resistance.

BACKGROUND: Low Helicobacter pylori eradication rates are common in pediatric trials especially in developing countries. The aim of the study was to investigate the role of antibiotic resistance, drug dosage, and administration frequency on treatment outcome for children in Vietnam. MATERIALS AND METHODS: Antibiotics resistance of H. pylori was analyzed by the Etest in 222 pretreatment isolates from children 3-15 years of age who were originally recruited in a randomized trial with two treatment regiments: lansoprazole with amoxicillin and either clarithromycin (LAC) or metronidazole (LAM) in two weight groups with once- or twice-daily administration. The study design was an observational study embedded in a randomized trial. RESULTS: The overall resistance to clarithromycin, metronidazole, and amoxicillin was 50.9%, 65.3%, and 0.5%, respectively. In LAC, eradication was linked to the strains being susceptible to clarithromycin (78.2% vs 29.3%, p = .0001). Twice-daily dosage of proton-pump inhibitor (PPI) and clarithromycin was more effective for eradication than once-daily dosage for resistant strains (50.0% vs 14.7%, p = .004) and tended to be so also for sensitive strains (87.5% vs 65.2%, p = .051). Exact antibiotic dose per body weight resulted in more eradication for resistant strains (45.3% vs 8.0%, p = .006). These differences were less pronounced for the LAM regimen, with twice-daily PPI versus once daily for resistant strains resulting in 69.2% and 50.0% eradication (p = .096), respectively. CONCLUSIONS: Helicobacter pylori clarithromycin resistance was unexpectedly high in young children in Vietnam. Clarithromycin resistance was an important cause for eradication treatment failure. Twice-daily administration and exact antibiotic dosing resulted in more eradicated infections when the strains were antibiotic resistant, which has implications for the study design in pediatric H. pylori eradication trials.

Antimicrobial activity of tigecycline and comparative agents against clinical isolates of staphylococci and enterococci from ICUs and general hospital wards at three Swedish university hospitals.

The activities of tigecycline and comparative agents on staphylococci and enterococci isolated from patients at general hospital wards (GHWs) and intensive care units (ICUs) at 3 university hospitals in Sweden were investigated. Oxacillin disc diffusion and minimal inhibitory concentration with E-test were used. The presence of mecA, vanA or vanB genes was determined with PCR. Statistically significant higher incidence of clindamycin, fusidic acid, rifampicin and multidrug-resistant CoNS was found at ICUs compared to GHWs. Resistance rates were low among S. aureus. Tigecycline, linezolid and vancomycin were the only agents with high activity against methicillin-resistant S. aureus and multidrug-resistant CoNS. Resistance rates were low among E. faecalis, except for high-level gentamicin-resistant (HLGR) E. faecalis. E. faecium showed high resistance rates to ampicillin, piperacillin/tazobactam and imipenem. The HLGR rates among E. faecium were lower than the rates for E. faecalis. Tigecycline and linezolid were the only drugs with high activity against all enterococci including vancomycin-resistant enterococci. No statistically significant differences in susceptibility rates were found between the ward levels for S. aureus and enterococcal isolates and no statistically significant differences were found between the hospitals.

Role of outer membrane protein OprD and penicillin-binding proteins in resistance of Pseudomonas aeruginosa to imipenem and meropenem.

The main mechanism of imipenem resistance in Pseudomonas aeruginosa is via downregulation of the gene for OprD porin. In a previous study, it was shown that the level of resistance did not parallel with the degree of downregulation of the porin gene, thus arguing for the existence of other resistance mechanisms. Penicillin-binding protein (PBP) 2 and PBP3 are involved in carbapenem resistance in Escherichia coli. The genes for PBPs were sequenced in three imipenem-resistant clinical strains and these strains were conjugated with two susceptible P. aeruginosa PA0 strains, selecting for auxotrophic markers. In all the clinical and resistant isolates there was no obvious elevation of AmpC cephalosporinase. The active sites of PBP1b (ponB), PBP2 (pbpA), PBP3 (pbpB) and PBP6 (dacC) had no mutations in any of the examined strains. Production of oprD mRNA was significantly lower in clinical strains and transconjugants after selection for the proB marker (PA4565 at 5113kb). The clinical strains had alterations in OprD that were not found in transconjugants. Our findings suggest that PBPs do not play a role in imipenem resistance in the clinical strains examined here, but that a regulatory gene for oprD contributing to carbapenem resistance is located close to the proB gene.

Evaluation of two triple-therapy regimens with metronidazole or clarithromycin for the eradication of H. pylori infection in Vietnamese children: a randomized, double-blind clinical trial.

BACKGROUND: Eradication of Helicobacter pylori infection in children in developing countries needs further investigations upon which to base treatment recommendations. The aim of the study was to compare two 2-week triple therapies in a randomized double-blind trial. MATERIALS AND METHODS: In order not to exceed recommended dosages, the 238 H. pylori-infected children, aged 3 to 15 years (mean 8.6), were divided in two weight categories receiving at weights 13-22 kg: lansoprazole 15 mg once-daily and amoxicillin 500 mg twice-daily with metronidazole 250 mg twice-daily or clarithromycin 250 mg once-daily; at weights 23-45 kg: lansoprazole 15 mg and amoxicillin 750 mg with metronidazole 500 mg or clarithromycin 250 mg, all administered twice daily. H. pylori status was assessed by culture and a monoclonal-based antigen-in-stool test (Premier Platinum HpSA PLUS) and side effects by structured questionnaires. RESULTS: The overall per-protocol eradication (n = 233) was similar in the two treatment regimens, 62.1% for the metronidazole and 54.7% for the clarithromycin-containing therapy. Eradication rate was higher in children >or= 23 kg (70.9%) than in children < 23 kg (45.7%). In children >or= 23 kg (n = 117) that received twice-daily administration of all drugs, efficacy of the metronidazole and clarithromycin-containing treatments were 69.5% and 72.4%, respectively. CONCLUSIONS: The two treatments gave similar eradication rates. Significant differences for both treatments were found by weight, which could be the result of the once-daily proton pump inhibitor and clarithromycin and/or more antibiotic resistant strains in younger children.

Epidemiological MIC cut-off values for tigecycline calculated from Etest MIC values using normalized resistance interpretation.

OBJECTIVES: To apply the normalized resistance interpretation (NRI) method to Etest MIC results which have higher precision than conventional log2 dilution MIC tests due to the inclusion of intermediate values. If successful, NRI might provide an objective tool for the definition of epidemiological MIC cut-off values. METHODS: MICs of tigecycline and other antimicrobial agents were determined for 4771 clinical isolates comprising five Gram-positive and 13 Gram-negative species or species groups using the Etest. Histograms of MIC values were constructed for each species and NRI calculations were applied to them. An upper MIC limit of 2.5 SD above the theoretical mean of the normalized distribution was used for setting the epidemiological cut-off values. RESULTS: Calculated cut-off values for wild-type strains were between 0.11 and 0.96 mg/L for Gram-positive species, and between 0.44 and 8.3 mg/L for Gram-negative species, except for Pseudomonas aeruginosa, which had a cut-off value of 450 mg/L, consistent with earlier reports on the lack of activity of tigecycline against this species. CONCLUSIONS: NRI offers an objective method for the analysis of MICs produced using Etests and the determination of epidemiological MIC cut-off values.

Immunogenicity and tolerability of a heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 12 months of age.

BACKGROUND: The recommended vaccination schedule for the pneumococcal conjugate vaccine (PCV) includes 4 immunizations, according to the national programs in the United States and some European countries. Other countries use a national schedule for routine vaccinations in early childhood that includes only 3 doses. AIMS: The goals were to assess the immunogenicity and tolerability of PCV with a vaccination schedule that included 3 doses during the first 1 year of life (a 2+1 dose schedule) and to determine the immune responses to concomitantly administered Haemophilus influenzae type b (Hib) vaccine. METHODS: A total of 101 healthy Swedish infants were enrolled in an open, nonrandomized, multicenter study. PCV was administered concomitantly with (at separate sites) a diphtheria-tetanus toxoids-acellular pertussis vaccine, inactivated polio vaccine and Hib conjugate vaccine combination at 3, 5 and 12 months of age. IgG antibody concentrations for the 7 serotypes included in the PCV and the Hib capsular polysaccharide in serum samples taken at 3, 6, 12 and 13 months were determined with enzyme immunoassays. Local and systemic reactions were monitored for 3 days after each immunization, and serious adverse reactions were monitored for the whole study period. RESULTS: Two doses of PCV induced satisfactory antibody responses, with the exception of serotypes 6B and 23F. The third dose evoked strong responses for all serotypes, which suggests good immunologic priming with the primary series of 2 doses. The mean anti-Hib antibody concentrations were similar to those noted in earlier studies among Swedish children. The PCV was well tolerated. CONCLUSION: The pneumococcal antibody concentrations at 13 months were comparable with those noted previously with the 4-dose schedule. The results suggest that the implementation of a 2+1 dose schedule for PCV should be considered.

Seroprevalence of Helicobacter pylori infection in urban and rural Vietnam.

Helicobacter pylori-associated diseases, such as peptic ulcer and gastric cancer, are common in Vietnam, but the prevalence of the infection is largely unknown. A validated enzyme-linked immunosorbent assay was used for seroepidemiology with 971 samples from the general population, ages 0 to 88 years, with 546 samples from an urban population (Hanoi), and with 425 samples from a poor, rural province (Hatay). The overall seroprevalence of the infection was 746 per 1,000, with a prevalence of 788 per 1,000 in Hanoi and 692 per 1,000 in Hatay (P=0.0007). The risk for infection in the rural area of Hatay was 40% lower than in the urban population of Hanoi, with the odds ratio being 0.59 (95% confidence interval, 0.43 to 0.81). The study shows that the prevalence of H. pylori infection is high in Vietnam and especially high in a large urban area, such as the city of Hanoi.

Enzyme-linked immunosorbent assay for Helicobacter pylori needs adjustment for the population investigated.

Helicobacter pylori infection and peptic ulcer disease are common in developing countries, e.g., Vietnam. An enzyme-linked immunosorbent assay (ELISA) for screening of patients and for seroepidemiology is a useful tool but needs to be validated in the population studied. We used in-house ELISA with sonicated Swedish and Vietnamese strains as antigens to measure immunoglobulin G antibodies after absorption with sonicated Campylobacter jejuni in sera from 270 H. pylori culture-confirmed peptic ulcer patients, 128 Swedish urea-breath test and immunoblot-positive healthy controls, and 432 Vietnamese immunoblot-positive population controls. Sonicated whole-cell antigen based on the local strains showed a significantly better performance. Immunoblot-positive peptic ulcer patients had significantly higher antibody concentrations than immunoblot-positive population controls, necessitating a lower cutoff level if serology is used for screening or epidemiological purposes. The study shows that the parameters of ELISA for H. pylori need to be adjusted for the population being investigated.

Concordance of Helicobacter pylori strains within families.

Helicobacter pylori infection is typically acquired in early childhood, and a predominantly intrafamilial transmission has been postulated. To what extent family members share the same strains is poorly documented. Our aim was to explore patterns of shared strains within families by using molecular typing. Family members of H. pylori-infected 10- to 12-year-old index children identified in a school survey were invited to undergo gastroscopy. Bacterial isolates were typed with random amplified polymorphic DNA and PCR-restriction fragment length polymorphism of the genes ureA-B, glmM, or flaA. The presence or absence of the cag pathogenicity island, a bacterial virulence factor, was determined by PCR. GelCompar II software, supplemented with visual inspection, was used in the cluster analysis. In 39 families, 104 individuals contributed 208 bacterial isolates from the antrum and corpus. A large proportion, 29 of 36 (81%) of the offspring in a sibship, harbored the same strain as at least one sibling. Mother-offspring strain concordance was detected in 10 of 18 (56%) of the families. Of 17 investigated father-offspring relations in eight families, none were strain concordant. Spouses were infected with the same strains in 5 of 23 (22%) of the couples. Different strains in the antrum and corpus were found in 8 of 104 (8%) of the subjects. Our family-based fingerprinting study demonstrates a high proportion of shared strains among siblings. Transmission between spouses seems to be appreciable. The data support mother-child and sib-sib transmission as the primary transmission pathways of H. pylori.

Capsular types and antibiotic susceptibility of invasive Streptococcus pneumoniae among children in Sweden.

To investigate the serotype distribution and antibiotic susceptibility patterns 204 isolates of Streptococcus pneumoniae obtained from blood or cerebrospinal fluid (CSF) of children < or = 18 y of age were collected from 19 clinical microbiological laboratories in Sweden during the years 1998-2001. 166 isolates were from blood only, and 38 isolates were from CSF. The most common serotypes found were 6B, 1, 7F, 14, 18C, 19F, 6A, 4, 23F, 9V and 19A, in descending order of frequency. During the study period serotype 6B increased in frequency from 14.3% in 1998 to 28.3% in 2001 and serotype 1 decreased simultaneously from 20.4% to 9.4%. Serotype 1 was the most common serotype among children > or = 2 y of age or older, but was not found among children < 2 y of age. The potential coverage rate for the heptavalent pneumococcal conjugate vaccine varied between 53 and 68% during the studied years, and was higher for children < 2 y of age (74%) than for older children (51%). The majority of isolates were susceptible to penicillin and other antibiotics tested.

Antibiotic use and Escherichia coli resistance trends for quinolones and cotrimoxazole in Sweden.

Resistance rates among Escherichia coli isolates for quinolones and cotrimoxazole were analysed at 12 Swedish hospitals, and compared with antibiotic use. Resistance figures for E. coli were retrieved from the diagnostic microbiology service databases for the period 1989-99, and antibiotic sales figures were obtained from the National Corporation of Swedish Pharmacies. At the 2 university teaching hospitals included, norfloxacin resistance of E. coli increased significantly (p < 0.001) from 0% to 2.7% and 2.5%, respectively. Ciprofloxacin resistance increased (p < 0.001) in parallel. Quinolone use increased until 1992; subsequently, sales have remained at a stable level. The increase in norfloxacin and ciprofloxacin resistance started relatively simultaneously in all hospitals, around 1991. Cotrimoxazole resistance has also been increasing significantly in most hospitals, in spite of decreasing sales of cotrimoxazole and trimethoprim. Similar trends could be seen in blood isolates from the same hospitals for the period 1991-98. Clinical laboratory data are subject to bias but surveillance over longer periods of time provides a useful method for detecting trends in increasing resistance and therefore functions as a resistance warning system.

Long-term antibiotic resistance surveillance of gram-negative pathogens suggests that temporal trends can be used as a resistance warning system.

Antibiotic resistance among Gram-negative bacteria and antibiotic consumption were investigated at the Karolinska Hospital, Stockholm, Sweden over a 12-y period. The investigation showed an increase in ciprofloxacin resistance of Escherichia coli from 0% in 1991 to 7% in 1997 and to 11% in 1999. Resistance among Pseudomonas aeruginosa isolates to ciprofloxacin increased from 2.5% in 1991 to 9.0% in 1997 and to 13% in 1999. Resistance levels for norfloxacin showed the same high statistical significance in terms of the temporal trend. A more detailed analysis showed higher resistance against norfloxacin in specific wards. Relationships between antibiotic use and antibiotic susceptibility showed different patterns. The increased ciprofloxacin resistance of E. coli and P. aeruginosa during the study period was paralleled by an increased consumption of quinolones. During the 12-y study period the total use of cephalosporins increased 2.5-fold, while the levels of E. coli resistance to cefuroxime and cefotaxime remained stable. A third pattern was seen with trimethoprim-sulfamethoxazole, namely increasing resistance of E. coli as the use of trimethoprim-sulfamethoxazole declined. The analysis of resistance levels and antibiotic consumption in the present study suggests different mechanisms for the increased resistance. The significant trend of increased resistance to antibiotics over time constitutes an important warning system.

Pharmacodynamic effects of nitroimidazoles alone and in combination with clarithromycin on Helicobacter pylori.

Pharmacodynamic studies of Helicobacter pylori exposed to metronidazole and tinidazole alone and in combination with clarithromycin were performed by bioluminescence assay of intracellular ATP. The pharmacodynamic parameter control-related effective regrowth time (CERT) was used. CERT is defined as the time required for the resumption of logarithmic growth and a return of the level of growth to the preexposure inoculum in the test culture minus the corresponding time in the control culture. CERT measures the combined effects of the initial level of killing and postantibiotic effect. The incubation times and drug concentrations were chosen according to their half-lives and their clinically achievable concentrations. The study shows that the parameter CERT is useful for the testing of antibiotic combinations. The CERTs induced by clarithromycin, metronidazole, and tinidazole alone and in the combinations tested were concentration dependent, with no maximum response, indicating that the use of high doses may be preferable. The combinations with the highest concentrations induced synergistic effects and prevented regrowth. The use of tinidazole in combination with clarithromycin proved to give the longest CERTs, indicating that this is the most effective combination.