Societal costs versus savings from wild-card patent extension legislation to spur critically needed antibiotic development.

BACKGROUND: Over the last two decades, an alarming rise in infections caused by antibiotic-resistant microbes has been paralleled by an equally alarming decline in the development of new antibiotics to deal with the threat. In response to this brewing "perfect storm" of infectious diseases, the Infectious Diseases Society of America (IDSA) has released a white paper that proposes incentives to stimulate critically needed antibiotic development by pharmaceutical companies. A cornerstone of the recommendations is establishment of a "wild-card patent extension" program. This program would allow a company receiving United States (US) Food and Drug Administration (FDA) approval for a new anti-infective agent targeting a drug-resistant pathogen to extend the patent on a drug within their active portfolio. However, wild-card patent extension legislation is highly controversial due to concerns regarding its societal cost. METHODS: We performed a systematic literature review to estimate the societal cost of wild-card patent extension compared to the savings resulting from the availability of one new antibiotic to treat multi-drug-resistant Pseudomonas aeruginosa. RESULTS: We conservatively estimate that wild-card patent extension applied to one new antibiotic would cost $7.7 billion over the first 2 years, and $3.9 billion over the next 18 years. Thus, even if the new antibiotic abrogated only 50% of the annual societal cost of multidrug-resistant P. aeruginosa (estimated $2.7 billion), wild-card patent extension would be cost neutral by 10 years after approval of the new antibiotic, and would save society approximately $4.6 billion by 20 years after approval. CONCLUSIONS: Wild-card patent extension appears to be a cost-effective strategy to spur anti-infective development. Although our analysis is limited by the precision of published data, our model employed conservative assumptions.

A pseudo-outbreak of nosocomial infections associated with the introduction of an antibiotic management programme.

An abrupt and persistent 30% increase in the rate of nosocomial infections was detected at a university teaching hospital after a prolonged period with a relatively constant nosocomial infection rate. Demographic data, risk factors for nosocomial infection, features of reported cases of nosocomial infection, and policy and procedure changes were evaluated for the periods of 1 January 1997 to 30 April 1998 (endemic period) and 1 May to 31 December 1998 (epidemic period). An extensive outbreak investigation revealed no evidence of a true outbreak of nosocomial infection. The apparent outbreak involved all four major body sites, began during the same month that an antibiotic management programme was started, involved the same adult medical and surgical units where antibiotics were being controlled, and occurred months before any significant change in antibiotic usage. A greater proportion of nosocomial infection during the epidemic period was reported by the nosocomial infection surveillance nurses, based on a treating physician's diagnosis rather than on specific clinical criteria. In an attempt to justify existing antibiotic prescribing practices after the implementation of an antibiotic management programme, clinicians altered the threshold at which they documented the presence of nosocomial infection. This change in documentation produced a large pseudo-outbreak of nosocomial infection.

Rigid nasal endoscopy versus sinus puncture and aspiration for microbiologic documentation of acute bacterial maxillary sinusitis.

Sinus puncture and aspiration is an invasive procedure that hinders patient enrollment in studies of acute bacterial maxillary sinusitis (ABMS). Pain and minor bleeding also limit its potential diagnostic utility in clinical practice. Cultures obtained by rigid nasal endoscopy were compared with those from sinus puncture and aspiration in 53 patients with ABMS; 46 patients were assessable. Considering recovery of Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae from puncture and aspiration as the gold standard, endoscopy cultures demonstrated a sensitivity of 85.7% (95% confidence interval, 56.2-97.5), specificity of 90.6% (73.8-97.5), positive predictive value of 80% (51.4-94.7), negative predictive value of 93.5% (77.2-98.9), and accuracy of 89.1% (75.6-95.9). Ten adverse events related to puncture and aspiration occurred in 5 (9.6%) of 52 patients; there were no endoscopy-related adverse events. In our study, the largest to date, endoscopic sampling compared favorably with puncture and aspiration for identifying H. influenzae, M. catarrhalis, and S. pneumoniae in ABMS and produced less morbidity.

Cyclic AMP-dependent inhibition of human neutrophil oxidative activity by substituted 2-propynylcyclohexyl adenosine A(2A) receptor agonists.

Novel 2-propynylcyclohexyl-5'-N:-ehtylcarboxamidoadenosines, trans-substituted in the 4-position of the cyclohexyl ring, were evaluated in binding assays to the four subtypes of adenosine receptors (ARs). Two esters, 4-(3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl)-cyclohexanecarboxylic acid methyl ester (ATL146e) and acetic acid 4-(3-[6-amino-9-(5-ethylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl] -prop-2-ynyl)-cyclohexylmethyl ester (ATL193) were >50 x more potent than 2-[4-(2-carboxyethyl)phenethylamino]-5'-N:-ethylcarboxamidoadenosine (CGS21680) for human A(2A) AR binding. Human A(2A) AR affinity for substituted cyclohexyl-propynyladenosine analogues was inversely correlated with the polarity of the cyclohexyl side chain. There was a comparable order of potency for A(2A) AR agonist stimulation of human neutrophil [cyclic AMP](i), and inhibition of the neutrophil oxidative burst. ATL146e and CGS21680 were approximately equipotent agonists of human A(3) ARs. We measured the effects of selective AR antagonists on agonist stimulated neutrophil [cyclic AMP](i) and the effect of PKA inhibition on A(2A) AR agonist activity. ATL193-stimulated neutrophil [cyclic AMP](i) was blocked by antagonists with the potency order: ZM241385 (A(2A)-selective)>MRS1220 (A(3)-selective)>>N-(4-Cyano-phenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-2,3,4,5,6,7-hexahydro-1H-purin-8-yl)-phenoxy]-acetamide (MRS1754; A(2B)-selective) approximately 8-(N-methylisopropyl)amino-N(6)-(5'-endohydroxy-endonorbornyl)-9-methyladenine (WRC0571; A(1)-selective). The type IV phosphodiesterase inhibitor, rolipram (100 nM) potentiated ATL193 inhibition of the oxidative burst, and inhibition by ATL193 was counteracted by the PKA inhibitor H-89. The data indicate that activation of A(2A)ARs inhibits neutrophil oxidative activity by activating [cyclic AMP](i)/PKA.

Effects of fibrin sealant-containing antibiotics in a rabbit model of chronic sinusitis.

Postoperative complications of sinus surgery include bleeding, infection, and synechiae. Improved subjective outcomes in humans treated with fibrin sealant (FS) after endoscopic sinus surgery (ESS) have been reported. Streptococcus pneumoniae was used to initiate chronic sinusitis in occluded rabbit sinuses in order to evaluate the role of FS in mucosal healing. Six weeks later, all animals had maxillary antrostomies. Homologous FS-containing ciprofloxicin (100 mg/mL) and clindamycin (15 mg/mL) was applied topically to treatment rabbits (n = 9). Control rabbits (n = 10) received no antibiotics. Two weeks into the recovery phase after antrostomies, all animals were re-examined. Mucociliary transport velocity (mean +/- standard deviation in mm/minute) was measured in all sinuses (n = 38) during healthy (100% measurable, 13.82 +/- 4.16), infected (18% measurable, 4.74 +/- 0.42), and recovery phases (5% measurable, 6.30 +/- 4.67). In both groups, mucopurulent discharge was present in the majority of sinuses (control group 18/20, FS group 16/18). In addition, there was no significant difference in the recovery phase between the two groups when comparing changes in the size of antrostomies, light microscopy, or culture clearance. Scanning electron microscopy did suggest a possible improvement in ciliary regeneration in the FS group. Application of FS-containing antibiotics did not appear to improve healing after ESS in our rabbit model of chronic sinusitis.

Neutrophil A2A adenosine receptor inhibits inflammation in a rat model of meningitis: synergy with the type IV phosphodiesterase inhibitor, rolipram.

Bacterial meningitis is a disease worsened by neutrophil-induced damage in the subarachnoid space. In this study, the A2A adenosine receptors on human neutrophils were characterized, and the role of A2A receptors on the trafficking of leukocytes to the cerebrospinal fluid and on blood-brain barrier permeability (BBBP) was assessed in a rat meningitis model. Neutrophils bind the A2A selective antagonist, 125I-ZM241385 (Bmax=843 receptors/neutrophil; KD=0.125 nM). A selective A2A receptor agonist, WRC-0470 (2-cyclohexylmethylidene-hydrazinoadenosine; 0.03-1 microM), alone and synergistically with the type IV phosphodiesterase inhibitor, rolipram, increased neutrophil [cAMP]i and reduced cytokine-enhanced neutrophil adherence, superoxide release, and degranulation. These effects of WRC-0470 were reversed by ZM241385 (100 nM). In a lipopolysaccharide-induced rat meningitis model, WRC-0470 (0-0.9 microgram/kg/h), with or without rolipram (0-0.01 microgram/kg/h), inhibited pleocytosis and reduced the lipopolysaccharide-induced increase in BBBP, indicative of decreased neutrophil-induced damage.

Time course of hearing loss in an animal model of pneumococcal meningitis.

A leading cause of morbidity from bacterial meningitis is an irreversible, usually profound sensorineural hearing loss, with an incidence as high as 30% in some studies. Bacterial meningitis remains the most common cause of acquired postnatal sensorineural deafness. Although several clinical studies have examined the long-term outcome of hearing in meningitis, few studies have examined the time course of hearing loss during the acute course of the disease. We have developed an animal model of meningogenic hearing loss in the rat and have plotted the time course of that hearing loss. Serial auditory brain stem responses (ABRs) were measured in rats inoculated in the cisterna magna (subarachnoid space) with Streptococcus pneumoniae (10(5) to 10(7) colony-forming units). All rats injected developed meningitis as evidenced by increased cerebrospinal fluid (CSF) white cell counts and positive CSF cultures. Serial ABR measurements taken 6, 12, 15, 18, 21, and 24 hours after inoculation demonstrated significant threshold shifts and eventual loss of the ABR waveform as compared with measurements in control rats injected with sterile culture medium. Hearing loss began approximately 12 to 15 hours after inoculation and progressed to complete loss by 24 hours (17 of 18 animals). No correlation was found between the magnitude of hearing loss and CSF white cell count or bacterial titer. Temporal bone histology of rats with meningitis shows a dense inflammatory cell infiltrate throughout the subarachnoid space. Labyrinthine inflammatory cells were confined to the scala tympani. The cochlear aqueduct is the proposed route of infection from the meninges to the labyrinth (scala tympani). Endolymphatic hydrops was also noted throughout the cochlea. These experiments both establish a reproducible animal model of meningogenic hearing loss and support the hypothesis that this hearing loss is progressive rather than abrupt in onset and is related to the duration of untreated infection. CSF inflammatory cells appear to enter the cochlea through the cochlear aqueduct. This reliable animal model will enable future studies directed toward further understanding the pathogenesis and pathophysiology of this hearing loss.

Comparison of sparfloxacin and clarithromycin in the treatment of acute bacterial maxillary sinusitis. Sparfloxacin Multicenter AMS Study Group.

Five hundred four patients were enrolled in a randomized, double-masked, multicenter study comparing the efficacy and tolerability of a 10-day regimen of sparfloxacin with a 14-day regimen of clarithromycin in the treatment of acute maxillary sinusitis. Two hundred fifty-two patients received sparfloxacin as a single 400-mg dose on day 1 and 200 mg once daily for 9 additional days, and 252 patients received clarithromycin 500 mg twice daily for 14 days. In the all-treated population, clinical success was observed at 6 to 10 days after therapy in approximately 82% of the patients in each treatment group. A total of 430 patients met the inclusion criteria for clinical assessment. The success rates in these patients were also comparable, at 83.1% and 83.4% for the sparfloxacin and clarithromycin groups, respectively. Sustained clinical success rates in the all-treated population 3 to 4 weeks after therapy were 71.6% for the sparfloxacin group and 68.6% for the clarithromycin group. All treated patients were included in the tolerability analysis. The frequency of adverse events in the clarithromycin and sparfloxacin groups was 57.9% and 48.4%, respectively. The most frequently noted adverse events were diarrhea, photosensitivity reaction, taste perversion, nausea, and abdominal pain; >96% of adverse events in the sparfloxacin group and 94% of adverse events in the clarithromycin group were of mild or moderate severity. Among adverse events at least possibly related to study drug, photosensitivity reaction was more common in the sparfloxacin group (9.5% vs. 0.4%), whereas taste perversion (8.7% vs. 0.8%) and abdominal pain (3.6% vs. 1.6%) were more common in the clarithromycin group. Thus the sparfloxacin's more convenient regimen was as effective as clarithromycin in the treatment of acute bacterial maxillary sinusitis, and the overall frequency of adverse events with sparfloxacin was comparable to that with clarithromycin.

Predicting pass rates on the American Board of Internal Medicine certifying examination.

Our objective was to determine the ability of the internal medicine In-Training Examination (ITE) to predict pass or fail outcomes on the American Board of Internal Medicine (ABIM) certifying examination and to develop an externally validated predictive model and a simple equation that can be used by residency directors to provide probability feedback for their residency programs. We collected a study sample of 155 internal medicine residents from the three Virginia internal medicine programs and a validation sample of 64 internal medicine residents from a residency program outside Virginia. Scores from both samples were collected across three class cohorts. The Kolmogorov-Smirnov z test indicated no statistically significant difference between the distribution of scores for the two samples (z = 1.284, p = .074). Results of the logistic model yielded a statistically significant prediction of ABIM pass or fail performance from ITE scores (Wald = 35.49, SE = 0.036, df = 1, p < .005) and overall correct classifications for the study sample and validation sample at 79% and 75%, respectively. The ITE is a useful tool in assessing the likelihood of a resident's passing or failing the ABIM certifying examination but is less predictive for residents who received ITE scores between 49 and 66.

Monoclonal antibody-mediated, complement-independent binding of human tumor necrosis factor-alpha to primate erythrocytes via complement receptor 1.

Monoclonal antibody (MAb)-based heteropolymers (HP) were used to simulate immune adherence. The HP is constructed by cross-linking MAbs that recognize complement receptor 1 (CR1) and tumor necrosis factor-alpha (TNF-alpha). 125I-labeled TNF-alpha was cocultured with either sheep, monkey, or human erythrocytes in the presence or absence of HP. Human erythrocytes demonstrated 63% +/- 0 (mean +/- SD) binding of 125I-labeled TNF-alpha, while binding of 125I-labeled TNF-alpha in the absence of HP was 4% +/- 1% (P < .001). Monkey erythrocytes showed similar results, while sheep erythrocytes (which lack CR1) demonstrated low binding. The effect of HP binding on biologic activity of TNF-alpha was examined in an assay of stimulated human neutrophils. The HP completely inhibited the ability of TNF-alpha to prime neutrophils, occurring regardless of the presence or absence of erythrocytes but solely dependent on the addition of HP. Thus, the HP facilitated specific, saturable, and significant binding of 125I-labeled TNF-alpha to primate erythrocytes in vitro.

Issues in the management of bacterial meningitis.

Acute bacterial meningitis is associated with significant morbidity and mortality despite the availability of effective antimicrobial therapy. The emergence of antibiotic-resistant bacterial strains in recent years has necessitated the development of new strategies for empiric antimicrobial therapy for bacterial meningitis. Specifically, the emergence of strains of Streptococcus pneumoniae that are resistant to penicillin and the cephalosporins have led to empiric therapy for patients with pneumococcal meningitis consisting of vancomycin plus a third-generation cephalosporin pending susceptibility testing. Third-generation cephalosporins are also effective as empiric therapy against other pathogens that cause community-acquired bacterial meningitis, with the exception of Listeria monocytogenes, for which ampicillin or penicillin G is the antimicrobial agent of choice. Adjunctive dexamethasone should be administered to infants and children with suspected or proven Haemophilus influenzae type b meningitis to reduce audiologic and neurologic sequelae; administration concomitant with or just before the first dose of the antimicrobial agent is optimal for best results.

Comparative effectiveness and safety of cefdinir and amoxicillin-clavulanate in treatment of acute community-acquired bacterial sinusitis. Cefdinir Sinusitis Study Group.

Cefdinir is an extended-spectrum oral cephalosporin that is active against pathogens commonly seen in acute community-acquired bacterial sinusitis (ACABS), including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Two randomized, investigator-blind, multicenter trials (one in the United States and one in Europe) compared two dosage regimens of cefdinir (600 mg once a day for 10 days and 300 mg twice a day for 10 days) to amoxicillin-clavulanate (A-C) (500 mg three times a day for 10 days) for adult and adolescent patients with ACABS. Twelve hundred twenty-nine patients entered the U.S. study, 698 with antral puncture; 569 patients entered the European study, all with antral puncture. Clinical response (cure or improvement) was determined 7 to 14 days and 3 to 5 weeks posttherapy. Microbiologic eradication rates were determined 10 to 30 days posttherapy in a subset of patients who underwent pre- and posttherapy sinus aspirate culture. Rates of adverse events and treatment discontinuations due to adverse events were examined. Cefdinir, given once or twice daily, was as effective clinically (approximately 90% cure rate) as amoxicillin-clavulanate given three times daily in the treatment of ACABS. Microbiologic eradication rates were also similar in the three groups. The major side effect was mild diarrhea, occurring in approximately 20% of each group. Cefdinir caused fewer adverse events requiring treatment discontinuation.

Brain injury in bacterial meningitis: therapeutic implications.

Recent in-vitro studies have improved our understanding of how bacteria interact with cerebral endothelial cells and cross the blood-brain barrier. Several animal studies using rat and rabbit models of bacterial meningitis have revealed mediators of inflammation that are believed to play a key role in secondary brain damage, including reactive oxygen species, nitric oxide, and excitatory amino acids. Treatment with free-radical scavengers, nitric oxide synthase inhibitors, excitatory amino acid antagonists, as well as the anti-inflammatory cytokine interleukin-10 was beneficial in experimental bacterial meningitis. Apart from dexamethasone these agents hold major promise for the adjunctive therapy of bacterial meningitis in clinical practice.

Effect of a vancomycin restriction policy on ordering practices during an outbreak of vancomycin-resistant Enterococcus faecium.

BACKGROUND: With the development of nosocomial pathogens that are resistant to multiple antimicrobial agents, reasonable restriction of antibiotic use has become a priority. METHODS: During an outbreak of vancomycin-resistant enterococcal infections, an audit of vancomycin hydrochloride use was conducted during October 3 through 21, 1994, and January 24 through February 2, 1995. During these periods, all orders for vancomycin were reviewed by clinical pharmacists. Use was classified as either appropriate or inappropriate based on recommendations by the Hospital Infection Control Practice Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention, Atlanta, Ga. A policy restricting the use of vancomycin was adopted in November 1994. RESULTS: During the first audit in October 1994, 61% of vancomycin orders were considered inappropriate according to HICPAC criteria. At the time of this audit, the first cases of an outbreak of nosocomial vancomycin-resistant Enterococcus faecium had been detected. The follow-up audit showed that 30% of vancomycin orders were inappropriate by HICPAC criteria (P < .001). Overall use of vancomycin decreased by 50% and remained at this lower level for the following year. CONCLUSION: The institution of a vancomycin restriction policy was associated with a reduction of both inappropriate drug orders and total use.

The challenge of penicillin-resistant Streptococcus pneumoniae meningitis: current antibiotic therapy in the 1990s.

Bacterial meningitis caused by Streptococcus pneumoniae is an important cause of neurological morbidity and mortality in both children and adults. With increasing antibiotic resistance in pneumococci and documented microbiological failure in treatment of pneumococcal meningitis with cefotaxime and ceftriaxone, the need for alternative antibiotic therapy is critical. Of the currently available options, vancomycin has shown the most promise, particularly when used in combination with ceftriaxone or cefotaxime. Rifampin, also used in combination with either ceftriaxone or cefotaxime, has demonstrated encouraging preliminary results against antibiotic-resistant pneumococci as well. Chloramphenicol has unexpectedly yielded discouraging clinical results in children with infection caused by penicillin-resistant strains. Of the investigational antibiotics currently in clinical trials for the treatment of meningitis, meropenem, a carbapenem-class antibiotic, has demonstrated increased activity against penicillin-resistant pneumococci compared with that of other beta-lactam antibiotics, while having a safety profile similar to that of the cephalosporins.

The use of corticosteroids in the management of bacterial meningitis in adults.

Despite the introduction of newer antimicrobial agents, bacterial meningitis continues to be associated with significant morbidity and mortality. Evidence from in-vitro studies, experimental animal models, and clinical studies indicate that the host inflammatory response is responsible for much of the deleterious consequences of this disease. Thus, there is much interest in the adjunctive use of antiinflammatory agents in the therapy of bacterial meningitis. Although there is considerable evidence from animal models and from clinical trials in children that adjunctive antiinflammatory therapy with corticosteroids is effective in reducing inflammation and in improving long-term outcomes, similar data involving adults are largely lacking. The rationale for the use of corticosteroids in the management of bacterial meningitis, and the applicability to disease in adults, are discussed, and some recommendations for their use in this setting are made.