ABSTRACT
BACKGROUND: The burden of disease due to norovirus infection has been well described in the general United States population, but studies of norovirus occurrence among persons with chronic medical conditions have been limited mostly to the immunocompromised. We assessed the impact of norovirus gastroenteritis on health care utilization in US subjects with a range of chronic medical conditions. METHODS: We performed a retrospective cohort study using MarketScan data from July 2002 to December 2013, comparing the rates of emergency department visits, outpatient visits and hospitalizations among patients with chronic conditions (renal, cardiovascular, respiratory, immunocompromising, gastrointestinal, hepatic/pancreatic and neurological conditions and diabetes) with those in a healthy population. We estimated the rates of these outcomes due to norovirus gastroenteritis using an indirect modelling approach whereby cases of gastroenteritis of unknown cause and not attributed to a range of other causes were assumed to be due to norovirus. RESULTS: Hospitalization rates for norovirus gastroenteritis were higher in all of the risk groups analyzed compared with data in otherwise healthy subjects, ranging from 3.2 per 10,000 person-years in persons with chronic respiratory conditions, to 23.1 per 10,000 person-years in persons with chronic renal conditions, compared to 2.1 per 10,000 among persons without chronic conditions. Over 51% of all norovirus hospitalizations occurred in the 37% of the population with some form of chronic medical condition. Outpatient visits for norovirus gastroenteritis were also increased in persons with chronic gastrointestinal or immunocompromising conditions. CONCLUSION: Norovirus gastroenteritis leads to significantly higher rates of healthcare utilization in patients with a chronic medical condition compared to patients without any such condition.
Subject(s)
Caliciviridae Infections/epidemiology , Chronic Disease/epidemiology , Models, Statistical , Norovirus/physiology , Acute Disease , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Child , Child, Preschool , Delivery of Health Care/statistics & numerical data , Emergency Service, Hospital/statistics & numerical data , Gastroenteritis/diagnosis , Gastroenteritis/epidemiology , Gastroenteritis/virology , Hospitalization/statistics & numerical data , Humans , Incidence , Infant , Infant, Newborn , Middle Aged , Outpatients/statistics & numerical data , Risk Factors , Seasons , Young AdultABSTRACT
BACKGROUND: In postmarketing vaccine surveillance, adverse events observed in a vaccinated population are compared to the number expected based on a background incidence rate. The background rate should be accurate and obtained from a population comparable to the one vaccinated. Such rates are often not available. METHODS: The incidence rate of generalised convulsive, febrile and afebrile seizures was estimated in individuals born after 01-January-1998 and aged between 2 months and 15 years of age using the UK Clinical Practice Research Datalink (1999-2011). RESULTS: The study population consisted of 1532,992 individuals (4917,369 person years (PY) of follow up). A total of 28,917 generalised convulsive seizure events were identified during follow-up, the overall incidence rate was 5.88 per 1000PY. Age specific rates increased sharply from 4/1000PY at 2 months of age, peaked at 19/1000PY at 16 months and decreased until approximately 6 years of age at which point they became relatively stable at 2/1000PY. 67% of GCSs were categorised as febrile: 56% using Read codes, 11% using free text. Febrile seizures accounted for the age trend in GCS, with rates peaking at 16.1/1000PY at 16 months of age while afebrile seizure rates remained relatively stable across all ages (24 seizures per 1000PY). Analysis by first occurrence of febrile seizure showed a similar pattern, comparable to published studies on the incidence of seizures in childhood. DISCUSSION: The rates reported in this study could be used in the postmarketing surveillance of infant vaccines. However, given the variation across strata, and the potential underascertainment of seizure events presenting to A&E, care must be taken when interpreting and using these rates.
Subject(s)
Seizures/epidemiology , Adolescent , Child , Child, Preschool , Epidemiological Monitoring , Humans , Incidence , Infant , Male , Retrospective Studies , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant results that may be due to differences in design, conduct and analysis. PURPOSE: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different safety issues using different databases across European countries. This article describes the selection of the safety issues and the description of the databases to be systematically studied. METHODS: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public health impact, and the potential to investigate a broad range of methodological issues. RESULTS: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2) antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to evaluate the drug-AE pairs retrospectively, are also described. CONCLUSION: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.
Subject(s)
Adverse Drug Reaction Reporting Systems/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions/epidemiology , Pharmacoepidemiology/methods , Databases, Factual/statistics & numerical data , Europe/epidemiology , Humans , Reproducibility of Results , Retrospective Studies , Risk Assessment/methodsABSTRACT
OBJECTIVE: The 2009-2010 A/H1N1 pandemic provided a unique setting to study the safety of MF59-adjuvanted vaccination in pregnancy. STUDY DESIGN: This was an observational cohort study of the safety of an MF59-adjuvanted A/H1N1 vaccine (Focetria) conducted among 4508 pregnant women (2295 vaccinated vs 2213 unvaccinated), with 3 month follow-up of neonates. RESULTS: No maternal deaths or abortions occurred among the vaccinated women. No differences between the vaccinated and unvaccinated cohorts were observed for gestational diabetes, preeclampsia, stillbirth, low birthweight, neonatal deaths, or congenital malformations. The risk of premature birth was significantly decreased among the vaccinated women (adjusted proportional hazard, 0.69; 95% confidence interval, 0.51-0.92). No differences were observed in rates of congenital malformations after vaccination in the first (2.1%), second (2.7%), or third (2.1%) trimesters. CONCLUSION: There was no evidence of a safety risk for MF59-adjuvanted A/H1N1 vaccination in pregnant women; protection was observed against premature birth.
Subject(s)
Adjuvants, Immunologic/adverse effects , Influenza Vaccines/adverse effects , Influenza, Human/prevention & control , Polysorbates/adverse effects , Pregnancy Complications, Infectious/prevention & control , Squalene/adverse effects , Adolescent , Adult , Cohort Studies , Female , Humans , Middle Aged , Pregnancy , Young AdultABSTRACT
OBJECTIVE: To estimate the incidence rate and predictors of seizures in patients with mild to moderate Alzheimer disease (AD). DESIGN: Cohort study of patients with mild to moderate AD in clinical trials. Risk factors for potential seizures were evaluated by stratified descriptive statistics and univariable and multivariable Cox proportional hazards regressions. SETTING: Pooled patient-level data from 10 Alzheimer Disease Cooperative Study clinical trials in mild to moderate AD from 1995 to 2010. PATIENTS: Three thousand seventy-eight subjects randomized to the treatment or placebo arms of 10 AD clinical trials. Screening Mini-Mental State Examination scores ranged between 10 and 28. RESULTS: Eighteen seizures were reported in 3078 randomized subjects, with an incidence rate of 484 per 100 000 person-years (95% CI, 287-764). Statistically significant independent risk factors for seizure were younger age (adjusted hazard ratio, 0.80; 95% CI, 0.69-0.93 per every 5 years of age), greater cognitive impairment at baseline (adjusted hazard ratio, 2.79; 95% CI, 1.06-7.33 for Mini-Mental State Examination scores <18 compared with Mini-Mental State Examination scores ≥18), and antipsychotic use at baseline (adjusted hazard ratio, 3.47; 95% CI, 1.33-9.08). CONCLUSIONS: Seizure rates in patients with mild to moderate AD in clinical trials are similar to rates observed in longer observational cohort studies, but they are greater than expected in the general elderly population. Younger age, greater degree of cognitive impairment, and history of antipsychotic use were independent risk factors for new-onset seizures in AD.
Subject(s)
Alzheimer Disease/complications , Alzheimer Disease/epidemiology , Seizures/complications , Seizures/epidemiology , Age of Onset , Aged , Apolipoproteins E/genetics , Cognition Disorders/epidemiology , Cognition Disorders/psychology , Confidence Intervals , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neuropsychological Tests , Proportional Hazards Models , Risk Factors , Seizures/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Use of pregnancy registries is a common method of postmarketing surveillance of pregnancy outcomes to identify potential teratogens. However, with the increase in electronic capture of healthcare data for administrative, audit and research purposes, data generated during routine clinical practice might be used to address questions similar to those explored using pregnancy registries. OBJECTIVES: To establish how data from the UK General Practice Research Database (GPRD) compares with data from the UK Epilepsy and Pregnancy Register and to assess how it can contribute to postmarketing surveillance of pregnancy outcomes. METHODS: Pregnancy outcomes were identified from the GPRD for women aged 14-49 years with a diagnosis of epilepsy and supporting evidence. Outcomes with a major congenital malformation (MCM) were identified and the relative risks (RRs) of an MCM following a range of first-trimester antiepileptic drug (AED) exposures were calculated and compared with those reported by the UK Epilepsy and Pregnancy Register. In addition, we also evaluated whether the known association between valproate and spina bifida could be identified using data from the GPRD. The study period ran from 1 January 1990 until 31 December 2006. RESULTS: A total of 1766 live mother-baby pairs were identified, as well as 551 pregnancy terminations, 13 stillbirths and 1 neonatal death. Including those that resulted in a termination, there were 62 unique pregnancy outcomes with an MCM. An increased risk of spina bifida was identified using the GPRD following first-trimester monotherapy exposure to valproate when compared with those with no AED exposure (RR 8.02; 95% CI 1.5, 43.5). More generally, comparing the GPRD with the UK register, the GPRD ascertained a lower number of first-trimester AED exposures: monotherapy 711 versus 2468; polytherapy 156 versus 718. We reproduced the UK register results of an increased MCM risk following first-trimester polytherapy AED exposure compared with no AED exposure (RR 2.89; 95% CI 1.43, 5.84). Using the GPRD, we identified similar point estimates to the UK register following monotherapy and polytherapy exposures (4.1% vs 3.7% and 7.1% vs 6.0%, respectively) but we were unable to reproduce the level of statistical significance. For individual AEDs, the MCM rate following valproate exposure was 4.9% (11/225) in the GPRD compared with 6.2% (44/715) in the UK register. CONCLUSIONS: The GPRD has potential for the identification of malformations and of a teratogenic association. For epilepsy, the GPRD does, however, identify fewer exposed pregnancies than a pregnancy registry. Therefore, in many circumstances pregnancy registries are likely to remain preferable as a method of surveillance. The GPRD may be better suited to monitoring medicines used in the treatment of more prevalent conditions, such as depression, or for monitoring medicines that have been on the market for a long time and for which no registry has been set up.
Subject(s)
Abnormalities, Drug-Induced/etiology , Anticonvulsants/adverse effects , Epilepsy/drug therapy , Product Surveillance, Postmarketing/methods , Registries , Teratogens , Abnormalities, Drug-Induced/epidemiology , Adolescent , Adult , Anticonvulsants/therapeutic use , Databases, Factual , Female , General Practice , Humans , Infant, Newborn , Middle Aged , Pregnancy , Pregnancy Complications/drug therapy , Pregnancy Outcome , Pregnancy Trimester, First , Risk , United Kingdom , Young AdultABSTRACT
BACKGROUND: Postmarketing teratogen surveillance is essential and requires a data source that can reliably capture a wide range of congenital malformations. The UK General Practice Research Database (GPRD) may have the potential to be used for this kind of surveillance. OBJECTIVE: To assess the extent to which this database can be used to accurately identify major congenital malformations. METHODS: This study was carried out as part of a broader study to compare data on anticonvulsant use and safety in pregnancy between the GPRD and a pregnancy registry. The study period ran from 1 January 1990 until 31 December 2006. Mother-baby pairs where the mother had a record of epilepsy, seizure or convulsion were identified using the GPRD computerized medical records. Infants of mother-baby pairs who had a record of a major congenital malformation were identified. Full photocopied paper medical records were requested from the infant's general practitioner and where this was not possible any data entries consisting of uncoded comments, so-called 'free text', in the electronic GPRD record were requested from the database provider. This additional information was then reviewed in order to determine the extent to which the congenital malformation diagnoses identified via the computerized records could be confirmed or rejected and then classified as being major or minor. RESULTS: Within the study population of 3869 live mother-baby pairs, 188 potentially major congenital malformations were identified from the GPRD computerized record relating to 161 unique individuals. Using a combination of photocopied medical records and free text it was possible to verify 160 malformations (85.1%) as the malformation indicated by the computerized records; this ranged from 91.7% of those cases verified using photocopied medical records and 77.9% of cases verified using free text. Of the verified congenital malformations, using a combination of computerized data, photocopied medical records and free text, it was possible to classify 78.1% as being major and 15.0% as minor, and this percentage was found to be the same for those cases reviewed by photocopied records and those where free text was used. The proportions of malformations that could be verified and those that could be classified as major or minor were found to vary by malformation class. CONCLUSIONS: The GPRD can be used to ascertain a wide range of congenital malformations. In many cases, when a malformation is identified in the GPRD via the computerized medical records, the malformation is likely to exist. However, in this study a small proportion of identified cases had to be excluded because they had been coded incorrectly or diagnostically ruled out. Therefore, depending on the congenital malformation of interest, verification of such malformations using photocopied medical records or free text is generally recommended.
Subject(s)
Abnormalities, Drug-Induced/epidemiology , Congenital Abnormalities/epidemiology , Databases, Factual/statistics & numerical data , Medical Records/statistics & numerical data , Abnormalities, Drug-Induced/etiology , Anticonvulsants/adverse effects , Congenital Abnormalities/etiology , Drug-Related Side Effects and Adverse Reactions , Epilepsy/complications , Epilepsy/drug therapy , Female , Humans , Infant, Newborn , Pregnancy , Pregnancy Complications/drug therapy , Registries/statistics & numerical data , Teratogens/toxicity , United Kingdom/epidemiologyABSTRACT
OBJECTIVE: Serum creatinine (Cr) is used to monitor renal function during pre-marketing clinical trials. Standard thresholds for a serum creatinine (Cr) increase predictive of renal injury remain to be established in this setting. STUDY DESIGN AND SETTING: Aggregated clinical trial data were utilized to evaluate the background frequency of Cr increases of ≥ 0.3 mg/dl and ≥ 0.5 mg/dl from baseline. RESULTS: Ten thousand and eighteen subjects who participated in 15 clinical trials were included: 311 (4%) male, 7521 (96%) female, mean age of 48.1 years. Mean follow-up time was 6 months. The incidence of Cr increase ≥ 0.3 mg/dl from baseline was 7.5 per 1000 person-months (95%CI 6.81-8.24) and 1.2 per 1000 person-months (95%CI 0.94-1.52) for ≥ 0.5 mg/dl. The Cr increase was sustained at the following visit in 15.9% of subjects with a Cr increase of 0.3 mg/dl, and in 8.9% of those with a 0.5 mg/dl increase from baseline. CONCLUSION: A sustained increase in Cr of 0.5 mg/dl from baseline as a stopping criteria for potential nephrotoxicity would have resulted in study drug cessation in approximately 1 in 1000 participants in this selected clinical trial population and would not have caused undue clinical trial attrition.
Subject(s)
Creatinine/blood , Drug-Related Side Effects and Adverse Reactions , Kidney Diseases/diagnosis , Adult , Clinical Trials as Topic/methods , Female , Follow-Up Studies , Humans , Kidney Diseases/chemically induced , Kidney Diseases/physiopathology , Kidney Function Tests , Male , Middle AgedABSTRACT
OBJECTIVES: One limitation of neuropathic pain clinical trials is the often large and variable extent of response in the placebo group, possibly obscuring true medication effects. We pooled data from 252 individuals in the placebo arms of 3 clinical trials of lamotrigine in patients with neuropathic pain to examine the relationship of baseline patient and study site characteristics with 12-week change in the Pain Intensity Numerical Rating Scale score (DeltaPI-NRS). The 574 patients in the pooled lamotrigine treatment arms were used as a replication dataset. MATERIALS AND METHODS: We performed univariable and multivariable regression analysis of predictors of DeltaPI-NRS. Clinical factors examined were baseline pain intensity score (mean daily PI-NRS over the week prior to randomization), age, sex, diagnosis, prior and concurrent gabapentin use, prior and concurrent tricyclic antidepressant use, pain duration, variability of daily pain scores during the baseline week, and slope of daily pain scores over the baseline week. Site factors evaluated were study site, US geographic region, recruitment rate, and recruitment period. RESULTS: Baseline PI-NRS and site recruitment rate were independent predictors of the 12-week DeltaPI-NRS in the last observation carried forward, observed case, and repeated measures analyses. Patients with higher baseline PI-NRS scores had a significantly greater 12-week reduction in pain intensity than patients with lower baseline scores. Patients within sites with a faster recruitment rate also had a significantly greater reduction of pain intensity than those in sites with slower recruitment. DISCUSSION: These results suggest that both patient and study site characteristics can influence the response in the placebo arms of neuropathic pain studies.
Subject(s)
Anticonvulsants/therapeutic use , Neuralgia/drug therapy , Placebo Effect , Triazines/therapeutic use , Aged , Dose-Response Relationship, Drug , Female , Humans , Lamotrigine , Male , Middle Aged , Models, Statistical , Neuralgia/psychology , Pain Clinics , Predictive Value of Tests , Randomized Controlled Trials as Topic , Regression Analysis , Time FactorsABSTRACT
One limitation of several recent 24 week Alzheimer's disease (AD) clinical trials was the lack of cognitive decline detected by the AD Assessment Scale-cognitive subscale (ADAS-cog) in the placebo groups, possibly obscuring true medication effects. Data from 733 individuals in the placebo arms of six AD clinical trials performed 1996-1997 were pooled to examine the relationship of clinical, demographic, and genetic characteristics with the 24 week change in ADAS-cog. Baseline cognitive and functional status and the screening-to-baseline change in ADAS-cog were the strongest independent predictors of the 24 week change in ADAS-cog. The ADAS-cog did not detect progression in patients with mild dementia (screening Mini-Mental State Exam, MMSE, >or=20). The change in ADAS-cog from screening to baseline was inversely correlated with the 24 week change score; it was more difficult to detect cognitive decline at 24 weeks if individuals markedly worsened from screening to baseline. The effects of baseline MMSE and screening-to-baseline change in ADAS-cog generalized to the placebo group (N=106) of another AD study performed in 2004-2005. Overcoming lack of placebo decline in AD clinical trials will require scales more sensitive to cognitive decline in mild AD and strategies to reduce within-person variability in outcome measures.
Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/epidemiology , Cognition Disorders/epidemiology , Neuropsychological Tests , Aged , Alzheimer Disease/drug therapy , Cognition Disorders/diagnosis , Double-Blind Method , Female , Humans , Male , Predictive Value of Tests , Prospective Studies , Risk Factors , Rosiglitazone , Severity of Illness Index , Thiazolidinediones/therapeutic use , Vasodilator Agents/therapeutic useABSTRACT
BACKGROUND: The FDA has recently proposed pre-marketing liver chemistry subject stopping criteria. The study was undertaken to determine the background rates of liver chemistry abnormalities in clinical trial populations without underlying liver disease. METHODS: Data from 28 Phase II-IV trials in diseases with normal risk of underlying liver abnormalities were included. Information on 18,672 subjects, mean age of 44.3 years and 92.3% female was available. Prevalence and incidence of abnormal liver chemistries were calculated. RESULTS: At baseline, the overall prevalence of alanine aminotransferase (ALT) elevations of 3 x ULN (upper limit of normal) and 5 x ULN was 0.08% and 0.01%, respectively. The prevalence of liver chemistry abnormalities was similar at study entry and exit. Overall, elevated liver chemistry incidence rates per 10,000 person months were 6.5 (95% CI 4.8; 8.5) for ALT 3 x ULN, 2.6 (1.6; 4.0) for ALT 5 x ULN, 0.3 (0.03; 0.9) for ALT 8 x ULN, 0.09 (0.04; 0.2) for alkaline phosphatase (ALP) 2 x ULN, and 0 for combined ALT+bilirubin elevation. CONCLUSION: Elevations of ALT (3 x ULN) and ALP (2 x ULN) are rare in clinical trial populations without underlying liver disease and can be considered a safety signal. No events of ALT 3 x ULN with concomitant bilirubin 1.5 x ULN were noted. These analyses create a liver chemistry evidence base in normal risk clinical trial populations.
Subject(s)
Alanine Transaminase/metabolism , Alkaline Phosphatase/metabolism , Liver/pathology , Adult , Bilirubin/metabolism , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Clinical Trials, Phase IV as Topic , Female , Humans , Incidence , Liver/metabolism , Liver Diseases/epidemiology , Liver Function Tests , Male , Middle Aged , PrevalenceABSTRACT
Pregnancy registries are the most commonly used data resource for the post-marketing surveillance of drug teratogenicity. However, the limited sample size and potential selection bias in these registries has led us to investigate the potential of the UK General Practice Research Database (GPRD) as an alternative data source for monitoring drug safety during pregnancy. In addition, a literature review identified further observational data sources that monitor pregnancy outcomes for future evaluation. Initial feasibility studies focused on the ability of the GPRD to capture pregnancy outcomes for a range of drug class exposures, all of which are currently under investigation in pregnancy registries, during pregnancy. The comparator pregnancy registries were identified via a MEDLINE search, whilst eligible pregnancies, in which women received one or more prescriptions for the drug of interest during pregnancy, were identified in the GPRD using the mother-baby link. The number of pregnancy outcomes following exposure to medication for a range of conditions with varying prevalence, including depression, migraine, epilepsy, herpes simplex and HIV, captured by the two data sources were compared. For depression, a relatively prevalent condition, the GPRD recorded the same number of mean annual intrauterine exposures to fluoxetine as the pregnancy registry (118 exposures/year). Ascertainment of intrauterine exposure to drug treatments for less prevalent conditions was found to be higher for the pregnancy registries than the GPRD; for the older antiepileptic drugs (valproate and carbamazepine), the pregnancy registry recorded between four and five times as many mean annual exposures as the GPRD. Virtually no antiretroviral exposures (three) were identified during the time period of interest on the GPRD, compared with 3946 in the Antiretroviral Pregnancy Registry. Data from the GPRD meet established criteria for evaluating outcomes of pregnancy. For prevalent conditions, it has the potential to replace or work alongside standard pregnancy registries and the alternative data sources identified. Further studies are now needed to assess its ability to replicate known teratogenic associations.
Subject(s)
Databases, Factual/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions , Prenatal Exposure Delayed Effects/chemically induced , Registries/statistics & numerical data , Female , Humans , Pregnancy , Pregnancy Outcome , Prenatal Exposure Delayed Effects/epidemiology , Product Surveillance, Postmarketing/methods , Product Surveillance, Postmarketing/statistics & numerical data , United Kingdom/epidemiologyABSTRACT
The Alexander Project is a global surveillance study conducted from 1992 to 2001. Minimum inhibitory concentrations and percent resistance to a panel of antimicrobial agents were determined according to National Committee for Clinical Laboratory Standards methodology. Resistance to penicillin (PEN-R) and erythromycin (ERY-R) have increased in the period 1992-2001 by 3.9 and 4.5 times to 20.7% and 27.9%, respectively. Joint PEN-ERY-R has increased 4.9 times, up to 15.3%. In 1992, 57.1% of all PEN-R isolates were also ERY-R, whereas in 2001, 75.8% were ERY-R. Resistance to only 1 antibiotic increased slightly, from 8% in 1992 to 12% in 2001, whereas resistance to more than 1 antibiotic increased 4.3 times, from 6.4% in 1992 to 27.8% of all strains in 2001. Multidrug-resistant pneumococci are an increasingly common finding in the United States. Three of four PEN-R isolates are also multiresistant. The rate of growth of multidrug resistance is higher than that of single antibiotic resistance.