Sigurdur Gudmundsson

Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross sectional prevalence study.

Abstract Objective: To study the correlation of antimicrobial consumption with the carriage rate of penicillin resistant and multiresistant pneumococci in children. Design: Cross sectional and analytical prevalence study. Setting: Five different communities in Iceland. Main outcome measure: Prevalence of nasopharyngeal carriage of penicillin resistant pneumococci in children aged under 7 years in relation to antibiotic use as determined by information from parents, patients records, and total sales of antimicrobials from local pharmacies in four study areas. Results: Total antimicrobial sales for children (6223 prescriptions) among the four areas for which data were available ranged from 9.6 to 23.2 defined daily doses per 1000 children daily (1.1 to 2.6 courses yearly per child). Children under 2 consumed twice as much as 2-6 year olds (20.5 v 10.9 defined daily doses per 1000 children daily). Nasopharyngeal specimens were obtained from 919 children, representing 15-38% of the peer population groups in the different areas. Pneumococci were carried by 484 (52.7%) of the children, 47 (9.7%) of the isolates being resistant to penicillin or multiresistant. By multivariate analysis age (<2 years), area (highest antimicrobial consumption), and individual use of antimicrobials significantly influenced the odds of carrying penicillin resistant pneumococci. By univariate analysis, recent antimicrobial use (two to seven weeks) and use of co-trimoxazole were also significantly associated with carriage of penicillin resistant pneumococci. Conclusions: Antimicrobial use, with regard to both individual use and total antimicrobial consumption in the community, is strongly associated with nasopharyngeal carriage of penicillin resistant pneumococci in children. Control measures to reduce the prevalence of penicillin resistant pneumococci should include reducing the use of antimicrobials in community health care. Key messages Study of the carriage of penicillin resistant pneumococci in 919 children in five different com- munities clearly showed the association of anti- microbial use with the level of resistance Repeated antimicrobial treatment courses and selective antimicrobial pressure may be particular risks for carrying resistant pneumococci Reducing the usage of antimicrobials, especially in children, is likely to be effective in preventing or reducing the spread of penicillin resistant and multiresistant pneumococci

Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long term follow up

Abstract Objective: To estimate the frequency, duration, and clinical importance of postherpetic neuralgia after a single episode of herpes zoster. Design: Prospective cohort study with long term follow up. Setting: Primary health care in Iceland. Participants: 421 patients with a single episode of herpes zoster. Main outcome measures: Age and sex distribution of patients with herpes zoster, point prevalence of postherpetic neuralgia, and severity of pain at 1, 3, 6, and 12 months and up to 7.6 years after the outbreak of zoster. Results: Among patients younger than 60 years, the risk of postherpetic neuralgia three months after the start of the zoster rash was 1.8% (95% confidence interval 0.59% to 4.18%) and pain was mild in all cases. In patients 60 years and older, the risk of postherpetic neuralgia increased but the pain was usually mild or moderate. After three months severe pain was recorded in two patients older than 60 years (1.7%, 2.14% to 6.15%). After 12 months no patient reported severe pain and 14 patients (3.3%) had mild or moderate pain. Seven of these became pain free within two to seven years, and five reported mild pain and one moderate pain after 7.6 years of follow up. Sex was not a predictor of postherpetic neuralgia. Possible immunomodulating comorbidity (such as malignancy, systemic steroid use, diabetes) was present in 17 patients. Conclusions: The probability of longstanding pain of clinical importance after herpes zoster is low in an unselected population of primary care patients essentially untreated with antiviral drugs.

The Etiology of Bacterial Cellulitis as Determined by Fine-Needle Aspiration

Bacterial cellulitis is a common problem, etiologic diagnosis often unrewarding and opinions differ on empiric therapy. The purpose of this study was to determine the major microbiologic causes of bacterial cellulitis in a walk-in Emergency Room setting. 94 cases in 89 patients with clinical signs of cellulitis were studied. The infection was closed in 74 cases and associated with an open skin lesion in 22. The infection site was aspirated with a suction air-buffer technique employing a Cameco handle for easier handling and stabilization of the aspiration needle. After exclusion of contaminated samples, positive cultures were obtained from 30 cases (31.9%). Cultures were positive in 30.6% of open lesions and in 36.4% of closed ones. Staphylococcus aureus was the most common organism, present in 11 cases, S. epidermidis in 8 and group A beta-hemolytic streptococci in 5. All S. aureus strains were methicillin-sensitive and only 1 was sensitive to penicillin. The most common site of infection was the lower extremity (59%). According to these data the optimal initial therapy for bacterial cellulitis in adults should be with drugs active against both staphylococci and streptococci.

Herpes zoster in children and adolescents.

OBJECTIVES To follow the clinical course of herpes zoster and to determine the incidence, frequency of complications and association with malignancy in children and adolescents. DESIGN Prospective cohort study in a primary health care setting in Iceland. The main outcome measures were age and sex distribution of patients and discomfort or pain 1, 3 and 12 months after the rash and general health before and 3 to 6 years after the zoster episode. RESULTS During observation of the target population for a period of 75750 person years, 121 episodes of acute zoster developed (incidence 1.6/1000/year) in 118 patients. End points were gained for all 118 patients after 554 person years of follow-up. Systemic acyclovir was never used. No patient developed postherpetic neuralgia, moderate or severe pain or any pain lasting longer than 1 month from start of the rash (95% confidence interval, 0 to 0.03). Potential immunomodulating conditions were diagnosed in 3 patients (2.5%) within 3 months of contracting zoster. Only 5 (4%) had a history of severe diseases. CONCLUSIONS The probability of postherpetic neuralgia in children and adolescents is extremely low. Zoster is seldom associated with undiagnosed malignancy in the primary care setting.

Clonal Spread of Resistant Pneumococci Despite Diminished Antimicrobial Use

The effects of community-wide interventions to reduce resistance rates are poorly understood. This study evaluated the effect of reduced antimicrobial usage on the spread of penicillin-nonsusceptible pneumococci (PNSP) in four communities in Iceland. The study was performed after interventions to reduce antimicrobial usage and compared to an identical study performed 5 years before. A randomized sample of 953 children was chosen from all 2,900 1- to 6-year-old children living in four well-defined communities. The main outcome measures were nasopharyngeal carriage of PNSP and individual and community use of antimicrobials. Pneumococci were carried by 51.7% of the 743 children enrolled, and 8.1% of the pneumococci were PNSP as opposed to 8.5% in the previous study. The antimicrobial use of participants had been reduced from 1.5 to 1.1 courses/year and the overall use among children <7 years old living in the study areas from 13.6 to 11.1 defined daily dosages/1000 children per day. The prevalence of PNSP increased in the two areas furthest away from the capital area despite reduced consumption. The major risk factors for carriage of PNSP remained the same. Interventions can be effective in reducing antimicrobial use. Pandemic multiresistant clones can also spread fast in small communities with low antimicrobial use, where their appearance may be delayed compared to highly populated urban areas. Clonal spread and herd immunity are important factors to be considered in the evaluation of intervention effects.

Impact of pH and cationic supplementation on in vitro postantibiotic effect.

Most studies on pharmacodynamic variables in vitro, including the postantibiotic effect (PAE), are performed at pH 7.4 in noncationic-supplemented media, a situation which may differ significantly from the true microenvironment in most infected foci. We studied the impact of five different pH levels (pH 5, 6, 7, 7.4, and 8) on the duration of the PAE, the MIC, and bactericidal activity. Acid pH was found to have in general a deleterious effect on the activity of aminoglycosides and ciprofloxacin against Escherichia coli and Pseudomonas aeruginosa, with the MIC being higher, the bactericidal rate being lower, and the PAE being shorter at pH 5 (and to a lesser extent at pH 6) than at more alkaline pH levels. Similar results were observed for imipenem against P. aeruginosa. The PAEs induced by ampicillin against E. coli and dicloxacillin against Staphylococcus aureus were not predictably dependent on the pH, whereas the PAEs induced by ciprofloxacin against S. aureus were longest at either end of the pH spectrum. The bactericidal activity of these agents was, however, pH dependent, being slower at acid pHs. The addition of 50 mg of Ca2+ and 20 mg of Mg2+ per liter of liquid medium at pH 7.4 did not affect the duration of the PAE. Since the pH in abscess cavities may be close to 5, these observations may be of importance for employment of the agents studied in closed or poorly drained infections.

Age specific prevalence of antibodies against Chlamydia pneumoniae in Iceland

Chlamydia pneumoniae is a newly recognized common cause of respiratory tract infections. The aim of this study was to examine its prevalence in Iceland. The study was based on 1020 serum samples from individuals 0-99 years old. The samples were divided into 10-year age groups. IgG and IgM antibodies were determined with microimmunofluorescence assay. An IgG titer > or = 32 and IgM titer > or = 16 were considered positive. The prevalence of positive IgG titer in the study population was 53 +/- 16% (mean +/- SD, age group range 14-66%). Neither seasonal nor gender-based difference in IgG antibody prevalence was demonstrated. It was lowest in the youngest group, 0-9 years old (p < 0.001), but rose linearly to age 70 (p < 0.005). 34 samples were IgM positive on initial testing; most from the older age groups. 12 were rheumatoid factor positive as well. After treatment with caprine antihuman IgG antibodies all became negative. The prevalence of C. pneumoniae infections is high in Iceland according to these results and similar to that in neighbouring countries. The presence of IgM rheumatoid factor may cause false positive tests for pathogen-specific IgM by immune complex binding with pathogen-specific IgG, thereby requiring its removal before testing.

Selection of Resistant Streptococcus pneumoniae during Penicillin Treatment In Vitro and in Three Animal Models

ABSTRACT Pharmacokinetic (PK) and pharmacodynamic (PD) properties for the selection of resistant pneumococci were studied by using three strains of the same serotype (6B) for mixed-culture infection in time-kill experiments in vitro and in three different animal models, the mouse peritonitis, the mouse thigh, and the rabbit tissue cage models. Treatment regimens with penicillin were designed to give a wide range of T>MICs, the amounts of time for which the drug concentrations in serum were above the MIC. The mixed culture of the three pneumococcal strains, 107 CFU of strain A (MIC of penicillin, 0.016 μg/ml; erythromycin resistant)/ml, 106 CFU of strain B (MIC of penicillin, 0.25 μg/ml)/ml, and 105 CFU of strain C (MIC of penicillin, 4 μg/ml)/ml, was used in the two mouse models, and a mixture of 105 CFU of strain A/ml, 104 CFU of strain B/ml, and 103 CFU of strain C/ml was used in the rabbit tissue cage model. During the different treatment regimens, the differences in numbers of CFU between treated and control animals were calculated to measure the efficacies of the regimens. Selective media with erythromycin or different penicillin concentrations were used to quantify the strains separately. The efficacies of penicillin in vitro were similar when individual strains or mixed cultures were studied. The eradication of the bacteria, independent of the susceptibility of the strain or strains or the presence of the strains in a mixture or on their own, followed the well-known PK and PD rules for treatment with β-lactams: a maximum efficacy was seen when the T>MIC was >40 to 50% of the observation time and the ratio of the maximum concentration of the drug in serum to the MIC was >10. It was possible in all three models to select for the less-susceptible strains by using insufficient treatments. In the rabbit tissue cage model, a regrowth of pneumococci was observed; in the mouse thigh model, the ratio between the different strains changed in favor of the less-susceptible strains; and in the mouse peritonitis model, the susceptible strain disappeared and was overgrown by the less-susceptible strains. These findings with the experimental infection models confirm the importance of eradicating all the bacteria taking part in the infectious process in order to avoid selection of resistant clones.

Penicillin Pharmacodynamics in Four Experimental Pneumococcal Infection Models

ABSTRACT Clinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cage infection in rabbits. Two multidrug-resistant isolates ofStreptococcus pneumoniae type 6B were used, one for which the penicillin MIC was 0.016 μg/ml and the other for which the penicillin MIC was 1.0 μg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations of drugs in serum (Cmaxs) and times that the concentrations were greater than the MIC (T>MICs). The endpoints were bacterial viability counts after 6 h of treatment in the mice and 24 h of treatment in the rabbits. Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T>MIC and to a lesser extent on the Cmax/MIC and the generation time but not on the area under the concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (∼6 log10 CFU/ml), followed by the thigh (∼3 log10 CFU/thigh), and being the lowest in the lung (∼1 log10 CFU/lung). In the rabbit model the maximal effect was ∼6 log10 CFU/ml after 24 h. In the mouse models bactericidal activity became marked whenT>MIC was ≥65% of the experimental time andCmax was ≥15 times the MIC, and in the rabbit model bactericidal activity became marked whenT>MIC was ≥35%, Cmaxwas ≥5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/MIC ratio andT>MIC, the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.

Different patterns of bacterial DNA synthesis during postantibiotic effect

Studies on bacterial metabolism during the postantibiotic effect (PAE) period are limited but might provide insight into the nature of the PAE. We evaluated the rate of DNA synthesis in bacteria during the PAE period after a 1-h exposure of organisms in the logarithmic growth phase to various antibiotics. Staphylococcus aureus ATCC 25923 was exposed to vancomycin, dicloxacillin, rifampin, and ciprofloxacin; Escherichia coli ATCC 25922 was exposed to gentamicin, tobramycin, rifampin, imipenem, and ciprofloxacin; and Pseudomonas aeruginosa ATCC 25783 was exposed to imipenem, tobramycin, and ciprofloxacin. DNA synthesis was determined by measuring the rate of [3H]thymidine incorporation in S. aureus and E. coli and [3H]adenine incorporation in P. aeruginosa. DNA synthesis in S. aureus was suppressed during the PAE phase with vancomycin, dicloxacillin, and rifampin, it was suppressed in E. coli with rifampin, and it was suppressed in P. aeruginosa after exposure to tobramycin. Conversely, DNA synthesis was relatively enhanced in the gram-negative bacilli after exposure to imipenem and in all three species after exposure to ciprofloxacin. However, DNA synthesis in E. coli was only minimally affected after exposure to tobramycin and gentamicin. The differences in DNA synthesis observed after exposure to various antimicrobial agents suggest multiple mechanisms for the PAE.