Quality indicators for hospital antimicrobial stewardship programmes: a systematic review.

BACKGROUND: Measuring the quality and effectiveness of antimicrobial stewardship (AMS) programmes with quality indicators (QIs) is an area of increasing interest. We conducted a systematic review to identify QIs of AMS programmes in the hospital setting and critically appraise their methodological quality. METHODS: We searched the Cochrane Library, PubMed, MEDLINE, EMBASE, CINAHL, Scopus/web of science databases and the grey literature for studies that defined and/or described the development process and characteristics of the QIs developed. The Appraisal of Indicators through Research and Evaluation (AIRE) instrument was used to critically appraise the methodological quality of the QI sets. RESULTS: We identified 16 studies of QI sets consisting of 229 QIs. The QI sets addressed a broad range of areas of AMS in the hospital setting and consisted of 75% process indicators, 24% structural indicators and 1% outcome indicators. There was a wide variation in the information and level of detail presented describing the methodological characteristics of the QI sets identified. CONCLUSIONS: The QIs identified in this study focused on process and structural indicators with few outcome indicators developed-a major deficiency in this area. Future research should focus on the development of outcome indicators or the use of process or structural indicators linked to outcomes to assess AMS. Testing of the QIs in practice is an essential methodological element of the QI development process and should be included in the QI development study or as planned validation work.

The Role of Physician and Practice Characteristics in the Quality of Diabetes Management in Primary Care: Systematic Review and Meta-analysis.

BACKGROUND: Despite evidence-based guidelines, high-quality diabetes care is not always achieved. Identifying factors associated with the quality of management in primary care may inform service improvements, facilitating the tailoring of quality improvement interventions to practice needs and resources. METHODS: We searched MEDLINE, EMBASE, CINAHL and Web of Science from January 1990 to March 2019. Eligible studies were cohort studies, cross-sectional studies and randomised controlled trials (baseline data) conducted among adults with diabetes, which examined the relationship between any physician and/or practice factors and any objective measure(s) of quality. Studies which examined patient factors only were ineligible. Where possible, data were pooled using random-effects meta-analysis. RESULTS: In total, 82 studies were included. The range of individual quality measures and the construction of composite measures varied considerably. Female physicians compared with males ((odds ratio (OR) = 1.07, 95% CI: 1.04, 1.10), 8 studies), physicians with higher diabetes volume compared with lower volume (OR = 1.24, 95% CI: 1.05-1.47, 4 studies) and practices with Electronic Health Records (EHR) versus practices without (OR = 1.43, 95% CI: 1.11-1.84, 4 studies) were associated with a higher quality of care. There was no association between physician experience, practice location and type of practice and quality. Based on the narrative synthesis, increasing physician age and higher practice socio-economic deprivation may be associated with lower quality of care. DISCUSSION: Identification of physician- and practice-level factors associated with the quality of care (female gender, younger age, physician-level diabetes volume, practice deprivation and EHR use) may explain differences across practices and physicians, provide potential targets for quality improvement interventions and indicate which practices need specific supports to deliver improvements in diabetes care.

An investigation of the effects of procalcitonin testing on antimicrobial prescribing in respiratory tract infections in an Irish university hospital setting: a feasibility study.

BACKGROUND: Diagnostic uncertainty and a high prevalence of viral infections present unique challenges for antimicrobial prescribing for respiratory tract infections (RTIs). Procalcitonin (PCT) has been shown to support prescribing decisions and reduce antimicrobial use safely in patients with RTIs, but recent study results have been variable. METHODS: We conducted a feasibility study of the introduction of PCT testing in patients admitted to hospital with a lower RTI to determine if PCT testing is an effective and worthwhile intervention to introduce to support the existing antimicrobial stewardship (AMS) programme and safely decrease antimicrobial prescribing in patients admitted with RTIs. RESULTS: A total of 79 patients were randomized to the intervention PCT-guided treatment group and 40 patients to the standard care respiratory control group. The addition of PCT testing led to a significant decrease in duration of antimicrobial prescriptions (mean 6.8 versus 8.9 days, P = 0.012) and decreased length of hospital stay (median 7 versus 8 days, P = 0.009) between the PCT and respiratory control group. PCT did not demonstrate a significant reduction in antimicrobial consumption when measured as DDDs and days of therapy. CONCLUSIONS: PCT testing had a positive effect on antimicrobial prescribing during this feasibility study. The successful implementation of PCT testing in a randomized controlled trial requires an ongoing comprehensive education programme, greater integration into the AMS programme and delivery of PCT results in a timely manner. This feasibility study has shown that a larger randomized controlled trial would be beneficial to further explore the positive aspects of these findings.

Sustaining quality in the community: trends in the performance of a structured diabetes care programme in primary care over 16 years.

AIM: To examine the quality of care delivered by a structured primary care-led programme for people with Type 2 diabetes mellitus in 1999-2016. METHODS: The Midland Diabetes Structured Care Programme provides structured primary care-led management. Trends over time in care processes were examined (using a chi-squared trend test and age- and gender-adjusted logistic regression). Screening and annual review attendance were reviewed. A composite of eight National Institute for Health and Care Excellence-recommended processes was used as a quality indicator. Participants who were referred to diabetes nurse specialists were compared with those not referred (Student's t-test, Pearson's chi-squared test, Wilcoxon-Mann-Whitney test). Proportions achieving outcome targets [HbA1c ≤58 mmol/mol (7.5%), blood pressure ≤140/80 mmHg, cholesterol <5.0 mmol/l] were calculated. RESULTS: Data were available for people with diabetes aged ≥18 years: 1998/1999 (n=336); 2003 (n=843); 2008 (n=988); and 2016 (n=1029). Recording of some processes improved significantly over time (HbA1c , cholesterol, blood pressure, creatinine), and in 2016 exceeded 97%. Foot assessment and annual review attendance declined. In 2016, only 29% of participants had all eight National Institute for Health and Care Excellence processes recorded. A higher proportion of people with diabetes who were referred to a diabetes nurse specialist had poor glycaemic control compared with those not referred. The proportions meeting blood pressure and lipid targets increased over time. CONCLUSIONS: Structured primary care led to improvements in the quality of care over time. Poorer recording of some processes, a decline in annual review attendance, and participants remaining at high risk suggest limits to what structured care alone can achieve. Engagement in continuous quality improvement to target other factors, including attendance and self-management, may deliver further improvements.

How long should we treat this infection for?

Infection accounts for approximately half of all paediatric admissions to hospital and an even greater proportion of primary care. Guidelines on duration of antibiotic therapy exist, but antibiotic therapy for children needs to be individualised. If a child is not improving the clinical condition and treatment should be reviewed and/or discussed with an expert. However, slavishly completing the recommended course of antibiotics in a child who is well, may not be appropriate. Recent studies on treatment duration advocate shortened courses with certain caveats, but guidelines and clinical practice do not always follow the evidence from the few randomised trials of treatment duration of infection.

Developing Specialist Perinatal Mental Health Services: the door of opportunity.

The development of Specialist Perinatal Mental Health Services in Ireland in recent years (2018-2021) is described. The paper highlights the role of unexpected opportunity in advancing this much needed service for women, infants and their families. It also emphasises the need for funding combined with an implementation mechanism to ensure that the service emerging is true to the Model of Care designed and is available in a uniform manner to women nationally.

Antimicrobial use and antimicrobial resistance in Enterobacterales and Enterococcus faecium: a time series analysis.

BACKGROUND: Irish and European antimicrobial resistance (AMR) surveillance data have highlighted increasing AMR in Enterobacterales and vancomycin resistance in Enterococcus faecium (VRE). Antimicrobial consumption (AC) in Irish hospital settings is also increasing. METHODS: A retrospective time series analysis (TSA) was conducted to evaluate the trends and possible relationship between AC of selected antimicrobials and AMR in Enterobacterales and vancomycin resistance in E. faecium, from January 2017 to December 2020. RESULTS: Increased AC was seen with ceftriaxone (P = 0.0006), piperacillin/tazobactam (P = 0.03) and meropenem (P = 0.054), while ciprofloxacin and gentamicin use trended downwards. AMR rates in Escherichia coli, Klebsiella pneumoniae and other Enterobacterales were largely stable or decreasing, an increase in ertapenem resistance in the latter from 0.58% in 2017 to 5.19% in 2020 (P = 0.003) being the main concern. The proportion of E. faecium that was VRE did not changed significantly (64% in 2017; 53% in 2020, P = 0.1). TSA identified a correlation between piperacillin/tazobactam use and the decreasing rate of ceftriaxone resistance in E. coli. CONCLUSION: Our data suggest that the hospital antimicrobial stewardship programme is largely containing, but not reducing AMR in key nosocomial pathogens. An increase in AC following the COVID-19 pandemic appears as yet to have had no impact on AMR rates.

Diagnostic efficacy of activated partial thromboplastin time waveform and procalcitonin analysis in pediatric meningococcal sepsis.

OBJECTIVE: A biphasic activated partial thromboplastin time waveform predicts sepsis and disseminated intravascular coagulation in adults. This has not been previously investigated in children. Our aim is to ascertain whether there are changes in the activated partial thromboplastin time waveform in children with meningococcal disease and to compare its diagnostic use with procalcitonin. SETTING: Alder Hey Children's National Health Service Foundation Trust, Liverpool, UK. PATIENTS: Thirty-six children admitted to the hospital for the treatment of suspected meningococcal disease had activated partial thromboplastin time waveform and procalcitonin analysis performed at admission. The light transmittance level at 18 secs was used to quantitate the waveform. Severity of disease was assessed using the Glasgow Meningococcal Septicaemia Prognostic Score, Pediatric Risk of Mortality III score, and the Pediatric Logistic Organ Dysfunction score. MEASUREMENTS AND MAIN RESULTS: Twenty-four children had proven meningococcal disease, 12 had a presumed viral illness, and 20 control subjects were recruited. Transmittance level at 18 secs was lower in children with meningococcal disease and those with a viral illness (p < .0001) and control subjects (p < .0005). Sensitivity and specificity was 0.91 and 0.96 for transmittance level at 18 secs and 0.92 and 1 for procalcitonin in identifying meningococcal disease. There was a significant difference in procalcitonin between children with meningococcal disease and those with a viral illness and control subjects (p < .0005). A negative correlation was found between transmittance level at 18 secs and length of hospital stay (p < .0001), C-reactive protein (p < .0001), procalcitonin (p < .0001), Glasgow Meningococcal Septicaemia Prognostic Score (p < .01), Pediatric Risk of Mortality III score (p < .0001), and Pediatric Logistic Organ Dysfunction score score (p < .0001). CONCLUSION: The activated partial thromboplastin time waveform is abnormal in children with meningococcal disease and may be a useful adjunct in the diagnosis and management of sepsis in children.

Antimicrobial usage in an intensive care unit: a prospective analysis.

Antimicrobial therapies in the Intensive Care Unit (ICU) need to be appropriate in both their antimicrobial cover and duration. We performed a prospective observational study of admissions to our semi-closed ICU over a three-month period and recorded the indications for antimicrobial therapy, agents used, duration of use, changes in therapy and reasons for changes in therapy. A change in therapy was defined as the initiation or discontinuation of an antimicrobial agent. There were 51 patients admitted during the three-month study period and all received antimicrobial therapy. There were 135 changes in antimicrobial therapy. 89 (66%) were made by the ICU team and 32 (24%) were made by the primary team. Changes were made due to a deterioration or lack of clinical response in 41 (30%) cases, due to the completion of prescribed course in 36 (27%) cases, and in response to a sensitivity result in 25 (19%) cases. Prophylactic antibiotic courses (n=24) were of a duration greater than 24 hours in 15 (63%) instances. In conclusion, the majority of changes in antimicrobial therapy were not culture-based and the duration of surgical prophylaxis was in excess of current recommended guidelines.

A qualitative process evaluation of the introduction of procalcitonin testing as an antimicrobial stewardship intervention.

Background Successful antimicrobial stewardship interventions are imperative in today's environment of antimicrobial resistance. New antimicrobial stewardship interventions should include qualitative analysis such as a process evaluation to determine which elements within an intervention are effective and provide insight into the context in which the intervention is introduced. Objective To assess the implementation process and explore the contextual factors which influenced implementation. Setting An academic teaching hospital in Cork, Ireland. Methods A process evaluation was conducted on completion of a feasibility study of the introduction of a procalcitonin antimicrobial stewardship intervention. The process evaluation consisted of semi-structured face-to-face interviews of key stakeholders including participating (senior) doctors (5), medical laboratory scientists (3) and a hospital administrator. The Consolidated Framework for Implementation Research was used to guide data collection, analysis, and interpretation. Main outcome measures Qualitative assessment of the intervention implementation process, the contextual factors which influenced implementation and identification of improvements to the intervention and its implementation and determine if proceeding to a randomised controlled trial would be appropriate. Results Analysis of the interviews identified three main themes. (1) The procalcitonin intervention and implementation process was viewed positively to support prescribing decisions. Participants identified modifications to procalcitonin processing and availability to improve implementation and allow procalcitonin to be "more of a clinical influence". (2) In the antimicrobial stewardship context the concept of fear of missing an infection and risks of potentially serious outcomes for patients emerged. (3) The hospital context consisted of barriers such as available resources and facilitators including the hospital culture of quality improvement. Conclusion This process evaluation provides a detailed analysis of the implementation of procalcitonin testing as an antimicrobial stewardship intervention. The positive findings of this process evaluation and feasibility study should be built upon and a full randomised controlled trial and economic evaluation should be conducted in a variety of hospital settings to confirm the effectiveness of procalcitonin as an antimicrobial stewardship intervention.

Medical pediatric inpatients and outpatients are at risk of influenza and pneumococcal disease.

Influenza and pneumococcal vaccines are recommended for certain risk groups. All children admitted to the Children's wards or attending Children's Outpatients were studied for these risk factors. Risk factors for influenza were present in 78 (41%) of 193 admissions and 93 (27%) of 348 outpatients. Risk factors for pneumococcal infection were present in 22 (11.5%) admissions and 42 (12%) outpatients. Only 29 of these children had been given influenza (n = 19) or pneumococcal (n = 10) vaccines. Pediatricians could improve the coverage of influenza and pneumococcal vaccines by identifying children with risk factors in hospital discharge summaries and outpatient clinic letters.

Imported malaria in children: a review of clinical studies.

Imported malaria is a preventable disease, yet it is responsible for several thousand cases and a substantial number of deaths every year. There has been a pronounced rise in the incidence of imported malaria in most developed countries over the past three decades and, more concerning, Plasmodium falciparum, which is responsible for almost all cases of severe malaria, is now the most prevalent species. Children account for around 15-20% of all imported malaria cases and must be considered separately from adults because they have different risk factors for developing malaria and a higher risk of developing severe disease since they are more likely to be non-immune to malaria. We did a thorough review of the literature since 1980 to identify and critically assess clinical case series on children with imported malaria with respect to travel destination, reason for travel, the use of antimalarial prophylaxis, clinical presentation, delay in diagnosis, laboratory features, complications, management, and outcome. Children living in non-endemic countries and travelling during school holidays to visit family and relatives in their parents' country of origin currently account for the largest proportion of cases in many European countries. This group of travellers deserves special attention because they often do not take antimalarial prophylaxis or other preventive measures. There is a need for standardised recommendations on management and prevention of imported malaria in children, which should be supported by large multicentre clinical trials. A prospective national surveillance study on imported malaria in children was launched in the UK and Ireland through the British Paediatric Surveillance Unit in 2006, which may provide answers to some of the questions raised in this Review.

Bacterial meningitis: the impact of vaccination.

Acute bacterial meningitis remains an important cause of morbidity and mortality in children. Children <2 years of age are particularly susceptible to infection with encapsulated bacteria due to their immature response to polysaccharide antigens. Conjugate vaccines, which induce T cell memory, can provide immunological protection for these children. The Haemophilus influenzae type b (Hib) conjugate vaccine was the first such vaccine to become available. The efficacy of the vaccine has been quoted as being 98%. Its introduction was followed by a dramatic decrease in the incidence of all invasive Hib disease, including meningitis. This reduction was in part due to the ability of these vaccines to reduce nasopharyngeal carriage of the organism and thereby induce herd immunity. Different Hib vaccines use a variety of protein carriers and differ in their immunogenicity and efficacy. The most suitable vaccine needs to be determined according to the local epidemiology of Hib disease. Commercial combination vaccines may lead to lower antibody levels. A recent increase in the incidence of Hib disease in the UK highlights the importance of continued surveillance and the need for booster vaccinations to ensure continued protection. Conjugate vaccines to Streptococcus pneumoniae and Neisseria meningitidis have been developed. The introduction of a pneumococcal conjugate vaccine in the US has led to a decrease in the rate of infection by nearly 60% in children <5 years of age. A reduction in pneumococcal carriage may also modify disease epidemiology. The UK introduced the conjugate meningococcal C vaccine into its infant schedule with a corresponding reduction in N. meningitidis group C disease. A recent decrease in the effectiveness of the vaccine, however, suggests a booster may be necessary in the future. Our present understanding of the immunology of conjugate vaccines is far from complete. Developed countries have introduced conjugate vaccines into their immunisation schedules to prevent bacterial meningitis; however, their high cost precludes their use in many developing countries. Progress needs to be made in order to get these highly effective vaccines to those areas that need them.

Central venous catheter infection with Bacillus pumilus in an immunocompetent child: a case report.

BACKGROUND: Bacillus organisms are common laboratory contaminants. The majority of Bacillus bacteraemias are transient and not clinically significant. Clinically significant infection due to Bacillus species is rare and mostly due to Bacillus cereus infections in immuno-compromised hosts. CASE PRESENTATION: We report a case of central venous catheter infection with Bacillus pumilus in an immunocompetent child with tufting enteropathy on long-term parenteral nutrition (PN). There were three episodes of central venous catheter infection with Bacillus pumilus in three months. Despite adequate and appropriate use of intravenous antibiotics, the infection failed to clear resulting in the need for removal of the catheter for complete cure. CONCLUSION: Bacillus species can cause clinically significant central venous catheter infection, even in an immunocompetent host. Despite adequate antibiotic treatment, the central venous catheter may need removal for complete cure.

"Random" gentamicin concentrations do not predict trough levels in neonates receiving once daily fixed dose regimens.

BACKGROUND: Monitoring plasma gentamicin concentrations in neonates 24 hours after a once daily dose (4 mg/kg) often necessitates additional blood sampling. In adults a nomogram has been developed enabling evaluation of gentamicin doses by sampling concentrations with other blood tests, 4-16 hours after administration. We attempted to develop a similar nomogram for neonates. METHODS: In addition to standard 24 hour sampling to monitor trough concentrations, one additional "random" gentamicin concentration was measured in each of 50 neonates < 4 days of age (median gestation 33 weeks [28-41]), when other blood samples were clinically necessary, 4-20 hours after gentamicin administration. 24 hour concentrations of > 1 mg/L were considered high, and an indication to extend the dosing interval. RESULTS: Highest correlation (r2 = 0.51) of plasma gentamicin concentration against time (4 to 20 hours) was with logarithmic regression. A line drawn 0.5 mg/L below the true regression line resulted in all babies with 24 hr gentamicin concentrations > 1 mg/L having the additional "random" test result above that line, i.e. 100% sensitivity for 24 hour concentrations > 1 mg/L, though only 58% specificity. Having created the nomogram, 39 further babies (median gestation 34 weeks [28-41]), were studied and results tested against the nomogram. In this validation group, sensitivity of the nomogram for 24 hr concentrations > 1 mg/L was 92%; specificity 14%, positive predictive value 66%, and negative predictive value 50%. Prematurity (< or = 37 weeks) was a more sensitive (94%) and specific (61%) indicator of high 24-hour concentrations. 62 (87%) of 71 preterm babies had high 24-hour concentrations. CONCLUSION: It was not possible to construct a nomogram to predict gentamicin concentrations at 24 hours in neonates with a variety of gestational ages. Dosage tailored to gestation with monitoring of trough concentrations remains management of choice.

Validation of two algorithms for managing children with a non-blanching rash.

BACKGROUND: Paediatricians are concerned that children who present with a non-blanching rash (NBR) may have meningococcal disease (MCD). Two algorithms have been devised to help identify which children with an NBR have MCD. AIM: To evaluate the NBR algorithms' ability to identify children with MCD. METHODS: The Newcastle-Birmingham-Liverpool (NBL) algorithm was applied retrospectively to three cohorts of children who had presented with NBRs. This algorithm was also piloted in four hospitals, and then used prospectively for 12 months in one hospital. The National Institute for Health and Care Excellence (NICE) algorithm was validated retrospectively using data from all cohorts. RESULTS: The cohorts included 625 children, 145 (23%) of whom had confirmed or probable MCD. Paediatricians empirically treated 324 (52%) children with antibiotics. The NBL algorithm identified all children with MCD and suggested treatment for a further 86 children (sensitivity 100%, specificity 82%). One child with MCD did not receive immediate antibiotic treatment, despite this being suggested by the algorithm. The NICE algorithm suggested 382 children (61%) who should be treated with antibiotics. This included 141 of the 145 children with MCD (sensitivity 97%, specificity 50%). CONCLUSIONS: These algorithms may help paediatricians identify children with MCD who present with NBRs. The NBL algorithm may be more specific than the NICE algorithm as it includes fewer features suggesting MCD. The only significant delay in treatment of MCD occurred when the algorithms were not followed.

Evaluating the implementation of a national clinical programme for diabetes to standardise and improve services: a realist evaluation protocol.

BACKGROUND: Over the last three decades in response to the growing burden of diabetes, countries worldwide have developed national and regional multifaceted programmes to improve the monitoring and management of diabetes and to enhance the coordination of care within and across settings. In Ireland in 2010, against a backdrop of limited dedicated strategic planning and engrained variation in the type and level of diabetes care, a national programme was established to standardise and improve care for people with diabetes in Ireland, known as the National Diabetes Programme (NDP). The NDP comprises a range of organisational and service delivery changes to support evidence-based practices and policies. This realist evaluation protocol sets out the approach that will be used to identify and explain which aspects of the programme are working, for whom and in what circumstances to produce the outcomes intended. METHODS/DESIGN: This mixed method realist evaluation will develop theories about the relationship between the context, mechanisms and outcomes of the diabetes programme. In stage 1, to identify the official programme theories, documentary analysis and qualitative interviews were conducted with national stakeholders involved in the design, development and management of the programme. In stage 2, as part of a multiple case study design with one case per administrative region in the health system, qualitative interviews are being conducted with frontline staff and service users to explore their responses to, and reasoning about, the programme's resources (mechanisms). Finally, administrative data will be used to examine intermediate implementation outcomes such as service uptake, acceptability, and fidelity to models of care. DISCUSSION: This evaluation is using the principles of realist evaluation to examine the implementation of a national programme to standardise and improve services for people with diabetes in Ireland. The concurrence of implementation and evaluation has enabled us to produce formative feedback for the NDP while also supporting the refinement and revision of initial theories about how the programme is being implemented in the dynamic and unstable context of the Irish healthcare system.

Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism.

Synthetic ceramides induce apoptotic death of Jurkat and HL60 leukaemia cell lines. By contrast we show here that ceramide induces non-apoptotic killing of malignant cells from patients with B-chronic lymphocytic leukaemia (B-CLL) and of normal B lymphocytes. The protein phosphatase inhibitor okadaic acid readily induces apoptosis of B-CLL cells, indicating that this death pathway is fully functional in these cells. The ability of ceramide to activate the apoptotic protease caspase 3 in HL60 cells but not in B-CLL cells, as well as the lack of correlation of ceramide-mediated killing of different B-CLL isolates with expression of the apoptosis-regulating proteins bcl-2 and bax reinforce the conclusion that ceramide killing of B-CLL cells is by a non-apoptotic mechanism. Fludarabine treatment or gamma-irradiation of B-CLL cells resulted in ceramide elevation and in killing by both apoptotic and non-apoptotic mechanisms, suggesting that a ceramide-triggered non-apoptotic mechanism may play a role in the killing of these cells. Therefore, the results here show that ceramide can induce either apoptotic or non-apoptotic death, depending on the cellular context. The inability of synthetic dihydroceramide to kill B-CLL cells or normal B lymphocytes suggests that non-apoptotic killing by ceramide is via interaction with a specific, but unidentified, cellular target.

Herbimycin A accelerates the induction of apoptosis following etoposide treatment or gamma-irradiation of bcr/abl-positive leukaemia cells.

Philadelphia chromosome (Ph)-positive leukaemia cells express the chimeric bcr/abl oncoprotein, whose deregulated protein tyrosine kinase (PTK) activity antagonizes the induction of apoptosis by DNA damaging agents. Treatment of Ph-positive K562, TOM 1 and KCL-22 cells with etoposide for 2d induced cytosolic vacuolation, but not nuclear condensation or DNA fragmentation. The bcr/abl kinase-selective inhibitor herbimycin A increased the induction of nuclear apoptosis by etoposide or gamma-radiation. The concentration of herbimycin required to synergize with etoposide was similar to that required to decrease the level of tyrosine phosphorylated proteins or of the protein tyrosine kinase activity of anti-abl immune complexes in K562 cells. The ability of herbimycin A to sensitize K562, TOM 1 or KCL-22 cells to apoptosis induction correlated with its ability to decrease the cellular content of phosphotyrosyl proteins in these Philadelphia-positive lines. Enhancement of nuclear apoptosis by herbimycin was not attributable to downregulation of the bcl-2 or bcl-XL anti-apoptotic proteins. In contrast, herbimycin protected Philadelphia-negative HL60 cells from apoptosis induction by etoposide and did not affect killing of NC37 and CEM cells. The data suggest that the induction of apoptosis is blocked in cells expressing the bcr/abl oncoprotein and that herbimycin A increases induction of programmed cell death following DNA damage. Selective PTK inhibitors may therefore be of value in securing the genetic death of Ph-positive leukaemia cells.