Oral Beta-lactam Research Articles

€Qué estamos aprendiendo de Staphylococcus saprophyticus?

Staphylococcus saprophyticus is frequent cause of urinary tract infection in women; hence, it is important to know the epidemiology and antibiotic susceptibility of this microorganism. A retrospective longitudinal study was performed in urine specimens from outpatients in our health area cultured in the Microbiology Laboratory of C.E. Argüelles (Madrid, Spain) over a 10-year period (1997-2006). Among 35,136 urine cultures with a significant count, we identified 331 S. saprophyticus (0.9%); 324 in women and 7 in men. Mean age of the infected patients was 32.7 years. A total of 83.9% of the strains were in women aged 15 to 44 years (37 women in this group were pregnant) and the largest numbers of isolates were found during the months of June and November. All S. saprophyticus strains were susceptible to vancomycin, rifampin, gentamicin and amoxicillin-clavulanic acid. Of note, there was a high percentage of resistance to erythromycin (37.7%) (96% consistent with the MSB phenotype) which has significantly increased since 1997 (P < 0.05); 1.5% were also resistant to clindamycin. Only 0.9% were resistant to fluorquinolones. Resistance to chloramphenicol, trimethoprim/sulfamethoxazole, and penicillin was 3.9%, 6%, and 55.6%, respectively. Based on the 2006 CLSI guidelines, 45% of S. saprophyticus isolates were considered oxacillin-resistant. These results suggest the following: First, S. saprophyticus should be considered among agents causing urinary tract infection in women 15 to 44 years old, including pregnant women, particularly during spring and autumn. Second, cotrimoxazole may be an excellent option for treating cystitis in patients without risk factors. Third, almost half of S. saprophyticus strains were considered oxacillin-resistant, thereby denying the benefit of treatment with oral beta-lactams in urinary tract infections. This is especially important in pregnant women, who should avoid trimethoprim/sulfamethoxazole and quinolones (FDA Group C), as well as fosfomycin, with in vitro resistance.

Inhibitory Effect of Zinc on the Absorption of β-Lactam Antibiotic Ceftibuten via the Peptide Transporters in Rats

Zinc is an essential metal ion for the body, and is widely used for nutritional and clinical purposes. Previously, we showed that zinc inhibits the transport of glycylsarcosine via the intestinal peptide transporter PEPT1 in the human intestinal cell line Caco-2. In this study, we examined the effect of zinc on the activity of peptide transporters in rats using the oral beta-lactam antibiotic ceftibuten as a model drug. The plasma ceftibuten concentration after intraintestinal administration was decreased in the presence of zinc. The maximum plasma concentration (C(max)) was significantly decreased and the time required to reach C(max) (T(max)) was prolonged by zinc coadministration. The plasma ceftibuten concentration after iron coadministration or two hours after zinc administration was not affected. The in situ loop technique revealed 50% inhibition of ceftibuten absorption by zinc. In conclusion, zinc inhibits the transport activity of PEPT1 in vivo as well in vitro.

Pharmacodynamic Target Attainment of Oral β-Lactams for the Empiric Treatment of Acute Otitis Media in Children

To determine the probability of oral beta-lactam regimens achieving bactericidal pharmacodynamic exposure against pathogens causing acute otitis media (AOM) given contemporary prevalence and resistance rates. A 5000-patient Monte Carlo simulation was used to recreate steady-state concentration-time profiles for oral drug administration regimens of amoxicillin, amoxicillin/clavulanic acid, cefpodoxime, cefprozil, ceftibuten, and cefuroxime in a population of 12.5-month-old children. The percent of simulated children in whom free drug concentrations above the minimum inhibitory concentration (MIC) for 50% of the drug administration interval (50% fT>MIC) were achieved was determined; 180 middle ear fluid isolates (56 Haemophilus influenzae and 124 Streptococcus pneumoniae) collected during the 2004 Global Respiratory Antimicrobial Surveillance Project (GRASP) were used. The cumulative fraction of response (CFR) was calculated and weighted against the prevalence of organisms causing AOM extrapolated from the literature. The contribution of a 'Pollyanna phenomenon' for each organism was also incorporated to estimate clinical effectiveness. Against S. pneumoniae isolates, amoxicillin 30 mg/kg every 8 hours (84.7%) achieved the greatest CFR followed by amoxicillin/clavulanic acid and the other amoxicillin-based regimens. Against H. influenzae isolates, cefpodoxime, ceftibuten, and amoxicillin/clavulanic acid each achieved a CFR of >90%. When weighted by the prevalence of AOM-causing pathogens, CFR was highest for cefpodoxime (87.5%), amoxicillin/clavulanic acid (85.7%), and amoxicillin 30 mg/kg every 8 hours (70.8%). The contribution of a 'Pollyanna phenomenon' increased the probability of clinical effectiveness for all agents, with amoxicillin/clavulanic acid (90.2%) and cefpodoxime (90.1%) having the highest weighted CFR. Based on the recent epidemiologic and resistance profiles of S. pneumoniae and H. influenzae, amoxicillin/clavulanic acid (45 mg/kg every 12 hours) and cefpodoxime (5 mg/kg every 12 hours) provide the greatest likelihood of achieving optimal pharmacodynamic exposures empirically in children with AOM.

分子遺伝学的にみた小児における耐性インフルエンザ菌保有の危険因子に関する検討

The present study investigated the host risk factors for carriage of Haemophilus influenzae (H. influenzae) with resistant gene (s) against antibiotics. From September 2001 to January 2004, 174 strains of H. influenzae were isolated from the nasopharynx of children with respiratory tract infections. We classified these strains on the basis of the MIC to Ampicillin and the presence of resistant gene (s) for antibiotics resistance (gene for beta-lactams and altered pbp gene (s)). The patients' background such as previous antibiotic usage, age, daycare attendance, siblings and underlying diseases was investigated. The risk factor for carriage of strains with altered pbp gene (s) was the usage of beta-lactams within the last 3 months. Controlled usage of oral beta-lactams might be an important issue for preventing the spread of resistant H. influenzae strains such as beta-lactamase non-producing ampicillin resistant H. influenzae. We have to reconsider a therapeutic approach for the treatment of young children with respiratory tract infection.

New developments in antibacterial choice for lower respiratory tract infections in elderly patients.

Elderly patients are at increased risk of developing lower respiratory tract infections compared with younger patients. In this population, pneumonia is a serious illness with high rates of hospitalisation and mortality, especially in patients requiring admission to intensive care units (ICUs). A wide range of pathogens may be involved depending on different settings of acquisition and patient's health status. Streptococcus pneumoniae is the most common bacterial isolate in community-acquired pneumonia, followed by Haemophilus influenzae, Moraxella catarrhalis and atypical pathogens such as Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae. However, elderly patients with comorbid illness, who have been recently hospitalised or are residing in a nursing home, may develop severe pneumonia caused by multidrug resistant staphylococci or pneumococci, and enteric Gram-negative bacilli, including Pseudomonas aeruginosa. Moreover, anaerobes may be involved in aspiration pneumonia. Timely and appropriate empiric treatment is required in order to enhance the likelihood of a good clinical outcome, prevent the spread of antibacterial resistance and reduce the economic impact of pneumonia. International guidelines recommend that elderly outpatients and inpatients (not in ICU) should be treated for the most common bacterial pathogens and the possibility of atypical pathogens. The algorithm for therapy is to use either a selected beta-lactam combined with a macrolide (azithromycin or clarithromycin), or to use monotherapy with a new anti-pneumococcal quinolone, such as levofloxacin, gatifloxacin or moxifloxacin. Oral (amoxicillin, amoxicillin/clavulanic acid, cefuroxime axetil) and intravenous (sulbactam/ampicillin, ceftriaxone, cefotaxime) beta-lactams are agents of choice in outpatients and inpatients, respectively. For patients with severe pneumonia or aspiration pneumonia, the specific algorithm is to use either a macrolide or a quinolone in combination with other agents; the nature and the number of which depends on the presence of risk factors for specific pathogens. Despite these recommendations, clinical resolution of pneumonia in the elderly is often delayed with respect to younger patients, suggesting that optimisation of antibacterial therapy is needed. Recently, some new classes of antibacterials, such as ketolides, oxazolidinones and streptogramins, have been developed for the treatment of multidrug resistant Gram-positive infections. However, the efficacy and safety of these agents in the elderly is yet to be clarified. Treatment guidelines should be modified on the basis of local bacteriology and resistance patterns, while dosage and/or administration route of each antibacterial should be optimised on the basis of new insights on pharmacokinetic/pharmacodynamic parameters and drug interactions. These strategies should be able to reduce the occurrence of risk factors for a poor clinical outcome, hospitalisation and death.

Antimicrobial activity of LB10827, a new orally administered cephalosporin, tested against Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae

A new orally administered cephalosporin, LB10827, was compared to 16 other antimicrobial agents tested against Streptococcus pneumoniae (520 strains), Haemophilus influenzae (302 strains) and Moraxella catarrhalis (188 strains) by reference broth microdilution methods. LB10827 (MIC90, 0.12 mg/L; highest MIC, 0.5 mg/L) was 8-16-fold more potent than cefdinir, cefpodoxime or cefuroxime when tested against S. pneumoniae. All Gram-negative strains were inhibited at </= 0.5 mg/L LB10827, which is an activity equal or superior to that of currently available and tested oral beta-lactams. LB10827 appears to be a promising agent worthy of continued investigations both in vitro and in vivo.

Breakthrough pneumococcal bacteraemia in patients treated with clarithromycin or oral beta-lactams.

The incidence of penicillin- and erythromycin-resistant strains of Streptococcus pneumoniae has increased considerably in Belgium. The medical charts of all patients with pneumococcal bacteraemia who were admitted to hospital over a period of 3 years (n = 136) were reviewed to identify treatment failure of outpatient antibiotic therapy. Twelve patients had received antibiotics for at least 48 h prior to admission. Four treatment failures received clarithromycin as pre-hospitalization therapy, and S. pneumoniae from all four patients were highly resistant to macrolides. Five patients failed on co-amoxiclav, whereas their S. pneumoniae were susceptible to penicillin and amoxicillin. This observation suggests that macrolide resistance is clinically relevant and leads to treatment failure, whereas suboptimal dosing may explain breakthrough pneumococcal bacteraemia in beta-lactam-treated patients.

Inhibitory effect of zinc on PEPT1-mediated transport of glycylsarcosine and beta-lactam antibiotics in human intestinal cell line Caco-2.

The aim of this study was to examine the effects of zinc on the intestinal peptide transporters (PEPT1 and basolateral peptide transporter) and to elucidate the mechanism of the interactions. Caco-2 cells were pretreated with zinc, and the uptake studies were carried out. Zinc treatment resulted in the inhibition of [14C]glycylsarcosine (Gly-Sar) uptake via PEPT1 in a concentration-dependent manner, whereas it showed moderate inhibitory effect on the basolateral peptide transporter. Zinc also inhibited the uptake of oral beta-lactam antibiotics such as ceftibuten and cephradine by PEPT1. Kinetic analysis showed that zinc treatment increased Km values without affecting Vmax values of the [14C]Gly-Sar uptake. The inhibition of [14C]Gly-Sar uptake induced by zinc was observed in the presence of an H+ gradient but not in the absence of an H+ gradient. These results indicate that zinc is a competitive inhibitor of PEPT1. Zinc inhibited the PEPT1 function, possibly by interacting with histidine residues of PEPT1 that are part of an H+-binding site. These findings would provide important information for clinical, physiologic, and biochemical aspects of peptide transporters.

Cefditoren pivoxil versus cefpodoxime proxetil for community-acquired pneumonia: Results of a multicenter, prospective, randomized, double-blind study

Background: According to recently issued treatment guidelines, appropriate empiric choices for ambulatory patients with community-acquired pneumonia (CAP) are a macrolide, doxycycline (for patients aged ≥8 years), or an oral beta-lactam agent with good activity against pneumococci. Objective: This study was designed to compare cefditoren pivoxil, a new beta-lactam, with cefpodoxime proxetil, a beta-lactam with an established role in the treatment of CAP. Methods: This was a multicenter, prospective, randomized, double-blind study conducted in the United States and South Africa. Ambulatory patients with a diagnosis of CAP were randomized to 14 days of treatment with cefditoren 200 or 400 mg BID or cefpodoxime 200 mg BID. Assessments of clinical cure and pathogen eradication were conducted at 2 visits during treatment, 1 posttreatment visit ( ≤48 hours after completion of treatment), and 1 follow-up visit (7–14 days after completion of treatment). The development of resistant pathogens was assessed at the follow-up visit but not thereafter. The relative cost of treatment was not assessed. Results: The study enrolled 851 patients. Comparable clinical cure rates were observed among evaluable patients in the 3 treatment groups at both the posttreatment and follow-up visits: at the posttreatment visit, cure rates were 90.5% (162/179) for cefditoren 200 mg, 89.7% (148/165) for cefditoren 400 mg, and 92.2% (153/166) for cefpodoxime 200 mg; at the follow-up visit, they were a respective 88.4% (160/181), 87.2% (143/164), and 90.4% (151/167). Of the 171 strains of Streptococcus pneumoniae isolated before treatment, 22 (12.9%) had reduced susceptibility to penicillin, 5 (2.9%) of them penicillin resistant (minimum inhibitory concentration ≥2 μg/mL). At the posttreatment visit, the overall eradication rates of pathogens isolated from microbiologically evaluable patients were 88.7% (134/151), 89.9% (134/149), and 95.7% (134/140) in the respective treatment groups ( P = 0.031, cefditoren 200 mg vs cefpodoxime). Eradication rates of S pneumoniae were 93.8% (45/48), 95.7% (45/47), and 95.6% (43/45) in the respective treatment groups; those of Haemophilus influenzae were 90.2% (46/51), 97.7% (43/44), and 97.4% (37/38). The rates of resolution and/or improvement in clinical signs and symptoms were comparable between groups. The study drugs were well tolerated, with 1.7%, 2.5%, and 1.4% of patients in the respective groups discontinuing study drug prematurely due to a treatment-related adverse event, the majority of these associated with the digestive system. Conclusion: The results of this study suggest that cefditoren may have a role in the treatment of CAP in ambulatory patients.

Diagnosis and management of pneumonia in children.

This paper describes challenges in etiologic diagnosis and treatment of childhood community-acquired pneumonia and the means of addressing some of them. From about one-third to two-thirds of cases of pneumonia can be attributed to a specific etiology depending on which culture, antigen detection and specialized serologic techniques, some of which are unavailable to clinicians, are used. Results of studies in which microbiologic causes have been sought confirm the importance of Streptococcus pneumoniae as the primary bacterial cause of pneumonia in infants and children. Viral etiologies become less prevalent and mycoplasmal and chlamydial infections become more prevalent with increasing age. Because definitive information about causative pathogens is seldom available, treatment of pneumonia is most often empiric. Antibiotic therapy can be withheld in mildly ill, ambulatory patients in whom viral infection is likely. Most guidelines suggest initial treatment with orally administered amoxicillin or amoxicillin/clavulanate or with intravenous cefuroxime when patients require hospitalization. In May, 2000, the Centers for Disease Control-convened Drug-Resistant S. pneumoniae Therapeutic Working Group identified oral beta-lactams including cefuroxime axetil, amoxicillin and amoxicillin/clavulanate as appropriate options for first line therapy of community-acquired pneumonia in ambulatory adults and children. New diagnostic techniques such as pneumococcal serologies and polymerase chain reaction testing have improved the ability to determine the microbiologic etiology of childhood pneumonia. Because these tests are not generally available, empiric treatment is necessary. Efforts to identify new intervention strategies, diagnostic tools, therapies and vaccines will be helpful in managing this disease.

Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.

To provide recommendations for the management of community-acquired pneumonia and the surveillance of drug-resistant Streptococcus pneumoniae (DRSP). We addressed the following questions: (1) Should pneumococcal resistance to beta-lactam antimicrobial agents influence pneumonia treatment? (2) What are suitable empirical antimicrobial regimens for outpatient treatment of community-acquired pneumonia in the DRSP era? (3) What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era? and (4) How should clinical laboratories report antibiotic susceptibility patterns for S pneumoniae, and what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest? Experts in the management of pneumonia and the DRSP Therapeutic Working Group, which includes clinicians, academicians, and public health practitioners, met at the Centers for Disease Control and Prevention in March 1998 to discuss the management of pneumonia in the era of DRSP. Published and unpublished data were summarized from the scientific literature and experience of participants. After group presentations and review of background materials, subgroup chairs prepared draft responses, which were discussed as a group. When implicated in cases of pneumonia, S pneumoniae should be considered susceptible if penicillin minimum inhibitory concentration (MIC) is no greater than 1 microg/mL, of intermediate susceptibility if MIC is 2 microg/ mL, and resistant if MIC is no less than 4 microg/mL. For outpatient treatment of community-acquired pneumonia, suitable empirical oral antimicrobial agents include a macrolide (eg, erythromycin, clarithromycin, azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral beta-lactam with good activity against pneumococci (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). Suitable empirical antimicrobial regimens for inpatient pneumonia include an intravenous beta-lactam, such as cefuroxime, ceftriaxone sodium, cefotaxime sodium, or a combination of ampicillin sodium and sulbactam sodium plus a macrolide. New fluoroquinolones with improved activity against S pneumoniae can also be used to treat adults with community-acquired pneumonia. To limit the emergence of fluoroquinolone-resistant strains, the new fluoroquinolones should be limited to adults (1) for whom one of the above regimens has already failed, (2) who are allergic to alternative agents, or (3) who have a documented infection with highly drug-resistant pneumococci (eg, penicillin MIC > or =4 microg/mL). Vancomycin hydrochloride is not routinely indicated for the treatment of community-acquired pneumonia or pneumonia caused by DRSP.

In vitro activity and pharmacodynamics of oral beta-lactam antibiotics against Streptococcus pneumoniae from southeast Missouri.

To determine the frequency of reduced susceptibility to penicillin, and to compare the in vitro activity and pharmacodynamics of oral beta-lactam antibiotics against clinical isolates of Streptococcus pneumoniae from southeast Missouri. Cape Girardeau, Missouri (population 35,500). Interventions. Minimum inhibitory concentrations (MICs) were determined for penicillin, amoxicillin, amoxicillin-clavulanic acid, cefprozil, cefuroxime, cefpodoxime, cefaclor, and loracarbef by E test for 108 isolates of S. pneumoniae. The MIC50, MIC90, and percentage susceptibility were calculated for each agent. Pharmacokinetic variables were obtained from the literature, and serum concentration-time profiles were simulated for a 25-kg child taking pediatric dosages commonly administered to treat otitis media. The average time above MIC (T > MIC) was calculated as percentage of the dosing interval using free concentrations and the MIC for each individual isolate. Analysis of variance (Scheffe post hoc test) was used to determine differences among agents for in vitro activity and T > MIC (level of significance, p<0.05). The frequency of penicillin-nonsusceptible S. pneumoniae was 28.7% (31/108). For 25 penicillin-intermediate isolates, amoxicillin and amoxicillin-clavulanic acid were significantly more active than cefprozil, cefaclor, and loracarbef. The T > MIC for amoxicillin and amoxicillin-clavulanic acid, simulated at 13.3 mg/kg every 8 hours, was significantly longer than that for all other beta-lactams. Amoxicillin and amoxicillin-clavulanic acid have superior in vitro activity and longer T > MIC for penicillin-intermediate isolates than the other oral beta-lactams.

Resistance against oral antibiotics to Streptococcus pneumoniae isolated from adult respiratory tract infections

The resistance against oral antibiotics to Streptococcus pneumoniae (S. pneumoniae) isolated from adult patients with respiratory tract infections in the Kurume area in 1998 was studied. The frequency of resistant strains, which were isolated penicillin-intermediate S. pneumoniae and resistant S. pneumoniae (PISP, PRSP) were both 41.2%. We examined the minimal inhibitory concentrations (MIC) of oral antibiotics and the susceptibility ratio of the strains for the drugs based on the breakpoint MIC. The breakpoint MIC of pneumonia against oral beta-lactam antibiotics to PISP, PRSP, which were determined by Japan Society of Chemotherapy, were high in the order of FRPM > CDTR, CFPN > CFTM > CFDN, CPDX. In the case of the new oral quinolones, DU6859a > SPFX > LVFX > CPFX showed good results, in this order, DU6859a showed the most significant inhibitory effect to PISP, PRSP (MIC90 0.06 microgram/ml). By serotyping the percentage of 19, 6, 23 was 42.9%, 21.4% and 14.3%.

Systematic review of the treatment of early Lyme disease.

Lyme disease is a rapidly emerging infectious disease and there are still many unanswered questions with respect to appropriate laboratory tests required for diagnosis of early Lyme disease, types of antimicrobials required for treatment and duration of therapy. A qualitative systematic review was used to summarise the existing data for the treatment of early Lyme disease. Eleven antibacterial therapy trials and 3 cost-effectiveness analyses met the inclusion criteria for this review. Antibacterial regimens that have been studied include phenoxymethylpenicillin (penicillin V), amoxicillin, amoxicillin/probenecid, tetracycline, doxycycline, cefuroxime axetil, erythromycin, roxithromycin, azithromycin and ceftriaxone. The data support the use of oral beta-lactam antibacterials [phenoxymethylpenicillin (penicillin V), amoxicillin, cefuroxime axetil] and oral tetracyclines as effective first-line treatment modalities for early Lyme disease. Oral macrolides are considered second-line agents as their clinical efficacy has been less than that of the beta-lactams and tetracyclines. Courses of therapy ranging from 10 to 21 days are supported by the available evidence, although the optimal duration of therapy is unknown.

In-vitro, in-vivo and ex-vivo studies with oral beta-lactams against Streptococcus pneumoniae.

In-vitro killing curves, a protection model in immunocompetent mice and an ex-vivo model in volunteers were used to evaluate the efficacy of amoxycillin, cefuroxime axetil and cefpodoxime proxetil against a penicillin-intermediate-resistant Streptococcus pneumoniae (MIC = 1 mg/L) (PRP) and a penicillin-susceptible S. pneumoniae (MIC = 0.01 mg/L) (PSP). In vitro, the maximal bactericidal activity was obtained with amoxycillin (1 x MIC versus 2 x MIC cefpodoxime and 4 x MIC cefuroxime). Mice were challenged by intraperitoneal inoculation and treated orally every 8 h for 48 h with 2.5, 5, 7.5 and 10 mg/kg doses of these three beta-lactams. The rate of survival for the PSP strain was 100% with any dose of the three tested antibiotics. For the PRP strain only amoxycillin showed 100% survival with 5, 7.5 or 10 mg/kg doses. Twelve healthy volunteers were randomized in three groups and each received two doses of the oral antibiotic. Blood samples were collected from each subject 0.5 h and 2 h after drug administration and serum inhibitory and bactericidal titres were measured. Similar values were obtained with the three beta-lactams against PSP but against PRP only the serum of volunteers that had taken amoxycillin exhibited serum bactericidal titres of > or = 8. This study suggests a more predictable therapeutic efficacy against pneumococcal infection with amoxycillin than with available oral cephalosporins.

Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae.

The spread of drug-resistant Streptococcus pneumoniae in the community is a public health problem in developed and developing nations, but whether antibiotic use is responsible for the increase in drug resistance is not known. To analyze the relationship between penicillin-resistant S pneumoniae (PRSp) pharyngeal carriage and characteristics of beta-lactam use. Observational study of children attending 20 randomly sampled schools. The Loiret, in the center of France. A total of 941 children, 3 to 6 years old. Pharyngeal carriage of S pneumoniae, antibiotic use, and medical events during the preceding 30 days. Pneumococcal penicillin G sodium minimal inhibitory concentrations and serotyping were performed. Medical illnesses and the use of antibiotics were not associated with PRSp carriage. However, oral beta-lactam use was associated with an increased risk of PRSp carriage (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.1-8.3; P=.03). Children treated by low daily doses of an oral beta-lactam (defined as lower than clinical recommendations) had an increased risk of PRSp carriage, as compared with children who did not (OR, 5.9; 95% CI, 2.1-16.7; P=.002). A treatment of long duration (>5 days) with a beta-lactam was associated with an increased risk of PRSp carriage (OR, 3.5; 95% CI, 1.3-9.8; P=.02). Our results suggest that a low daily dose and a long duration of treatment with an oral beta-lactam contribute to the selective pressure in promoting pharyngeal carriage of PRSp.

Immunopharmacology of Oral Betalactams

Among the oral beta-lactam antibiotics only cefaclor has demonstrated a consistent in vitro and in vivo immunopharmacological effect which favors phagocytic chemotaxis and antimicrobial potential by inducing a T-helper 1 or pro-inflammatory response. Together with cefpimizole, cefaclor significantly reduces the minimum bactericidal concentration (MBC) against some bacterial species when cultured together with a suspension of polymorphonuclear leukocytes, as opposed to some other oral beta-lactams, co-amoxiclav and cefixime, which do not show this effect. The pro-inflammatory component of cefaclor's activity explains the clinical success of this antibiotic in a high percentage of cases, even when laboratory tests indicate in vitro resistance by the pathogen.

Antipneumococcal activity of BAY 12-8039, a new quinolone, compared with activities of three other quinolones and four oral beta-lactams

Activities of BAY 12-8039 against 205 pneumococci were tested by agar dilution. MICs (in micrograms per milliliter) at which 50 and 90% of the isolates are inhibited (MIC50s and MIC90s, respectively) were 0.125 and 0.25 (BAY 12-8039), 2.0 and 4.0 (ciprofloxacin and ofloxacin), and 0.25 and 0.5 (sparfloxacin). Beta-lactam MIC50s and MIC90s for penicillin-susceptible, -intermediate, and -resistant strains, in that order, were 0.016 and 0.03, 0.25 and 2.0, and 2.0 and 4.0 (amoxicillin); 0.03 and 0.06, 0.25 and 4.0, and 4.0 and 8.0 (ampicillin); 0.03 and 0.06, 0.5 and 4.0, and 4.0 and 8.0 (cefuroxime); and 0.03 and 0.125, 0.25 and 2.0, and 4.0 and 8.0 (cefpodoxime). At two times their MICs after 24 h, BAY 12-8039, ciprofloxacin, ampicillin, and cefuroxime were uniformly bactericidal (99.9% killing) against 12 strains; other compounds were bactericidal at four times their MICs.

Comparison of cefprozil, cefpodoxime proxetil, loracarbef, cefixime, and ceftibuten.

To discuss the pharmacokinetics, spectrum of activity, clinical trials, and adverse effects of cefprozil, cefpodoxime proxetil, loracarbef, cefixime, and ceftibuten, an investigational cephalosporin. Literature was identified by a MEDLINE search from 1986 to January 1995. Randomized, controlled studies were selected for evaluation; however, uncontrolled studies were included when data were limited for indications approved by the Food and Drug Administration. Data were evaluated with respect to in vitro activity, study design, clinical and microbiologic outcomes, and adverse drug reactions. Cefprozil, cefpodoxime proxetil, loracarbef, cefixime, and cefributen are active in vitro against organisms frequently involved in community-acquired infections such as Streptococcus pneumoniae, Escherichia coli, beta-lactamase-positive or -negative Haemophilus influenzae, and Moraxella catarrhalis. Except for cefixime and ceflibuten, they all are active against methicillin-susceptible Staphylococcus aureus. Even though there were problems in study design (discussed within the text), clinical data demonstrate that these new oral beta-lactam compounds are as efficacious as conventional therapies for a variety of community-acquired infections. Cefprozil, cefpodoxime, cefixime, loracarbef, and ceftibuten demonstrate in vitro activity against the major organisms that cause community-acquired infections. Clinical trials confirm that these agents are as effective as traditional therapies for the management of acute otitis media, pharyngitis/tonsillitis, sinusitis, bronchitis, pneumonia, urinary tract infections, and skin and skin-structure infections. In addition, cefixime and cefpodoxime are effective therapies for uncomplicated gonococcal infections. Selection of a specific agent will be influenced by susceptibility data and safety, as well as issues of compliance and cost.

Emerging resistance to antimicrobial agents in gram-positive bacteria. Pneumococci.

The prevalence of penicillin-resistant pneumococci is increasing worldwide. Methods for susceptibility testing, as well as in vitro susceptibility of penicillin-susceptible and -resistant strains to new and existing agents (including oral and parenteral streptogramins), are described. For all specimens except CSF, oxacillin screening followed by determination of penicillin minimum inhibitory concentrations (MICs) is satisfactory. For CSF, simultaneous testing of penicillin and cefotaxime or ceftriaxone by E-test is necessary. Of all available oral beta-lactams, amoxicillin yields the lowest MICs against penicillin-susceptible and -resistant pneumococci, and is the drug of choice for the treatment of otitis media. Cefotaxime and ceftriaxone yield MICs that are low enough to permit therapy of meningitic and nonmeningitic infections (the former in combination with vancomycin). The higher the strain's benzylpenicillin (penicillin G) MIC, the more likely it is that simultaneous resistance to nonrelated compounds such as tetracyclines, macrolides, and cotrimoxazole (trimethoprim/ sulfamethoxazole) will occur. None of the available quinolones should be used for therapy of pneumococcal infections. Of new and experimental drugs, some of the new quinolones, trovafloxacin, and oral and parenteral streptogramins are promising agents. Imipenem is epileptogenic, but meropenem has potential in the therapy of meningitis. Problematical infections caused by penicillin-resistant pneumococci include meningitis and otitis media. The optimal therapy of the latter two diseases has not yet been clearly delineated.