The immunization data quality audit: verifying the quality and consistency of immunization monitoring systems.

OBJECTIVE: To evaluate the consistency and quality of immunization monitoring systems in 27 countries during 2002-03 using standardized data quality audits (DQAs) that had been launched within the framework of the Global Alliance for Vaccines and Immunization. METHODS: The consistency of reporting systems was estimated by determining the proportion of third doses of diphtheria-tetanuspertussis (DTP-3) vaccine reported as being administered that could be verified by written documentation at health facilities and districts. The quality of monitoring systems was measured using quality indices for different components of the monitoring systems. These indices were applied to each level of the health service (health unit, district and national). FINDINGS: The proportion of verified DTP-3 doses was lower than 85% in 16 countries. Difficulties in verifying the doses administered often arose at the peripheral level of the health service, usually as the result of discrepancies in information between health units and their corresponding districts or because completed recording forms were not available from health units. All countries had weaknesses in their monitoring systems; these included the inconsistent use of monitoring charts; inadequate monitoring of vaccine stocks, injection supplies and adverse events; unsafe computer practices; and poor monitoring of completeness and timeliness of reporting. CONCLUSION: Inconsistencies in immunization data occur in many countries, hampering their ability to manage their immunization programmes. Countries should use these findings to strengthen monitoring systems so that data can reliably guide programme activities. The DQA is an innovative tool that provides a way to independently assess the quality of immunization monitoring systems at all levels of a health service and serves as a point of entry to make improvements. It provides a useful example for other global health initiatives.

Linezolid in the treatment of osteomyelitis: results of compassionate use experience.

BACKGROUND: This case series examines osteomyelitis patients enrolled into a prospective, open label, noncomparative, non-randomized compassionate use program. Patients received 600 mg bid iv or po linezolid. PATIENTS AND METHODS: 89 patients were enrolled into the compassionate use program with the diagnosis of osteomyelitis and were evaluated for clinical efficacy, safety and tolerability. Informed consent was obtained from the patients or their guardians and guidelines for human experimentation of the US Department of Health and Human Services and/or those of the investigators' institutions were followed in the conduct of this clinical research. RESULTS: 55 cases of osteomyelitis met the inclusion criteria for clinical assessment. The 55 courses included long bone (53%), diabetic foot (18%), sternal wound (14.5%) and vertebral osteomyelitis (15%). Clinical assessment at longterm follow-up occurred at a median of 195 days after the last dose, and the clinical cure rate in 22 evaluable cases was 81.8% and failure rate 18.2%. The most common clinical adverse drug events (ADEs) were gastrointestinal disturbances. Reduction in hemoglobin/hematocrit and in platelet counts were the most common laboratory ADEs. CONCLUSION: Linezolid iv or po was successful in treating patients with osteomyelitis caused by resistant grampositive organisms or those with intolerance or nonresponsiveness to other potentially effective treatments. Larger comparator controlled studies should be performed to confirm these findings.

Tetanus in developing countries: an update on the Maternal and Neonatal Tetanus Elimination Initiative.

Tetanus is a vaccine-preventable disease that yearly causes a total of 309,000 deaths. Of particular concern is maternal and neonatal tetanus (MNT), which can be prevented through immunization of the mother in pregnancy. In 2000, neonatal tetanus alone was responsible for an estimated 200,000 deaths. While the focus is on 57 priority countries, 90% of the neonatal tetanus deaths occur in 27 countries. UNICEF is spearheading the effort to eliminate MNT by the year 2005, with the support of numerous partners. MNT elimination is defined as less than one case of neonatal tetanus per 1000 live births at district level. The main strategies consist of promotion of clean delivery practices, immunization of women with a tetanus toxoid (TT) containing vaccine, and surveillance. Maternal tetanus immunization is, in most developing countries, implemented as part of the routine immunization program. However, large areas remain underserved, due to logistical, cultural, economical or other reasons. In order to achieve the target of MNT elimination by 2005, and to offer protection to women and children otherwise deprived from regular immunization services, countries are encouraged to adopt the "high risk approach". This approach implies that, in addition to routine immunization of pregnant women, all women of child bearing age living in high risk areas are targeted for immunization with three doses of a tetanus toxoid containing vaccine (TT or Td), implemented as "supplemental immunization activities" (SIAs). Through SIAs, about 17 million women have been reached with at least two doses of TT vaccine in the past 3 years, and it is estimated that another 200 million need to be targeted in the years to come. SIAs should substantially reduce the burden of disease. Countries will also have to improve their existing immunization and clean delivery programs to ensure that the elimination of maternal and neonatal tetanus is maintained.

How best to estimate the global burden of pertussis?

In most countries, pertussis surveillance is inadequate for accurately estimating numbers of cases or deaths. Good estimates are needed to help set priorities for vaccination programmes. We aimed to develop a simple, reliable, and explicit method for estimating pertussis cases and deaths for children under 15 years to calculate the global disease burden in 1999. We estimated the proportion of susceptible children becoming infected in countries with poor vaccination coverage (<70%) in 1999 at 30% by 1 year, 80% by 5 years, and 100% by 15 years of age and for countries with good coverage (> or =70%) at 10% by 1 year, 60% by 5 years, and 100% by 15 years. Vaccine efficacy was estimated at 80% for preventing infection and 95% for preventing deaths. We used UN population estimates and vaccination coverage reported to WHO (adjusted for specific survey data if available). Case fatality ratios for countries with high and low child mortality were derived from published and unpublished work. For some countries with good vital events registration we used reported deaths adjusted for underascertainment. In 1999 there were an estimated 48.5 million pertussis cases in children worldwide. Deaths from pertussis were estimated at 390000 and at 295000 after adjustment for local data sources. Based on this approach, disability-adjusted life years from pertussis (12.7 million) in 2000 exceeded those of other preventable diseases such as lung cancer (11.4 million) and meningitis (5.8 million). This simple approach yields estimates that can be used for setting vaccination programme priorities. Better data are needed on the public health importance of pertussis in high mortality countries, the benefits of incomplete vaccination, and the harm from delayed vaccination.

Assessment of neonatal tetanus elimination in an African setting by lot quality assurance cluster sampling (LQA-CS).

Neonatal tetanus (NT) elimination, < 1 case per 1,000 live births (LB), was assessed at district level in Zimbabwe using a combined lot quality assurance-cluster sampling survey (LQA-CS). Three of the highest risk districts were selected. NT was considered eliminated if fewer than a specified number of NT deaths (proxy for NT cases) were found in the sample determined using operating characteristic curves and tables. TT2 + vaccine coverage was measured in mothers who gave birth 1-13 months before the survey and women aged 15-49 years. NT was considered as eliminated, TT2+ coverage was 78% (95% CI 71-82%) in women aged 15-49 and 83% (95% CI 76-89%) in mothers. The survey cost 30,000 US dollars excluding costs of consultants. NT incidence was below the elimination threshold (< 1/1,000 LB) in the surveyed districts and probably in all districts. LQA-CS is a practical, relatively cost effective field method which can be applied in an African setting to assess NT elimination status.

Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia.

BACKGROUND: Linezolid is a recently approved oxazalidinone with extended activity against Gram-positive bacteria. We evaluated the results of linezolid therapy in neutropenic cancer patients with Gram-positive bacterial infections from a compassionate-use program. PATIENTS AND METHODS: This was a prospective, multicenter, open-label, non-comparative, non-randomized compassionate-use treatment program in patients with serious Gram-positive infections. To qualify for enrollment patients were required to have an infection resistant to available antimicrobial agents, or in whom available agents had failed or to which they were intolerant. Patients with absolute neutrophil counts (ANC) <500 cells/mm(3) or <1000 cells/mm(3) and expected to decrease to <500 cells/mm(3), and who received linezolid 600 mg twice daily were included. Plasma samples for population pharmacokinetic analysis were collected. Clinical and microbiological assessments of outcomes were made at the end of therapy and at short-term follow-up. RESULTS: Of the patients in the compassionate-use trial, 103 were neutropenic. The mean [standard deviation (SD)] age was 50.1 (17.5) years, 47% were female, and 47.6% had a baseline ANC

Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus.

Treatment factors predictive of clinical and microbiological outcomes and the relationship between a pneumonia scoring system and clinical outcomes in vancomycin-treated patients with a Staphylococcus aureus-associated lower-respiratory-tract infection (LRTI) were studied. A computer database review identified patients for whom S. aureus was isolated from a respiratory-tract specimen between January 1 and December 31, 1998, and who had antimicrobials ordered within 72 hours of isolation of that organism. Through further review of individual patient charts, this group was restricted to those treated with vancomycin for a documented S. aureus-associated LRTI. Classification-and-regression-tree (CART) modeling was performed to determine which clinical variables were correlated with clinical outcomes and microbiological outcomes. Median changes in clinical pneumonia scores from baseline in two patient groups (those with clinical success and those with clinical failure) were compared. Seventy patients met the study criteria. CART modeling found that both outcomes were associated with area under the inhibitory curve (AUIC). The pneumonia scoring system was predictive of eventual clinical success as early as day 3 of treatment; having at least a 4-point decrease in the pneumonia score by day 3 was correlated with an 87% clinical success rate. Both AUIC and a pneumonia scoring system were useful for predicting clinical and microbiological outcomes of vancomycin therapy in patients with LRTIs caused by S. aureus.

Childhood mortality impact and costs of integrating vitamin A supplementation into immunization campaigns.

Country-specific activity and coverage data were used to estimate the childhood mortality impact (deaths averted) and costs of integrating vitamin A supplements into immunization campaigns conducted in 1998 and 1999. More than 94 million doses of vitamin A were administered in 41 countries in 1998, helping to avert nearly 169,000 deaths. During 1999, delivery of more than 97 million doses in 50 countries helped avert an estimated 242,000 deaths. The estimated incremental cost per death averted was US$72 (range: 36-142) in 1998 and US$64 (range: 32-126) in 1999. The estimated average total cost of providing supplementation per death averted was US$310 (range: 157-609) in 1998 and US$276 (range: 139-540) in 1999. Costs per death averted varied by campaign, depending on the number and proportion of the child population reached, number of doses received per child, and child mortality rates.

Pharmacokinetics and metabolism of moxifloxacin.

Moxifloxacin is a recently developed fluoroquinolone antibiotic. It is rapidly absorbed following oral administration, reaching a mean peak drug plasma concentration (C(max)) of approximately 3.56 mg/l within 2 h after a 400 mg dose. The rate and extent of absorption are not significantly affected by food or elevated gastric pH. Moxifloxacin binds weakly to plasma proteins and penetrates well into most tissue and fluid compartments, with generally higher drug concentrations in tissue and fluid compartments than those observed in plasma. Moxifloxacin is metabolized to an N-sulfate conjugate and an acyl glucuronide in humans. The N-sulfate and the unchanged moxifloxacin are detected in plasma, urine and feces. The acyl-glucuronide is detected in plasma and urine, but not in feces. The plasma elimination half-life ranges from 8.2-15.1 h in healthy individuals. The urinary excretion of the unchanged drug accounts for 19-22% of the given dose. Neither renal nor hepatic impairment significantly affect the pharmacokinetics of moxifloxacin.

E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators.

CONTEXT: Knowledge and understanding of gram-negative sepsis have grown over the past 20 years, but the ability to treat severe sepsis successfully has not. OBJECTIVE: To assess the efficacy and safety of E5 in the treatment of patients with severe gram-negative sepsis. DESIGN: A multicenter, double-blind, randomized, placebo-controlled trial conducted at 136 US medical centers from April 1993 to April 1997, designed with 90% power to detect a 25% relative risk reduction, incorporating 2 planned interim analyses. SETTING: Intensive care units at university medical centers, Veterans Affairs medical centers, and community hospitals. PATIENTS: Adults aged 18 years or older, with signs and symptoms consistent with severe sepsis and documented or probable gram-negative infection. INTERVENTION: Patients were assigned to receive 2 doses of either E5, a murine monoclonal antibody directed against endotoxin (n = 550; 2 mg/kg per day by intravenous infusion 24 hours apart) or placebo (n = 552). MAIN OUTCOME MEASURES: The primary end point was mortality at day 14; secondary end points were mortality at day 28, adverse event rates, and 14-day and 28-day mortality in the subgroup without shock at presentation. RESULTS: The trial was stopped after the second interim analysis. A total of 1090 patients received study medication and 915 had gram-negative infection confirmed by culture. There were no statistically significant differences in mortality between the E5 and placebo groups at either day 14 (29.7% vs 31.1%; P = .67) or day 28 (38.5% vs 40.3%; P = .56). Patients presenting without shock had a slightly lower mortality when treated with E5 but the difference was not significant (28.9% vs 33.0% for the E5 and placebo groups, respectively, at day 28; P = .32). There was a similar profile of adverse event rates between E5 and placebo. CONCLUSIONS: Despite adequate sample size and high enrollment of patients with confirmed gram-negative sepsis, E5 did not improve short-term survival. Current study rationale and designs should be carefully reviewed before further large-scale studies of patients with sepsis are conducted.

Poliomyelitis eradication.

Since the poliomyelitis eradication program began in 1988, the number of poliovirus infected continents and countries have decreased from five to two and from greater than 100 to 53, respectively. A nearly 90% reduction in the incidence of polio has been achieved with a corresponding decrease in virus genomic heterogeneity. Major challenges to eradication remain in south Asia and Africa in those areas with hot and humid climates, high population density, and high birth rates. Of particular concern are countries with ongoing social unrest and poor health infrastructure. With the approaching eradication of polio, post-eradication issues are now being addressed. The World Health Organization (WHO) draft plan for containment of wild polioviruses has been published for comment. Commissions and committees for certification of eradication have been established. Still under discussion is the question of the appropriate strategy for stopping oral polio vaccine (OPV) immunization. Studies are underway to determine whether vaccine-derived polioviruses will continue to circulate after OPV cessation and the potential disease consequences of that circulation.

Ciprofloxacin concentrations in lung tissue following a single 400 mg intravenous dose.

Intravenous ciprofloxacin is frequently prescribed for the treatment of infections due to nosocomially acquired gram-negative organisms, including those originating in the respiratory tract. In this study, the concentrations of ciprofloxacin in serum and lung tissue were determined by HPLC in patients undergoing lung surgery. A total of 22 patients scheduled for lung surgery received a single 400 mg i.v. dose of ciprofloxacin administered as a 1 h infusion. A specimen of healthy lung tissue was obtained from resected lung from 18 of the patients for analysis of ciprofloxacin concentration during the following time intervals after infusion (one sample/patient): 0-2, 2-4, 4-8 and 8-12 h. Corresponding mean serum and tissue concentrations were 2.37 mg/L and 3.84 mg/kg (0-2 h), 1.18 mg/L and 1.92 mg/kg (2-4 h), 0.69 mg/L and 1.77 mg/kg (4-8 h), and 0.13 mg/L and 0.67 mg/kg (8-12 h). Ciprofloxacin distributed rapidly to lung tissue, as seen by the high concentrations in the lung tissue as early as 2 h after infusion. Concentrations in lung tissue were generally higher than those in serum (tissue:serum ratios ranged from 1.7 to 7.1). The mean tissue concentrations found in this study remained above the MIC for most susceptible organisms.

Rehabilitation of the expanded programme on immunization in Sudan following a poliomyelitis outbreak.

In 1993 a large outbreak of paralytic poliomyelitis occurred in Sudan as a result of an accumulation of large numbers of susceptible children that was accelerated by faltering immunization services. The extent of the outbreak led to the rapid rehabilitation of Sudan's Expanded Programme on Immunization (EPI); the government began financing vaccine purchase, operational aspects of EPI were decentralized, vaccine delivery was changed from a mobile to a fixed-site strategy, a solar cold chain network was installed, inservice training was resuscitated, and social mobilization was enhanced. National immunization days (NIDs) for poliomyelitis eradication were conducted throughout the country, including the southern states during a cease fire in areas of conflict. Measles immunization coverage was increased by offering measles vaccine during the second round of NIDs and subsequently through routine immunization services. Supplemental tetanus toxoid immunization of women of child-bearing age began in three provinces at high risk for neonatal tetanus. From 1994 to 1996 reported immunization coverage increased and the incidence of all EPI target diseases fell. Trends in coverage, disease incidence, financing, and the implementation of WHO-recommended disease-control strategies suggest that more sustainable immunization services have been re-established in Sudan.

PIP: A large outbreak of paralytic poliomyelitis in 1993 in the Sudan prompted rapid rehabilitation of Sudan's Expanded Program on Immunization (EPI). A World Health Organization team visited Sudan in 1993, 1995, and 1996 to review such efforts and their impact. Measures taken to eradicate poliomyelitis, control measles, and eliminate neonatal tetanus included government financing of vaccine purchase, decentralization of EPI operations, a shift from a mobile to a less expensive fixed-site vaccine delivery strategy, installation of a solar cold chain network, resumption of managerial in-service training, and social mobilization. National immunization days were conducted in 1994, 1996, and 1997 throughout the country (during a cease fire in the southern areas). From 1993-96, reported infant immunization coverage increased for all antigens, with a concomitant decrease in the incidence of EPI target diseases. National coverage for the third dose of diphtheria-tetanus-pertussis increased from 51% in 1993 to 79% in 1996, while the proportion of immunizations delivered at fixed sites rose from 35% to 70%. By 1996, 19 of Sudan's 26 states were financing some of the operational costs for EPI.

Restricted diastolic opening of the mitral leaflets in patients with left ventricular dysfunction: evidence for increased valve tethering.

OBJECTIVES: We tested the hypothesis that patients with incomplete systolic mitral leaflet closure (IMLC: apically displaced coaptation) also have restricted diastolic leaflet opening that is independent of mitral inflow volume and provides evidence supporting increased leaflet tethering. BACKGROUND: Competing hypotheses for functional mitral regurgitation (MR) with IMLC include global left ventricular (LV) dysfunction per se (reduced leaflet closing force) versus geometric distortion of the mitral apparatus by LV dilation (augmented leaflet tethering). These are inseparable in systole, but restricted leaflet motion has also been observed in diastole, and attributed to reduced mitral inflow. METHODS: Diastolic mitral leaflet excursion and orifice area were measured by two-dimensional echocardiography in 58 patients with global LV dysfunction, 36 with and 22 without IMLC, compared with 21 normal subjects. The biplane Simpson's method was used to calculate LV ejection volume, which equals mitral inflow volume in the absence of aortic regurgitation. RESULTS: The diastolic mitral leaflet excursion angle was markedly reduced in patients with IMLC compared with those without IMLC, whose ventricles were smaller, and normal subjects (17 +/- 10 degrees vs. 58 +/- 13 degrees vs. 67 +/- 8 degrees, p < 0.0001). Excursion angle was dissociated from mitral inflow volume (r2 = 0.04); excursion was reduced in patients with IMLC despite a normal inflow volume in the larger ventricles with MR (60 +/- 25 vs. 61 +/- 12 ml in normal subjects, p = NS), and excursion was nearly normal in patients without IMLC despite reduced inflow volume (40 +/- 10 ml, p < 0.001 vs. normal subjects). The anterior leaflet when maximally open coincided well with the line connecting its attachments to the anterior annulus and papillary muscle tip (angular difference = 3 +/- 7 degrees vs. 25 +/- 9 degrees vs. 32 +/- 10 degrees in patients with and without IMLC vs. normal subjects, p < 0.0001). In patients with IMLC, the leaflet tip orifice was smaller in an anteroposterior direction but wider than in the other groups, giving a normal total area (6.8 +/- 1.8 vs. 7.1 +/- 1.2 vs. 6.9 +/- 0.8 cm2, p = NS). CONCLUSIONS: Patients with LV dysfunction and systolic IMLC also have restricted diastolic leaflet excursion that is independent of inflow volume, coincides with the tethering line connecting the annulus and papillary muscle and reflects limitation of anterior motion relative to the posteriorly placed papillary muscles without a decrease in total orifice area. These observations are consistent with increased tethering by displaced mitral leaflet attachments in the dilated ventricles of patients with IMLC that can restrict both diastolic opening and systolic closure.

Genesis of methicillin-resistant Staphylococcus aureus (MRSA), how treatment of MRSA infections has selected for vancomycin-resistant Enterococcus faecium, and the importance of antibiotic management and infection control.

We extensively studied the epidemiology and time course of endemic methicillin-resistant Staphylococcus aureus (MRSA) in the Millard Fillmore Hospital, a 600-bed teaching hospital in Buffalo. The changeover from methicillin-susceptible S. aureus to MRSA begins on the first hospital day, when patients are given cefazolin as presurgical prophylaxis. Under selective antibiotic pressure, colonizing flora change within 24 to 48 hours. For patients remaining hospitalized, subsequent courses of third-generation cephalosporins further select and amplify the colonizing MRSA population. Therefore, managing antibiotic selective pressure might be essential. Other strategies include attention to dosing, so that serum concentrations of drug exceed the minimum inhibitory concentration, and antibiotic cycling. Although there are some promising new antibiotics on the horizon, it is necessary to deal with many resistance patterns by using the combined strategies of infection control and antibiotic management.

Correlations between mood scores, LH, adrenocortical steroids, and urine volumes in a patient with a history of postpartum depression and monthly psychotic episodes.

A simple semantic differential test was administered twice daily and urinary hormones measured as described previously . The subjects included the patient and two controls, one of whom experienced premenstrual physical, but not mental, discomfort. The test scores of the two controls, administered for five weeks, did not differ significantly from one another but greatly differed from those of the patient. The highest scores in the patient (indicating improved mood) were obtained during the week containing the urinary LH peak, and daily ratings correlated significantly with LH values. Significant, positive, correlations were also found between mood and ratios for aldosterone/cortisol, 18-hydroxydeoxycorticosterone(18-OH-DOC)/cortisol, and 18-OH-DOC/18-hydroxycorticosterone. Urine volumes correlated positively with cortisol, negatively with 18-OH-DOC, and negatively with mood (P<0.01). Urinary hormone assays, affording the advantages of a non-invasive technique may thus reveal relationships of potential interest. Whether these are causal, rather than casual, remains to be assessed.

Assessing antibacterial pharmacoeconomics in the intensive care unit.

Intensive care units (ICUs) represent areas of high use of antibacterials and other pharmacy goods and services. Many institutions view their ICUs as a target for drug-use surveillance and cost-containment programmes. Economic assessment of antibacterial interventions in the ICU should include all direct costs and patient outcomes. Nonetheless, many of these institutions focus their efforts at reducing antibacterial costs without considering the consequences of these actions. It is possible that devoting more resources to antibacterials can have an overall positive economic impact if more appropriate antibacterial use reduces length of stay, decreases bacterial resistance or lowers frequency of adverse complications. Two consequences of antibacterial use which can result in substantial economic burdens to institutions are drug-induced complications (toxicities and adverse events) and the development of antibacterial-resistant organisms. These events are logical targets for performing pharmacoeconomic studies to evaluate appropriate and inappropriate antibacterial use. Either of these problems can increase length of stay, which is the single most important variable influencing the overall cost of patient care. The primary goal of patient care is to hasten patients' clinical improvement. This will result in decreased antibacterial acquisition costs, decreased lengths of ICU and hospital stays, and ultimately decreased consumption of hospital resources. These can be accomplished by using strategies to guide antibacterial use in order to reduce failures, adverse events, toxicity and antimicrobial resistance.