Adenosine stress CMR perfusion imaging of the temporal evolution of perfusion defects in a porcine model of progressive obstructive coronary artery occlusion.

Adenosine stress CMR perfusion imaging can quantify absolute perfusion and myocardial perfusion reserve (MPR) in coronary artery disease (CAD) with higher spatial resolution than positron emission tomography, the only clinically available technique for quantitative myocardial perfusion imaging. While porcine models of CAD are excellent for studying perfusion abnormalities in chronic CAD, to date there are a limited number of studies that use quantitative perfusion for evaluation. Therefore, we developed an adenosine stress CMR protocol to evaluate the temporal evolution of perfusion defects in a porcine model of progressive obstructive CAD. 10 Yucatan minipigs underwent placement of an ameroid occluder around the left circumflex artery (LCX) to induce a progressive chronic coronary obstruction. Four animals underwent a hemodynamic dose range experiment to determine the adenosine dose inducing maximal hyperemia. Each animal had a CMR examination, including stress/rest spiral quantitative perfusion imaging at baseline and 1, 3, and 6 weeks. Late gadolinium enhancement images determined the presence of myocardial infarction, if any existed. Pixelwise quantitative perfusion maps were generated using Fermi deconvolution. The results were statistically analyzed with a repeated mixed measures model to block for physiological variation between the animals. Five animals developed myocardial infarction by 3 weeks, while three developed ischemia without an infarction. The perfusion defects were located in the inferolateral myocardium in the perfusion territory of the LCX. Stress perfusion values were higher in remote segments than both the infarcted and ischemic segments (p < 0.01). MPR values were significantly greater in the remote segments than infarcted and ischemic segments (p < 0.01). While the MPR decreased in all segments, the MPR recovered by the sixth week in the remote regions. We developed a model of progressive CAD and evaluated the temporal evolution of the development of quantitative perfusion defects. This model will serve as a platform for understanding the development of perfusion abnormalities in chronic occlusive CAD.

Post COVID-19 Pandemic Increased Detection of Mycoplasma Pneumoniae in Adults Admitted to the Intensive Care.

Background: Mycoplasma pneumoniae (M. pneumoniae) infections can progress to severe respiratory complications, necessitating intensive care treatment. Recent post COVID-19 pandemic surges underscore the need for timely diagnosis, given potential diagnostic method limitations. Methods: A retrospective case series analysis was conducted on M. pneumonia PCR-positive patients admitted to two Dutch secondary hospitals' ICUs between January 2023 and February 2024. Clinical presentations, treatments, outcomes, and mechanical ventilation data were assessed. Results: Seventeen ICU-admitted patients were identified, with a median age of 44 years, primarily due to hypoxia. Non-invasive ventilation was effective for most, while five required invasive mechanical ventilation. None of the patients required extracorporeal membrane oxygenation. No fatalities occurred. Post-PCR, treatment was adjusted to doxycycline or azithromycin; seven received steroid treatment. Discussion: Increased ICU admissions for M. pneumoniae infection were observed. Diverse clinical and radiological findings emphasize heightened clinical awareness. Early molecular diagnostics and tailored antibiotic regimens are crucial since beta-lactam antibiotics are ineffective. Conclusion: This study highlights the escalating challenge of severe M. pneumoniae infections in ICUs, necessitating a multifaceted approach involving accurate diagnostics, vigilant monitoring, and adaptable treatment strategies for optimal patient outcomes.

Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines.

Umbilical Cord Procalcitonin to Detect Early-Onset Sepsis in Newborns: A Promising Biomarker.

Background: Up to 7% of neonates born in high-income countries receive antibiotics for suspected early-onset sepsis (EOS). Culture-proven neonatal sepsis has a prevalence of 0.2%, suggesting considerable overtreatment. We studied the diagnostic accuracy of umbilical cord blood and infant blood procalcitonin (PCT) in diagnosing EOS to improve antibiotic stewardship. Methods: Umbilical cord blood PCT was tested in newborns ≥ 32 weeks of gestation. Groups were defined as following: A) culture-proven or probable EOS (n = 25); B) Possible EOS, based on risk factors for which antibiotics were administered for <72 h (n = 49); C) Risk factor(s) for EOS without need for antibiotic treatment (n = 181); D) Healthy controls (n = 74). Additionally, venous or capillary blood PCT and C-reactive protein (CRP) were tested if blood drawing was necessary for standard care. Results: Between June 2019 and March 2021, 329 newborns were included. Umbilical cord blood PCT was significantly higher in group A than in group C and D. No difference between venous or arterial samples was found. Sensitivity and specificity for cord blood procalcitonin were 83 and 62%, respectively (cut-off 0.1 ng/mL). Antepartum maternal antibiotic administration was associated with decreased PCT levels in both cord blood and infant blood directly postpartum in all groups combined. Conclusion: Umbilical cord blood PCT levels are increased in newborns ≥32 weeks with a proven or probable EOS and low in newborns with risk factors for infection, but PCT seems not a reliable marker after maternal antibiotic treatment. PCT could be useful to distinguish infected from healthy newborns with or without EOS risk factors.

Insulin binding sites localized to nerve terminals in rat median eminence and arcuate nucleus.

Specific binding sites for blood-borne insulin were determined to be selectively localized on axons and axon terminals in the external median eminence and the hypothalamic arcuate nucleus by means of quantitative fine structural radioautography. This localization suggests that discrete populations of hypothalamic nerve terminals are potential targets for the direct effects of insulin and that insulin may act through synaptic mechanisms to influence hypothalamic circuits regulating energy balance and hypophyseal function.

[Outbreak of coxsackievirus infection in children]. / Uitbraak van coxsackievirusinfectie bij kinderen.

During the summer of 2006 in the paediatric ward of the Spaarne Hospital in Hoofddorp, the Netherlands, a large number of children were admitted with a coxsackievirus type-B infection, one of the enteroviruses. A total of 27 children were diagnosed with this virus. Patient A, a one-month-old boy, was admitted with fever. The spinal fluid showed a high leukocyte count. He was treated with amoxicillin, ceftriaxon and acyclovir, and recovered rapidly. The spinal fluid culture was positive for coxsackievirus type B5. Patient B, a 3-year-old girl, presented with attacks of abdominal pain and groaning respiration. Infection parameters were mildly elevated. The chest X-ray was normal. She was admitted for observation and recovered spontaneously. Viral faeces culture revealed coxsackievirus type B4. Rapid recognition of an enterovirus infection is important to prevent unnecessary diagnostic and therapeutic interventions. PCR is a diagnostic technique of great importance.

Meningococcal carriage in Dutch adolescents and young adults; a cross-sectional and longitudinal cohort study.

OBJECTIVES: Current information on rates and dynamics of meningococcal carriage is essential for public health policy. This study aimed to determine meningococcal carriage prevalence, its risk factors and duration in the Netherlands, where meningococcal C vaccine coverage is >90%. Several methods to identify serogroups of meningococcal carriage isolates among adolescent and young adults were compared. METHODS: Oropharyngeal swabs were collected from 1715 participants 13-23 years of age in 2013-2014; 300 were prospectively followed over 8 months. Cultured isolates were characterized by Ouchterlony, real-time (rt-) PCR or whole-genome sequencing (WGS). Direct swabs were assessed by rt-PCR. Questionnaires on environmental factors and behaviour were also obtained. RESULTS: A meningococcal isolate was identified in 270/1715 (16%) participants by culture. Of MenB isolates identified by whole genome sequencing, 37/72 (51%) were correctly serogrouped by Ouchterlony, 46/51 (90%) by rt-PCR of cultured isolates, and 39/51 (76%) by rt-PCR directly on swabs. A sharp increase in carriage was observed before the age of 15 years. The age-related association disappeared after correction for smoking, level of education, frequent attendance to crowded social venues, kissing in the previous week and alcohol consumption. Three participants carried the same strain identified at three consecutive visits in an 8-month period. In these isolates, progressively acquired mutations were observed. CONCLUSIONS: Whole genome sequencing of culture isolates was the most sensitive method for serogroup identification. Based upon results of this study and risk of meningococcal disease, an adolescent meningococcal vaccination might include children before the age of 15 years to confer individual protection and potentially to establish herd protection.

[Coma in a child after treatment with the 'magic salve' lidocaine-prilocaine cream]. / Coma bij een peuter na behandeling met de 'toverzalf' lidocaine-prilocaïnecrème.

A 2-year-old girl lost consciousness after the topical application of lidocaine-prilocaine cream (EMLA) in preparation for the removal of multiple mollusca contagiosa. Both the area on which cream was applied (80% of body surface) and the total amount of cream (90 g) exceeded the maximum dosage. Lidocaine-prilocaine cream is a widely used local anaesthetic with few side effects when used properly. Intoxication with a lidocaine-prilocaine preparation may have serious consequences, such as changes in intracardiac conduction, excitation or depression of the central nervous system and methaemoglobinaemia. In our patient both methaemoglobinaemia and depression of the central nervous system occurred, resulting in loss of consciousness. She was treated with 100% oxygen and fully recovered.

Binding of insulin by monkey and pig hypothalamus.

Membrane preparations from monkey and pig hypothalami bound [125I]insulin specifically. The binding appeared to be greater by preparations from anterior than posterior portions of the pig hypothalamus. Binding was time dependent, and its dissociation was first order with a half-time at 22 degrees C of 14 min. Desalanine insulin was as effective as native insulin in inhibiting the binding of [125I]insulin, while proinsulin was less effective and desoctapeptide insulin still less effective in accord with their biologic activities. Binding by membranes from cortex and thalamus appeared to be less than from hypothalamus. [125I]insulin was infused into an arterial split monkey brain preparation to determine if insulin that was blood borne bound specifically to the primate hypothalamus. Half the brain was perfused with [125I]insulin alone and the other half with [125I]insulin plus an excess of unlabeled insulin. Radioautography showed specific binding of insulin localized to the median eminence, infundibular nucleus, and microvessels. Thus, the monkey and pig hypothalami bind insulin with characteristics similar to those reported for known target tissues for insulin. Furthermore, insulin from the blood stream binds to specific anatomical structures in the hypothalamus of the monkey.

Cellular basis of direct insulin action in the central nervous system.

The in vivo radioautographic method has been applied to elucidate the mechanism of direct peptide hormone "feedback" action in the CNS. Using this method we have identified the circumventricular organs of the brain as general endocrine target tissues for a variety of blood-borne polypeptide hormones, including insulin. In the arcuatemedian eminence region of the hypothalamus blood-borne insulin directly interacts with receptive nerve terminals, suggesting that insulin acts to influence the electrical activity of select hypothalamic nerve circuits at the level of synaptic transmission. Recent results obtained from preliminary surgical and chemical lesion studies of brain indicate that insulin-receptive nerve terminals in the arcuate-median eminence region arise from neurons intrinsic to the medial basal hypothalamus. This has lead us to propose the concept of the hypothalamic tuberoinfundibular insulin-receptive neuron and its axon collaterals as a pathway for the centripetal flow of insulin "signals" in the form of electrical impulses. We envisige that the neuroanatomic pathway, provided by the hypothalamic tuberoinfundibular neuron, functions to link changes in body metabolic activity, as reflected in changing levels of circulating insulin, to the neuronal process of elaborating specific central metabolic-regulatory programs. This pathway could be of key importance in understanding and combating metabolic disease.

Specific binding and internalization of blood-borne [125I]-iodoinsulin by neurons of the rat area postrema.

The specificity and cellular location of binding sites for blood-borne [125I]iodoinsulin in the area postrema and adjacent paravagal region of the rat brain was determined by means of quantitative light and electron microscope radioautography. In both regions coinjected unlabeled insulin inhibited the binding of [125I]iodoinsulin in a dose-dependent manner, and insulin analogs blocked [125I]iodoinsulin binding in rank order of their known in vitro bioactivity. Electron microscope radioautography of this region showed that insulin specifically bound to neuronal dendrites and cell bodies and that some of the specifically bound radioactivity was internalized and concentrated in a variety of subcellular vacuoles. These observations demonstrate that certain neurons of the area postrema are endowed with the receptive capacity common to all known insulin-sensitive cells. Anatomic considerations suggest that insulin target neurons in the area postrema could mediate insulin feedback on parasympathetic function by relaying information regarding circulating insulin status to central autonomic circuits governing vagal activity. This study represents the first demonstration of a receptor-mediated uptake and concentration of a blood-borne polypeptide hormone by central neurons.

Origin of insulin-receptive nerve terminals in rat median eminence.

The origin of insulin-receptive axon terminals in the rat median eminence was determined by combining surgical and chemical ablation techniques and the in vivo radioautographic approach, in which labeling of the median eminence with blood-borne [125I]insulin served as a quantifiable marker for the presence of receptive axonal elements. Whereas unilateral deafferentation of the median eminence from the ipsilateral brain produced as much as a 50% ipsilateral loss of insulin-binding sites, transection of axonal projections to median eminence from neurons located lateral to the ventromedial hypothalamic nucleus produced no detectable loss in insulin-binding capacity. Unilateral electrocoagulation of various regions of the medial basal hypothalamus indicated that insulin-receptive axon terminals arise primarily from neurons in and about the hypothalamic arcuate nucleus and from the posterior ventrolateral subdivision of the hypothalamic ventromedial nucleus. A primary site of origin from the arcuate nucleus was confirmed in rats treated neonatally with monosodium L-glutamate, which, in addition to a selective destruction of arcuate neurons, produced a profound reduction in the insulin-specific binding capacity of the median eminence. The results of this study indicate that insulin-binding axon terminals arise from a unique class of tuberoinfundibular neuron with hormone-receptive capacity. These neurons may function to mediate direct interaction of circulating insulin with central autonomical, behavioral, and neuroendocrine systems.

Brain receptors for blood-borne calcitonin in rats: circumventricular localization and vasopressin-resistant deficiency in hereditary diabetes insipidus.

Specific binding sites for blood-borne calcitonin were localized by means of quantitative radioautography to the circumventricular organs of the rat brain. By this method, using normal Long-Evans rats as controls, specific binding of blood-borne calcitonin in the median eminence region of the hypothalamus was reduced by one-third in homozygous Brattleboro rats, which are genetically deficient in vasopressin. Competitive binding analysis in vitro of the hypothalami from these animals confirmed the binding deficit in homozygous rats, and Scatchard analysis suggested a reduction in the number of binding sites. In homozygous rats daily vasopressin replacement therapy restored normal water balance but did not normalize the hypothalamic calcitonin binding deficit. These studies delineate for the first time specific sites within the central nervous system which could serve to mediate direct actions of blood-borne calcitonin on brain function. The deficit in the Brattleboro rat may provide a model for further investigation of the role of calcitonin within selective regions of the central nervous system.

Blood-borne adrenocorticotropin binds specifically to the median eminence-arcuate region of the rat hypothalamus.

The quantitative light microscope radioautographic approach was utilized to locate specific binding sites for blood-borne 125I-labeled ACTH1-24 in the rat brain. Specific binding occurred exclusively in the external zone of the median eminence, adjacent to the primary portal plexus, and to a lesser extent in the ventral arcuate nucleus. This localization may indicate that the hypophysiotropic median eminence is a new target site for circulating adrenocorticotropin. Alternatively, ACTH binding sites in the median eminence-arcuate region may provide the hypothalamus with a hormone-selective capacity to concentrate pituitary ACTH for possible retrograde transport and redistribution within the central nervous system.

Immunocytochemical detection of insulin in rat hypothalamus and its possible uptake from cerebrospinal fluid.

Insulin-like immunoreactivity (IRI) was detected in the rat hypothalamus, particularly in the paraventricular, periventricular, supraoptic, suprachiasmatic, arcuate, and lateral hypothalamic nuclei. The immunostainable IRI was diffusely distributed in comparison to the neuronal concentrations of immunostainable vasopressin in the periventricular nucleus, or of IRI in islet B cells, suggesting that immunostainable IRI in the hypothalamus is not concentrated in neuronal perikarya. To determine if insulin in cerebrospinal fluid (CSF) may be a source of some insulin in brain tissue, [125I]iodoinsulin was stereotaxically injected into a lateral cerebral ventricle, and the uptake of radioactivity into periventricular hypothalamus was localized by both quantitative autoradiography of paraffin-embedded brain sections and by measuring the radioactivity present in microdissected brain regions. In brains that received lateral ventricular injections of labeled insulin, the concentration of radioactivity in the periventricular region of the hypothalamus, as revealed by autoradiographic grains, was significantly greater than that in the periventricular region of brains that received lateral ventricular injections of labeled insulin mixed with an equimolar excess of an unlabeled peptide (insulin, ribonuclease, or both together). The highest levels of radioactivity detected in both autoradiographic and microdissection procedures were in regions nearest to the third ventricle, suggesting that insulin in the lateral ventricles has access to the periventricular neuropile in the hypothalamus. The staining pattern of immunostainable insulin in the hypothalamus along with the distribution of radioactivity after CSF injection of labeled insulin are consistent with the hypothesis that insulin is taken up into brain from the CSF.

Regional variations in glia and neuropil within the hypothalamic ventromedial nucleus.

The normal fine structure of glia and neuropil in the various regional subdivisions of the hypothalamic ventromedial nucleus in the adult male albino rat is described in this report. Although most HVM astrocytes throughout the nucleus appear ordinary in cytology, certain astrocytes found in the posterior ventrolateral subdivision of the nucleus appear somewhat reactive, in that they contain numerous thick fascicles of gliofibrils and pleomorphic dense bodies. The processes of these reactive astrocytes elaborate multiple, concentric lamellae which encapsulate small, round, pyknotic masses (probably degenerate axonal elements). These degenerate profiles, which are greatly outnumbered by normal HVM boutons, may represent synaptic contacts that deteriorate spontaneously in the normal adult HVM. Other signs of spontaneous degeneration occurring within this neuropil include the occasional presence of large masses of necrotic debris which appear engulfed by microglia. These findings suggest the presence in the normal adult HVM neuropil of a low-grade degenerative process with attendant gliosis, which is topographically centered about the posterior ventrolateral region of the nucleus. Regions of neuropil containing degenerate boutons also contain altered neuronal processes, some of which may be growth cones. The topographic proximity of the degenerating boutons to possible signs of axonal or dendritic regeneration indicates that certain synaptic circuits in the normal adult HVM may be plastic, and subject to spontaneous remodelling.

[Sar,Ala]angiotensin II in cerebrospinal fluid blocks the binding of blood-borne [125I]angiotensin II to the circumventricular organs.

There is a specific, high affinity uptake of angiotensin II in the circumventricular organs when the peptide is injected systemically. The question of whether angiotensin II in cerebrospinal fluid can reach angiotensin receptors in the circumventricular organs was investigated in rats by determining the effect of intraventricular administration of the angiotensin II receptor blocking peptide [Sar,Ala]angiotensin II (saralasin) on the binding of blood-borne [125I]angiotensin II. Other rats received intraventricular saline, intraventricular ACTH as a peptide control, or intravenous saralasin. The brains of the rats were then sectioned and subjected to radioautography. ACTH had no effect on angiotensin II uptake. Intraventricular saralasin reduced the uptake of blood-borne angiotensin II in the median eminence and organum vasculosum of the lamina terminalis to the same degree as intravenous saralasin, and reduced uptake in the subfornical organ and area postrema to a lesser extent. Uptake was reduced 40% in the anterior lobe of the pituitary by intraventricular saralasin and 73% by intravenous saralasin, indicating that some saralasin entered the portal vessels. Uptake in the posterior lobe was unaffected by intraventricular saralasin, but reduced by intravenous saralasin. The data indicate that saralasin, and so presumably angiotensin II, in the cerebrospinal fluid can reach angiotensin II receptors in the circumventricular organs which bind blood-borne angiotensin II. Consequently, the effects of intraventricular angiotensin II that are also produced by intravenous angiotensin II can probably be explained by the peptide acting on the circumventricular organs.

Does the empiric use of vancomycin in pediatrics increase the risk for Gram-negative bacteremia?

BACKGROUND: Gram-negative bacteremia in children, a major cause of morbidity and mortality, may in part be induced by intensive treatment procedures and nonspecific use of antibiotics. Our primary objective was to study the causal relationship between the use of vancomycin and Gram-negative bacteremia, for which this antibiotic is not specifically indicated. METHODS: The study was conducted in a 105-bed tertiary care children's hospital in the period of 1994 to 1997. The study pertains to a cohort of children with suspected bacteremia, in whom a blood culture was performed during hospital stay. Using the bacteriologic laboratory registration system, we selected all pediatric cases with bacteriologically proved Gram-negative bacteremia (n = 105) and a random sample of 225 pediatric controls with negative blood cultures. Using logistic regression analysis we examined associations between Gram-negative bacteremia and the following factors: preceding use of antibiotics, antacids, corticosteroids, surgery, mechanical ventilation, parenteral nutrition, and invasive instrumentation; and the intensity of care assessed with the Therapeutic Intensity Scoring System (TISS 28). RESULTS: Gram-negative bacteremia was positively associated with the use of aminoglycosides, cephalosporins, surgical interventions, central venous catheters, parenteral nutrition, antacids and dexamethasone. The strongest association was with the use of vancomycin (odds ratio, 8.1; 95% confidence interval, 3.1 to 20.9). In a multiple logistic regression model containing all above-mentioned variables, the use of vancomycin remained positively and strongly associated with Gram-negative bacteremia (odds ratio, 3.88; 95% confidence interval, 1.34 to 11.21). Further adjustments and restrictions in the analysis did not materially change these findings concerning vancomycin. CONCLUSIONS: Among children suspected of bacteremia there are several drugs and clinical procedures influencing the risk for Gram-negative bacteremia. Empiric use of vancomycin is strongly and independently associated with Gram-negative bacteremia. The safety of using vancomycin solely on the basis of suspicion of bacteremia in children may not be warranted.

Antibiotic utilisation for hospitalised paediatric patients.

Antibiotics are among the most commonly prescribed drugs in paediatrics. Because of an overall rise in health care costs, lack of uniformity in drug prescribing and the emergence of antibiotic resistance, monitoring and control of antibiotic use is of growing concern and strict antibiotic policies are warranted. Before such policies can be implemented, detailed knowledge of antibiotic prescribing patterns is important. In this combined retrospective and prospective study the utilisation of antibiotics in a paediatric university hospital over three consecutive years has been analysed. Over an 8-week period (1 November-22 December) in 1994, 1995 and 1996 patient charts were reviewed with regard to antibiotic prescription (generic class, dose, duration and indication). A total of 1120 patients were admitted during the study periods. Antibiotics were prescribed at least once for 36% of hospitalised children, although only 12.3% of the patients receiving antibiotics had a proven bacterial infection. During a single hospitalisation 13, 4.7, 2.6, and 2.7% of all children received 2, 3, 4 or more than four antibiotics, respectively. Infants less than 2 years received antibiotics more frequently than older children (25 and 11% respectively, P=0.0256). More children admitted to the intensive care unit received antibiotics compared with patients admitted on medium care units (49.7 and 29.3% respectively, P < 0.0001). They received more often several different antibiotic courses (2.6 courses per patient versus 1.9 courses per patient, P < 0.0001). These children were also given more often intravenous rather than oral antibiotics (P < 0.0001) Significant differences could be found between the generic classes of antibiotics prescribed to children admitted to the intensive care unit and the medium care. However high variability in dose and duration of antibiotic therapy for the same clinical indication was shown. A high percentage of all hospitalised children receive antibiotics. In most cases antibiotics are started on an empirical basis, without proof of a bacterial infection, either before the start of therapy or afterwards. The fact that children admitted to intensive care units and patients of younger age groups are at special risk of receiving multiple courses of antibiotics, together with the knowledge that antibiotic resistance develops in this setting, suggest that strategies to control antibiotic use should focus on these patient populations.