Category Archives: C. diff. for Healthcare Providers

Patient Safety Is Jeopardized by Unnecessary Antibiotics

Like any medication, antibiotics carry certain risks. While they are critical to treating a wide range of conditions, from strep throat and urinary tract infections to bacterial pneumonia and sepsis, these drugs also increase a patient’s chances of developing Clostridium difficile infections—which can result in life-threatening diarrhea—and can lead to adverse drug events, including allergic reactions.

Because of these dangers, it is important to use antibiotics only when needed. However, many antibiotics prescribed in the United States are unnecessary.

See what the research tells us and what leading antibiotic use experts say about inappropriate prescribing, the threat it poses to patient health, and how improved antibiotic stewardship can help to protect patient safety.

Improving Outpatient Antibiotic Use: The Role of Pediatricians

“For a long time, we believed that ‘erring on the safe side’ for our patients might be to prescribe an antibiotic just in case, even when we weren’t completely certain of the diagnosis. … Increasingly, we’re realizing that ‘being on the safe side’ often means not prescribing an antibiotic.”

Adam Hersh, M.D., University of Utah, Primary Children’s Hospital


Improving Outpatient Antibiotic Use: The Role of Emergency Room Doctors

“Acute bronchitis is one of the very common conditions we see in the emergency department and it’s also one … for which we have the best evidence that antibiotics should not be used, as these infections are typically caused by viruses and will resolve on their own. … I’ve seen … patients that received antibiotics for simple bronchitis or sinusitis that probably didn’t need the antibiotic, and then came in with life-threatening diarrheal illness, known as C. difficile infection.”

Larissa May, M.D., University of California, Davis


Improving Outpatient Antibiotic Use: The Role of Pharmacists

“I’ve had patients with antibiotic-associated adverse drug reactions … serious ones, such as Stevens-Johnson’s syndrome and [the] development of C. difficile.”

Katie Suda, Pharm.D., M.S., University of Illinois, Chicago


Improving Outpatient Antibiotic Use: The Role of Primary Care Physicians

“There’s a misperception on the part of doctors that patients want antibiotics. … [There] are millions of individual visits where we’re doing the wrong thing by our patients. We’re giving them medicines that they don’t need.”

Jeff Linder, M.D., M.P.H., Brigham and Women’s Hospital, Harvard Medical School


One study estimated that a 30 percent reduction in broad-spectrum antibiotic use in hospitals could result in a 26 percent reduction in hospital-associated C. difficile infections.

Improving Outpatient Antibiotic Use: The Role of Nurse Practitioners

“What is concerning is a lot of people think every sore throat is strep throat, and they want antibiotics. The reality is that most sore throats are not strep throat. It is important that we make sure that we don’t give antibiotics just for a viral sore throat. … If we continue to prescribe antibiotics inappropriately … we will get to a point where children are not responding to antibiotics. And that’s very scary.”

Teri Woo, Ph.D., National Association of Pediatric Nurse Practitioners


David Hyun, M.D., works on The Pew Charitable Trusts’ antibiotic resistance project.


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Study Investigators Find Combination of Vancomycin and FMT Superior In Treating Recurrent C.difficile Infection (rCDI)

The combination of vancomycin and fecal microbiota transplantation was found to be superior to fidaxomicin or vancomycin in the treatment of patients with recurrent Clostridium difficile infection (rCDI), according to a study published in Gastroenterology.

This randomized, single-center trial was designed to compare the efficacy of fecal microbiota transplantation with that of fidaxomicin and vancomycin.

Sixty-four adults with recurrent CDI seen at a gastroenterology clinic in Denmark between April 5, 2016 and June 10, 2018 were randomly assigned to a group receiving fecal microbiota transplantation applied by colonoscopy or nasojejunal tube after 4 to 10 days of 125 mg vancomycin 4 times daily (n=24), or 10 days of 200 mg fidaxomicin 2 times daily (n=24), or 10 days of 125 mg vancomycin 4 times daily (n=16).

Patients experiencing a CDI recurrence after this course of treatment, and those who could not be randomly assigned were provided rescue fecal microbiota transplantation. The primary study outcome was combined clinical resolution and negative polymerase chain reaction test for C difficile toxin at 8 weeks post-treatment, and secondary end points included week 8 clinical resolution.

The combination of negative C difficile test results and clinical resolution was observed in 71% of the 24 participants who received fecal microbiota transplantation (95% CI, 49-87%; n=17), 33% of the 24 participants who received fidaxomicin (95% CI, 16-55%; n=8), and 19% of the 16 participants (95% CI, 5-46%; n=3) who received vancomycin (fecal microbiota transplantation vs fidaxomicinP=.009; fecal microbiota transplantation vs vancomycin, P=.001; fidaxomicin vs vancomycin, P=.31). Clinical resolution was observed in 92% of participants who received fecal microbiota transplantation (n=22; P=.0002), 42% of participants who were treated with fidaxomicin (n=10; <.0001), and 19% of participants who were treated with vancomycin (n=3; P=.13). No significant differences in results were seen between patients receiving initial fecal microbiota transplantation therapy and those who received rescue treatment with such a transplant.

Of note, adverse events (transient abdominal pain, constipation, bloating and diarrhea) were observed in 10 of the participants who received a fecal microbiota transplant, 1 of which was classified as severe.

Researchers noted limitation of a lack of patients with C difficile ribotype 027, such that results may not be generalizable to settings with a high ribotype 027 frequency. Study interventions were also unblinded, introducing the possibility of observer bias, although the C difficile toxin test was applied to all patients at all time points in an effort to obtain objective outcome measures.

Study investigators concluded, “[fecal microbiota transplantation] was superior to both fidaxomicin and vancomycin monotherapies for [recurrent] CDI, with regard to both combined clinical and microbiological resolution and clinical resolution alone.”


Hvas CL, Jørgensen SMD, Jørgensen SP, et al. Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent Clostridium difficile infection [published online January 2, 2019]. Gastroenterology. doi: 10.1053/j.gastro.2018.12.019

Summit Therapeutics Doses First Patient in Global Phase 3 Clinical Trials Oral Antibiotic ridinilazole for C.difficile Infection Treatment

Summit Doses First Patient in Phase 3 Clinical Trials of Precision Antibiotic Ridinilazole for C. Difficile Infection

  • Trials Aim to Show Superiority of Ridinilazole Over Standard of Care Treatment Vancomycin
  • Health Economic Outcomes Included to Support Commercialisation


Oxford, UK, and Cambridge, MA, US, 13 February 2019 – Summit Therapeutics plc (NASDAQ: SMMT, AIM: SUMM), a leader in new mechanism antibiotic innovation, today announces it has dosed the first patient in the global Phase 3 clinical trials of its precision oral antibiotic, ridinilazole, for C. difficile infection (‘CDI’). The trials aim to show superiority of ridinilazole over the standard of care, vancomycin, in a measure that combines CDI cure and recurrence called sustained clinical response (‘SCR’). Ridinilazole achieved statistical superiority over vancomycin in SCR in a Phase 2 clinical trial.

“Starting our Phase 3 programme is an important milestone for Summit,” commented Mr Glyn Edwards, Chief Executive Officer of Summit. With positive results, we believe ridinilazole could be positioned as the drug of choice in the front-line treatment of CDI, which potentially provides patients with sustained cures and hospitals with compelling cost savings.”

“Ridinilazole is the trail-blazer in our growing pipeline of innovative product candidates targeting serious infectious diseases,” added Dr David Roblin, President of R&D of Summit. “Our Phase 3 programme exemplifies our broader strategy of demonstrating significant advantages over current standards of care by gathering a carefully considered package of clinical and economic data to address the needs of physicians, regulators, healthcare providers, payors and, above all, patients.”

The Phase 3 clinical programme comprises two global, randomised, double-blind, active-controlled clinical trials called Ri-CoDIFy 1 and Ri-CoDIFy 2. The trials will be run concurrently with each expected to enrol approximately 680 patients at sites in North America, Latin America, Europe, Australia and Asia. Upon confirmation of a positive CDI toxin test, patients will be randomised to receive either ridinilazole (200mg twice a day) or vancomycin (125mg four times a day) for ten days. The primary endpoint of both clinical trials will test for superiority in SCR, defined as cure at the end of treatment and no recurrence of CDI within 30 days post-treatment. Secondary endpoints include cure at the end of treatment and SCR at 60 days and 90 days post-treatment. Additional endpoints will evaluate the impact of ridinilazole and vancomycin on the gut microbiome, which is known to protect against CDI. The Phase 3 clinical trials also include health economic outcome measures, such as readmission rates and length of hospital stay, to help support the commercialisation of ridinilazole, if approved.

Top-line data from the Phase 3 programme are expected to be reported in the second half of 2021.

The clinical and regulatory development of ridinilazole is being funded in part with Federal funds from the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (‘BARDA’), under Contract No. HHS0100201700014C. Summit is eligible to receive up to $62 million in funding from BARDA to support the clinical and regulatory development of ridinilazole.

About Ridinilazole
Ridinilazole is an oral small molecule new mechanism antibiotic that is designed to selectively kill C. difficile, thereby preserving patients’ protective gut microbiome and leading to sustained CDI cures. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin. In that trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy. Ridinilazole was also shown to be highly preserving of the gut microbiome in the Phase 2 proof of concept trial, which was believed to be the reason for the improved clinical outcome for the ridinilazole-treated patients. In addition, ridinilazole preserved the gut microbiome to a greater extent than the marketed narrow-spectrum antibiotic fidaxomicin in an exploratory Phase 2 clinical trial. Ridinilazole has received Qualified Infectious Disease Product (‘QIDP’) designation and has been granted Fast Track designation by the US Food and Drug Administration. The QIDP incentives are provided through the US GAIN Act and include a potential extension of marketing exclusivity for an additional five years upon FDA approval.

About Summit Therapeutics
Summit Therapeutics is a leader in antibiotic innovation. Our new mechanism antibiotics are designed to become the new standards of care for the benefit of patients and create value for payors and healthcare providers. We are currently developing new mechanism antibiotics for infections caused by C. difficile, N. gonorrhoeae and ESKAPE pathogens and are using our proprietary Discuva Platform to expand our pipeline.

For more information, visit

Researchers Find Systematically Addressing Penicillin Allergies May Be An Important Public Health Strategy to Reduce the Incidence of MRSA and C. difficile Among Patients With a Penicillin Allergy

BMJ 2018; 361 doi: (Published 27 June 2018) Cite this as: BMJ 2018;361:k2400

  1. Kimberly G Blumenthal, assistant professor of medicine123,
  2. Na Lu, biostatistician1,
  3. Yuqing Zhang, professor of medicine13,
  4. Yu Li, research assistant12,
  5. Rochelle P Walensky, professor of medicine234,
  6. Hyon K Choi, professor of medicine13

Author affiliations

  1. Correspondence to: K G Blumenthal (or @KimberlyBlumen1 on Twitter)
  • Accepted 30 April 2018


Objective To evaluate the relation between penicillin allergy and development of meticillin resistant Staphylococcus aureus (MRSA) and C difficile.

Design Population based matched cohort study.

Setting United Kingdom general practice (1995-2015).

Participants 301 399 adults without previous MRSA or C difficile enrolled in the Health Improvement Network database: 64 141 had a penicillin allergy and 237 258 comparators matched on age, sex, and study entry time.

Main outcome measures The primary outcome was risk of incident MRSA and C difficile. Secondary outcomes were use of β lactam antibiotics and β lactam alternative antibiotics.

Results:       Among 64 141 adults with penicillin allergy and 237 258 matched comparators, 1365 developed MRSA (442 participants with penicillin allergy and 923 comparators) and 1688 developed C difficile (442 participants with penicillin allergy and 1246 comparators) during a mean 6.0 years of follow-up.

Among patients with penicillin allergy the adjusted hazard ratio for MRSA was 1.69 (95% confidence interval 1.51 to 1.90) and for C difficile was 1.26 (1.12 to 1.40). The adjusted incidence rate ratios for antibiotic use among patients with penicillin allergy were 4.15 (95% confidence interval 4.12 to 4.17) for macrolides, 3.89 (3.66 to 4.12) for clindamycin, and 2.10 (2.08 to 2.13) for fluoroquinolones. Increased use of β lactam alternative antibiotics accounted for 55% of the increased risk of MRSA and 35% of the increased risk of C difficile.

Conclusions Documented penicillin allergy was associated with an increased risk of MRSA and C difficile that was mediated by the increased use of β lactam alternative antibiotics. Systematically addressing penicillin allergies may be an important public health strategy to reduce the incidence of MRSA and C difficile among patients with a penicillin allergy label.


One third of patients report a drug allergy (ie, adverse or allergic reaction),1 the most commonly implicated drug being penicillin and documented in 5-16% of patients.12345 Being labelled with a penicillin allergy affects future prescribing for infections in both outpatients and inpatients, with prescribed antibiotics often more broad spectrum and toxic.2678 Unnecessary use of broad spectrum antibiotics leads to the development of drug resistant bacteria, including meticillin resistant Staphylococcus aureus (MRSA), and healthcare associated infections such as Clostridium difficile related colitis.910111213

Most patients with a documented penicillin allergy are not allergic—that is, there is no immediate hypersensitivity.1415 After evaluation by an allergist, about 95% of patients with reported penicillin allergies were found to be penicillin tolerant.14 The discrepancy between labelled and confirmed penicillin allergy stems from misdiagnosis (eg, a viral exanthem is misinterpreted as an allergy), misassumptions (eg, an intolerance, such as a headache, is listed as an allergy), and remote timing of the allergy evaluation, since 80% of patients with immediate hypersensitivity to penicillin are no longer allergic after 10 years.16 Most patients with a penicillin allergy label therefore unnecessarily avoid penicillins, and often other related β lactam antibiotics, such as cephalosporins.67

To evaluate the public health consequences of having a penicillin allergy label, we conducted a population based matched cohort study and examined the relation between a newly recorded penicillin allergy and the risk of incident MRSA and C difficile.


Data source

We used data from the Health Improvement Network (THIN), an electronic medical record database of 11.1 million patients registered with general practices in the United Kingdom. Because the National Health Service requires people to register with a general practice regardless of health status, THIN is a population based cohort representative of the UK general population.17 During consultations with patients in primary care, general practitioners (GPs) enter clinical data, including height, weight, smoking status, diagnoses, and prescription drugs. Patient diagnoses are recorded using READ codes, the UK’s standard clinical terminology system.18 Drug allergies are linked to a drug prescription, or recorded as a diagnosis (eg, personal history of penicillin allergy). The GP enters details of the drug allergy, including reaction type, severity of reaction, and certainty of diagnosis. All GPs are trained in data entry, with the quality of their data periodically reviewed. Previous studies using THIN have confirmed the validity of both prescriptions and diagnoses.1920

Study design

We performed a matched cohort study among participants aged more than 18 years, who were enrolled in the THIN database between 1995 and 2015. Eligible participants had no history of MRSA or C difficile diagnoses before study entry and were required to have at least one year of enrolment with a general practice before entering the study to allow for assessment of exposure and covariates. We identified adults with their first recorded penicillin allergy and selected up to five penicillin users without a penicillin allergy matched on age (one year either way), sex, and study entry time (within one year either way). Such comparators were chosen to further ensure the comparability of indications for penicillin use (eg, infection tendency) and associated features. The index date for cases was the date of first entry of an allergy diagnosis in the THIN database; the matched index date for comparators was within one year of a penicillin prescription.

Assessment of exposure and outcomes

The exposure of interest was a documented penicillin allergy, defined as an allergy to a penicillin antibiotic linked to a penicillin prescription, or one or more relevant READ diagnosis codes for a penicillin allergy or adverse effect (see supplemental table 1).

The primary outcomes were incident cases of doctor diagnosed MRSA and C difficile during the follow-up period. We identified MRSA and C difficile by the presence of one or more relevant READ diagnosis codes.21222324 For MRSA, codes indicated MRSA infection, carriage, eradication, or decontamination whereas for C difficile, codes indicated C difficile infection or detection of antigen or toxin (see supplementary table 1).

We also assessed antibiotic utilization during the follow-up period, derived from the prescription record. We grouped all antibiotics prescribed into classes: penicillins, first generation cephalosporins, macrolides, clindamycin, fluoroquinolones, tetracyclines, and sulfonamides. Given that vancomycin, aminoglycosides, and linezolid are commonly administered parenterally and therefore seldom administered to outpatients by GPs, we assessed these antibiotics separately.

Assessment of covariates

We identified demographic and lifestyle factors before the index date, such as age, sex, body mass index, socioeconomic status, smoking status, and alcohol use. READ diagnosis codes at the index date were used to ascertain relevant comorbidities (diabetes, renal disease, hemodialysis, malignancy, liver disease, and infection with human immunodeficiency virus (HIV)) and to calculate the adapted Charlson comorbidity index25 at baseline. Using the prescription records, we identified the number of antibiotics prescribed in the year before the index date and whether proton pump inhibitors or systemic corticosteroids were used at baseline. Concomitant allergies to cephalosporin antibiotics and other antibiotics were linked to prescriptions or identified using READ diagnosis codes. We determined participants who were residents of nursing homes at baseline. Finally, we calculated the number of visits to a GP and hospital admissions during the year before the index date.

Statistical analysis

We compared baseline characteristics between participants with penicillin allergy and their comparators. Follow-up time for each participant was calculated from the index date to the date of one of several events: the study endpoints (MRSA or C difficile), death, or end of the study (31 December 2015), whichever occurred first.

We identified incident MRSA cases and number of person years of follow-up for each cohort separately. We calculated the hazard ratios for the relation of penicillin allergy status to the risk of MRSA using Cox proportional hazard models. In the multivariable Cox model we adjusted for age, sex, body mass index, socioeconomic status, smoking status, alcohol use, Charlson comorbidity index, hemodialysis, number of antibiotic prescriptions, proton pump inhibitor use, corticosteroid use, other antibiotic allergies, resident of nursing home, visits to a GP, and admissions to hospital. We repeated the same analyses for the risk of C difficile. We also calculated the absolute risk difference.

In both the penicillin allergy cohort and the comparison cohort we determined the rates of subsequent antibiotic utilization by class. We used Poisson regression models to estimate the incidence rate ratio for the relation of penicillin allergy status to the rates of subsequent antibiotic use, while adjusting for the same covariates.

We performed mediation analyses to examine the extent to which the effect of penicillin allergy status on the risk of MRSA or C difficile was through its effect on utilization of β lactam alternative antibiotics.26 Specifically, we grouped utilization into five categories based on previous studies that evaluated the impact of various antibiotics on the risk of MRSA and C difficile910111213: fluoroquinolones, clindamycin, macrolides, vancomycin, aminoglycosides, and linezolid (all β lactam alternative antibiotics considered in this study); fluoroquinolones, clindamycin, and macrolides; fluoroquinolones and macrolides; fluoroquinolones and clindamycin; and fluoroquinolones alone. Using marginal structural models we then estimated the natural direct effect (ie, the effect of penicillin allergy status on the risk of MRSA or C difficile not through a specific group of antibiotics) and the natural indirect effect (ie, the effect of penicillin allergy status on the risk of MRSA or C difficile through a specific group of antibiotics), while adjusting for the same confounding variables,26 and reported the adjusted risk ratio and percentage mediated.

For all analyses we imputed unknown values for covariates (ie, missing body mass index, alcohol use, and smoking status) using a sequential regression method based on a set of covariates as predictors. To minimize random error, we imputed five datasets and then combined estimates from these datasets by calculating effect estimates from each imputed dataset and then averaging estimates and their confidence intervals using Rubin’s rules.27 All analyses were performed using SAS, version 9.2 (SAS Institute, Cary, NC).

Patient and public involvement

No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community. Individual patient consent was not sought given the use of anonymized data.


Cohort identification and characteristics

We identified 64 141 patients with a documented penicillin allergy and 237 258 matched comparators (table 1). Patients with penicillin allergy were identified through allergies linked to prescriptions for penicillin antibiotics (63 245/64 141, 98.6%). Documented penicillin allergies consisted of allergies (74.4%), intolerances (14.5%), and adverse effects (11.1%). Most allergies were considered of moderate severity (86.0%) with likely certainty (73.6%).

Table 1

Reactions in patients with penicillin allergy (n=64 141)

Patients with penicillin allergy were similar to their comparators for age, sex, body mass index, socioeconomic status, smoking status, and alcohol use (table 2). They were also similar for diabetes, renal disease, hemodialysis, malignancy, liver disease, HIV, Charlson comorbidity index, previous antibiotic prescriptions, use of proton pump inhibitors and systemic corticosteroids, nursing home residency, visits to a GP, and hospital admissions. Other antibiotic allergies were more common in patients with a penicillin allergy.

Table 2

Cohort characteristics according to penicillin allergy status. Values are numbers (percentages) unless stated otherwise

Penicillin allergy and risk of MRSA and C difficile

During the mean follow-up time of 6.0 years for patients with penicillin allergy and 6.1 years for comparator patients, 442 patients with penicillin allergy and 923 comparator patients developed MRSA, and 442 patients with penicillin allergy and 1246 comparator patients developed C difficile (table 3 and supplemental table 2).

Table 3

Impact of listed penicillin allergy on risk of meticillin resistant Staphylococcus aureus (MRSA)and Clostridium difficile

The age, sex, and study entry time matched hazard ratios for patients with penicillin allergy were 1.84 (95% confidence interval 1.64 to 2.06) for MRSA and 1.37 (1.23 to 1.53) for C difficile. The matched and multivariable adjusted hazard ratios for patients with penicillin allergy were 1.69 (1.51 to 1.90) for MRSA and 1.26 (1.12 to 1.40) for C difficile, respectively. The corresponding adjusted risk differences were 49/100 000 person years for MRSA and 27/100 000 person years for C difficile.

Penicillin allergy and subsequent antibiotic utilization

Patients with penicillin allergy were less often prescribed penicillin than their comparators (adjusted incidence rate ratio 0.30, 95% confidence interval 0.30 to 0.31), but had increased use of macrolide antibiotics (4.15, 4.12 to 4.17), clindamycin (3.89, 3.66 to 4.12]), fluoroquinolones (2.10, 2.08 to 2.13), tetracyclines (1.75, 1.73 to 1.76), and sulfonamide antibiotics (1.26, 1.25 to 1.27; table 4). Though vancomycin, aminoglycosides, and linezolid were overall infrequently prescribed, they were more often prescribed to patients with penicillin allergy than to their comparators (supplemental table 3).

Table 4

Impact of listed penicillin allergy on antibiotic use

Mediation effects of alternative antibiotic use

Compared with patients who did not receive penicillins, patients receiving penicillins did not have an increased risk of MRSA (adjusted risk ratio 1.07, 95% confidence interval 0.95 to 1.20), but had an increased risk of C difficile (1.18, 1.06 to 1.31; supplemental table 4). Patients receiving macrolide antibiotics had an increased risk of MRSA (1.72, 1.54 to 1.91) and C difficile (1.30, 1.18 to 1.43). Patients receiving clindamycin had an increased risk of MRSA (2.97, 2.11 to 4.16) and C difficile (2.76, 2.00 to 3.81). Patients receiving fluoroquinolones had an increased risk of MRSA (2.38, 2.12 to 2.67) and C difficile (1.72, 1.54 to 1.93).

The effect of a penicillin allergy on the risk of MRSA was 55% mediated through β lactam alternative antibiotic classes; 55% mediated through fluoroquinolones, clindamycin, and macrolides; 54% mediated through fluoroquinolones and macrolides; 26% mediated through fluoroquinolones and clindamycin; and 24% mediated through fluoroquinolones alone (table 5). The effect of penicillin allergy on C difficile was 35% mediated through β lactam alternative antibiotic classes; 26% mediated through fluoroquinolones, clindamycin, and macrolides; 24% mediated through fluoroquinolones and macrolides; 20% mediated through fluoroquinolones and clindamycin; and 16% mediated through fluoroquinolones alone.

Table 5

Mediation analysis to estimate the indirect effect of listed penicillin allergy on meticillin resistant Staphylococcus aureus (MRSA) and Clostridium difficile


In this large cohort study reflective of the United Kingdom general population, we found that a penicillin allergy label was associated with a 69% increased risk of MRSA and a 26% increased risk of C difficile. Once documented, a penicillin allergy resulted in increased use of β lactam alternative antibiotics, with a fourfold increased incidence of macrolides and clindamycin utilization, and a twofold increased incidence of fluoroquinolone utilization. Furthermore, more than half of the increased MRSA risk and more than one third of the increased C difficile risk among patients with penicillin allergy was attributable to administered β lactam alternative antibiotics.

Comparison with other studies and policy implications

We found that patients with a penicillin allergy label had nearly a 70% increased risk of new MRSA than their matched comparators, even after adjustment for known MRSA risk factors.28 This provides supporting evidence for a previous US study that showed a 14% increased MRSA prevalence in inpatients who were allergic to penicillin.8 Our result emphasises that outpatient use of antibiotics is strongly associated with the risk of developing MRSA.2228 Consistent with previous studies, we found that β lactam alternative antibiotics increased the risk of MRSA to a greater degree than did penicillins12132930; whereas the mechanism of resistance is not known, the same factors that predispose staphylococcus to develop resistance to meticillin are thought to predispose staphylococcus to multidrug resistance that includes resistance to meticillin.122931 With more than half of the increased MRSA risk among patients with listed penicillin allergy directly attributable to increased outpatient β lactam alternative antibiotic use (largely fluoroquinolones and macrolides), this risk appears modifiable if prescribing patterns among those with penicillin allergy could be altered.

C difficile is responsible for almost one half million infections and 15 000 deaths each year in the US, and the Centers for Disease Control and Prevention consider C difficile one of three urgent threats to public health.32 Patients with penicillin allergy in this study had a 26% increased C difficile risk compared with age, sex, and study entry time matched comparators after adjustment for other known risk factors for C difficile.10333435 This result also corroborates the previous US study, which found a 23% increased C difficile prevalence in hospital patients with a penicillin allergy.8 While other studies similarly identified that clindamycin and fluoroquinolones were associated with the greatest risk of C difficile,91011 we found that 35% of the heightened risk of C difficile in patients with penicillin allergy was directly attributable to use of β lactam alternative antibiotics, with quinolone use alone responsible for 16% of the heightened risk. The mechanism by which antibiotic use precipitates C difficile is through disruption of the host microbiome and creation of an environment where C difficile can overgrow.36 Antibiotics not captured in this dataset (eg, those administered at dialysis or in hospitals) and non-antibiotic risk factors234 are likely responsible for the remainder of C difficile cases. Although current efforts to reduce C difficile largely focus on reducing C difficile infections in hospitals and rehabilitation centers, one third of C difficile infections occur in the community, and occur in outpatients.37 Our findings suggest that more systematic efforts to identify patients with listed penicillin allergy who are not truly allergic to penicillins could help decrease rates of community associated C difficile.

In this study, patients with documented penicillin allergy had an increased incidence of broad spectrum antibiotic use, including the extended Gram positive spectrum antibiotics vancomycin and linezolid, which should be reserved for patients with suspected or known MRSA (or vancomycin resistant enterococci for linezolid).3839 Use of the most narrow spectrum antibiotic that is effective for a given infection is a cornerstone of evidence based treatment for infection and is responsible antibiotic stewardship.38 Antibiotic stewardship committees enforce this aim in the hospital setting, with evaluations for penicillin allergy occasionally included in stewardship efforts.40 This analysis emphasises the importance of performing outpatient antibiotic stewardship and the role that penicillin allergy evaluations might play. Although diagnostic testing for penicillin allergy was developed in the 1960s, and has recently garnered the support of a variety of professional organizations,384142 less than 0.1% of patients with a penicillin allergy label undergo confirmatory testing.15 Evaluation of penicillin allergy often involves a skin test, and if the result of skin testing is negative, a challenge dose of penicillin or amoxicillin is administered under medical observation.15 With these evaluation tools, evaluation of penicillin allergy has a more than 99% negative predictive value, takes less than three hours to perform, and costs about $220 (£165; €188; 2016 currency conversion).1543 Previous observational cohorts have shown that more than 90% of patients with listed penicillin allergies can be safely treated with penicillins.141540

Strengths and limitations of this study

In this study we used a representative population based cohort to increase the generalizability of our findings. Clinical data to characterise drug use, outcomes, and covariates were entered by physicians and captured electronically. The dataset used included granular allergy data linked to penicillin prescriptions and defined by type, severity, and certainty. Our study design used a comparator group who had recently been prescribed a penicillin but did not have a resultant penicillin allergy. Patients had high antibiotic use in the previous year since almost the entire cohort had recently had a penicillin (for infection) at baseline for cohort eligibility. Our GP practice based dataset could have missed the detection of some inpatient cases of MRSA and C difficile; however, these potential non-differential misclassifications would have biased our results towards the null, rendering our findings conservative. MRSA and C difficile were identified by physician diagnosis records. This approach has been successfully used in many previous epidemiologic studies,131920212223244445 as microbial infections such as MRSA and C difficile are made objectively using highly accurate microbiologic and serologic tests. Although we used composite outcomes for MRSA and C difficile that were not restricted to infections, it is unlikely that GPs would screen asymptomatic patients and more likely that diagnoses occurred in relevant clinical contexts where infections were suspected. Further, our findings remained consistent and strong when we restricted the analyses to code subgroups suggestive of infections. Additionally, MRSA carriage alone is an important outcome that confers an increased risk of MRSA infection,46 and indicates antibiotic resistance—a healthcare priority throughout the world.3947 Finally, by choosing to study only the first documentation of MRSA and C difficile, we ensured capture of only new colonization or infection, which are clinically important outcomes. Although we controlled for many known potential confounders in these data, our observational study cannot rule out potential unknown or residual confounding.


In this population based cohort study, a listed penicillin allergy was associated with a statistically significantly increased risk of MRSA and C difficile compared with patients matched by age, sex, and study entry time. Approximately one third to more than one half of this risk was attributed to use of non-β lactam antibiotics administered to outpatients. As infections with resistant organisms increase, systematic efforts to confirm or rule out the presence of true penicillin allergy may be an important public health strategy to reduce the incidence of MRSA and C difficile.

What is already known on this topic

  • Penicillin allergy is the most commonly documented drug allergy, reported by about 10% of patients

  • Although documented allergies impact prescribing behavior, a documented penicillin allergy does not often represent true, immediate hypersensitivity to penicillin

  • Previous studies have identified specific antibiotic uses that increase the risk of MRSA and Clostridium difficile

What this study adds


  • Patients with a documented penicillin allergy have an increased risk of new MRSA and C difficile that are modifiable, to some degree, through changes in antibiotic prescribing

C.difficile (C.diff.) Infections Continue to Grow in Health Care Facilities Worldwide

The burden of Clostridium difficile (C. diff) continues to grow in health care facilities throughout the United States and around the world.

Gaining a better understanding of sources and risk factors for C. diff can help reverse colonization and transmission or prevent it altogether, authors of a new paper suggest.

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“This is a review/commentary article that provides a high-level overview of the literature dealing with C. diff colonization and the microbiome changes associated with C. diff colonization,” author Silvia Munoz-Price, MD, PhD, from the Medical College of Wisconsin in Milwaukee told our sister publication MD Magazine.

After reviewing the literature, authors of the study postulated that when it comes to the potential for C. diff colonization, exposure to and transmissions of the virus occurs outside of hospitals. In fact, it seemed like most of the patients became symptomatic during their hospital stay, rather than acquiring the virus while hospitalized.

For example, the investigators cited one study from Canada that had been conducted from 2006 to 2007 where more than 4000 patients were screened for C. diff colonization upon hospitalization, during their stay (on a weekly basis) and at discharge. They found that 4% of the patients were colonized upon hospitalization and 3% acquired C. diff during their stay in the hospital.

The authors also found evidence indicating that community-acquired C. diff appears to be on the rise. The authors discuss a decade-long study which took place in Minnesota where community-acquired C. diff infection rates rose from 2.8 to 14.9 per 100,000-person-years within the 10-year span. The patients in that study more likely to acquire C. diff were younger, female, and healthier than patients with hospitalization acquired C. diff. The reviewers also said that rates of community-acquired C. diff have also been rising in Finland, Australia, and England, according to published studies.

Most of the common risk factors for community-acquired C. diff infections still applied, the researchers found, including antibiotic exposure, household contact, and animals. A 2013 study showed that two-thirds of community-acquired C. difficile patients were exposed to antibiotics in the preceding 12 weeks of their infection, and about one-third had been exposed to proton pump inhibitors.

While studies examining transmissibility within households are difficult to come by, the study authors found one review from Quebec. The review consisted of 2222 cases of C. diff diagnosed between 1998 and 2009, and investigators found that 8 cases were designated to be transmitted by household contacts. However, the researchers noted, confirmation using strain typing was not performed in that study.

Looking at farm livestock, a 2013 Dutch study showed that individuals with daily contact with pigs showed rates of C. diff positivity of 25%; in those with weekly contact, it was 14%. In the same study, C. diff was found in the manure from all the farms in 10% to 80% of the samples per farm. The reviewers also said that C. diff has been found in the stool of farm chickens, calves, and retail ground meat. Dogs and cats are also known to culture positive for C. diff, and the researchers wrote that the bacteria can also be present in vegetables and water (tap water, swimming pools, as well as rivers, lakes, and seas). They hypothesized that the presence of C. diff in vegetables may come from the use of organic fertilizer.

“We envision that in the future we should be able to take advantage of our increasing knowledge about microbiome changes so that we will be able to: identify patients at risk for de novo C. difficile colonization during their hospitalization and manipulate our patients’ microbiome to prevent or reverse C. difficile colonization,” Dr. Munoz-Price said.

“Different from what we do now, the latter would be accomplished not by withholding or changing antibiotics but by correcting the deficient flora of a patient in an individualized fashion. This new approach would revolutionize the field of Infection Control and Antibiotic Stewardship,” she concluded.