Penicillin Tolerance Research Articles

Group A Streptococcus (Streptococcus pyogenes): the Most Interesting Pathogen in the World

Group A Streptococcus, or Streptococcus pyogenes, is a facultatively anaerobic Gram-positive coccus and one of the most common causes of bacterial infection in humans. The introduction of antibiotics has greatly reduced the morbidity and mortality associated with this organism, but despite uniform susceptibility to treatments of choice, it remains a significant human pathogen. It is particularly problematic in underdeveloped and lower socioeconomic status countries, where hygiene may be suboptimal. This review covers a wide range of topics related to the organism, including diagnosis, treatment, and clinical manifestations. Where possible, the review addresses less conventional and often controversial topics that have not been extensively reviewed elsewhere, such as the activity of trimethoprim sulfamethoxazole against the species, penicillin tolerance, and the use of protein synthesis inhibitors to reduce toxin production and improve outcomes.

Outpatient penicillin allergy evaluation during pregnancy and associated clinical outcomes

Beta-lactam antibiotics are often clinically indicated in the peripartum period, posing a challenge for pregnant women who report a penicillin allergy. Allergy verification testing is rarely performed during pregnancy, even though most women do not have a true allergy. This study aimed to evaluate a hospital-wide multidisciplinary program introduced in August 2020 to identify, refer, evaluate, and test pregnant women with unverified penicillin allergies and assess its association with maternal and neonatal outcomes. We conducted a retrospective cohort study at a large academic hospital of all pregnant women with a penicillin allergy documented in the electronic medical record who delivered from September 2020 to October 2021. Data were abstracted by medical record review. Women referred for penicillin allergy evaluation were compared with those who were not. Maternal outcomes were alternative antibiotic (clindamycin or vancomycin) use, postpartum infection, and maternal length of postpartum hospital stay. Neonatal outcomes were intensive care unit admission, postnatal blood draw, antibiotic treatment, and birth hospitalization length of hospital stay. Bivariate and multivariable analyses were performed. Of 689 women with a documented penicillin allergy, 232 (33.7%) were referred for allergy evaluation during the study period. Of those referred, 175 (75.4%) underwent allergy consultation, and of these patients, 167 (95.4%) were considered appropriate for allergy verification testing. Of note, 117 women (70.1%) underwent skin testing with or without graded oral amoxicillin drug challenge, and all but 1 woman (99.1%) were found to be penicillin tolerant. Moreover, 5 additional women were delabeled of their penicillin allergy based on history and pharmacy confirmation of penicillin tolerance subsequent to index reaction. Referred women had a 62% lower likelihood of receiving an alternative antibiotic than those who were not referred, and this significance persisted even after adjusting for potential confounders (adjusted odds ratio, 0.49; 95% confidence interval, 0.27-0.89). Other maternal and neonatal adverse outcomes were less frequent in those referred, but these associations did not reach statistical significance. This study documented the feasibility, safety, and clinical benefit of an outpatient penicillin allergy referral program for pregnant women. Referred patients were significantly less likely to receive alternative antibiotics; however, more patients are needed to assess whether there are additional clinical benefits.

Induction of penicillin tolerance during pregnancy : Allergological opinion on the recommendation of the current Guidelines on Diagnosis and Treatment of Syphilis (AWMF Registry No. 059-002)

Induction of penicillin tolerance during pregnancy : Allergological opinion on the recommendation of the current Guidelines on Diagnosis and Treatment of Syphilis (AWMF Registry No. 059-002)

In pediatric patients who have penicillin skin testing with minor determinants, an oral challenge isn't needed

Penicillin skin testing (PST) and oral drug challenges are two methods to prove penicillin tolerance. The current standard is PST with Pre-Pen (benzylpenicilloyl polylysine) and Penicillin G followed by direct oral challenge with amoxicillin. We hypothesized that in the pediatric population oral drug challenge is not needed following PST if minor determinant mixtures are included in PST.

Induction of penicillin tolerance during pregnancy: Allergological opinion on the recommendation of the current AWMF Guidelines on Diagnosis and Treatment of Syphilis (AWMF Registry No. 059-002).

Not available.

Assessing the Role of Pharyngeal Cell Surface Glycans in Group A Streptococcus Biofilm Formation.

Group A Streptococcus (GAS) causes 700 million infections and accounts for half a million deaths per year. Antibiotic treatment failure rates of 20–40% have been observed. The role host cell glycans play in GAS biofilm formation in the context of GAS pharyngitis and subsequent antibiotic treatment failure has not been previously investigated. GAS serotype M12 GAS biofilms were assessed for biofilm formation on Detroit 562 pharyngeal cell monolayers following enzymatic removal of all N-linked glycans from pharyngeal cells with PNGase F. Removal of N-linked glycans resulted in an increase in biofilm biomass compared to untreated controls. Further investigation into the removal of terminal mannose and sialic acid residues with α1-6 mannosidase and the broad specificity sialidase (Sialidase A) also found that biofilm biomass increased significantly when compared to untreated controls. Increases in biofilm biomass were associated with increased production of extracellular polymeric substances (EPS). Furthermore, it was found that M12 GAS biofilms grown on untreated pharyngeal monolayers exhibited a 2500-fold increase in penicillin tolerance compared to planktonic GAS. Pre-treatment of monolayers with exoglycosidases resulted in a further doubling of penicillin tolerance in resultant biofilms. Lastly, an additional eight GAS emm-types were assessed for biofilm formation in response to terminal mannose and sialic acid residue removal. As seen for M12, biofilm biomass on monolayers increased following removal of terminal mannose and sialic acid residues. Collectively, these data demonstrate that pharyngeal cell surface glycan structures directly impact GAS biofilm formation in a strain and glycan specific fashion.

A Closer Look at Penicillin Allergy History: Systematic Review and Meta-Analysis of Tolerance to Drug Challenge

BackgroundTrue allergy to penicillin is rare, despite the high frequency with which it is reported. While most patients reporting penicillin allergy are not prone to anaphylaxis, it is not currently known what percentage of these patients will tolerate dose challenges of penicillin-based antibiotics. This review aims to determine the rate of tolerance in patients reporting penicillin allergy when challenged with penicillin-based antibiotics. MethodsWe searched MedLine, Embase, and Cochrane Library for publications with English language translations between the years 2000 and 2017. We included randomized controlled trials, quasi-experimental, and observational studies of participants reporting penicillin allergy who received at least one systemic dose of a penicillin in the form of a drug challenge. At least 2 independent reviewers extracted data from included studies and assessed the quality of each included study. To generate primary outcome data, we calculated a summary estimate rate of penicillin tolerance from a pooled proportion of participants receiving penicillin with no adverse effects. ResultsInitial literature search yielded 2945 studies, of which 23 studies were ultimately included in our review; 5056 study participants with reported history of penicillin allergy were challenged with a penicillin. After weighting for study sample size, a pooled average of 94.4% (95% confidence interval, 93.7%-95%) of participants tolerated the dose challenge without any adverse reaction. ConclusionMisrepresented penicillin allergy drives unnecessary use of alternative antibiotics, which may be less effective, more toxic, and more expensive than using penicillin. In addressing the problem of penicillin allergy over-diagnosis, evaluation should go beyond risk for type 1 hypersensitivity. Our data suggest that 94.4% of 5056 participants with reported penicillin allergy determined to be clinically appropriate for allergy evaluation tolerated repeat administration of penicillin-based antibiotics without any adverse reactions. This review generates meaningful information useful to clinical predictive analytics, in evaluating and managing patients with a reported history of penicillin allergy.

Evaluating Penicillin Allergies Without Skin Testing.

An unconfirmed penicillin allergy is known to confer significant risk to patients. Only a small minority of patients labeled with penicillin allergy will be confirmed to be hypersensitive with the current reference standard test, an oral amoxicillin therapeutic dose challenge. Skin testing has been recommended prior to oral challenges to reduce the risk of severe acute challenge reactions. The rate of severe acute anaphylactic reactions with oral amoxicillin is currently extremely low. Unfortunately, penicillin skin testing, as commonly performed, has a high rate of false positive results. Encouraging skin testing in all individuals with an unconfirmed penicillin allergy, prior to a confirmatory oral challenge, would be technically difficult, make testing all individuals with an unconfirmed penicillin allergy very unlikely, and ultimately increase the risk to patients because of suboptimal antibiotic use. Most patients, who are appropriate candidates for a direct oral amoxicillin challenge, to confirm current penicillin tolerance, can be safely identified by their clinical histories. Higher risk individuals, those with a history of anaphylaxis or other acute onset potentially IgE-mediated reaction such as hives within 6h of the first dose of the last course of a penicillin, may benefit from properly performed puncture and intradermal skin testing, using commercially available penicilloyl-polylysine, prior to an oral challenge, if skin test negative. Direct oral amoxicillin challenges in low-risk individuals are well accepted by patients and a safe and effective part of penicillin allergy delabeling.

1924. Most Patients Tolerate Penicillin Administration Despite History of Nonanaphylactic Penicillin Allergy: A Systematic Review and Meta-Analysis

BackgroundTrue allergy to penicillin is rare, despite the high frequency with which it is reported. Misrepresented allergy drives unnecessary use of alternative antibiotics which may be less effective, more toxic, and more expensive than the penicillins. While most patients reporting penicillin allergy are not prone to anaphylaxis, it is not currently known what percentage of these patients go on to fully tolerate systemic doses of penicillin-based antibiotics. This review aims to determine the tolerance rate in patients with non-anaphylactic penicillin allergy when challenged with systemic doses of penicillin-based antibiotics.MethodsWe searched MedLine, Embase, and Cochrane Library for publications with English language translations between the years 2000 and 2017. We included controlled trials, quasi-experimental, and observational studies of reportedly penicillin-allergic subjects who received at least one systemic dose of a penicillin in the form of a challenge. At least two independent reviewers extracted data from included studies, and assessed the quality of each included study. To generate primary outcome data, we calculated a summary estimate rate of penicillin tolerance from a pooled fraction of subjects receiving a penicillin with no adverse effects, among all subjects receiving a penicillin challenge.ResultsInitial literature search yielded 5,554 studies, of which 22 studies were ultimately included in our review. A total of 4,572 study participants, each with a history of penicillin allergy low risk for anaphylaxis, were challenged with systemic dosing of a penicillin. After weighting for sample size, an average of 94.8% [95% CI 93.3%, 96.3%] of these patients tolerated penicillin challenge without any adverse reaction.ConclusionIn addressing the problem of penicillin allergy over-diagnosis, evaluation should go beyond risk for type 1 hypersensitivity. Our data suggest that 94.8% of 4,572 subjects with reported penicillin allergy determined to be low risk for anaphylaxis tolerated repeat administration of penicillin-based antibiotics without any adverse reactions. This review generates meaningful information useful to clinical predictive analytics, in evaluating and managing patients with a reported history of penicillin allergy.Disclosures All authors: No reported disclosures.

A Proactive Approach to Penicillin Allergy Testing in Hospitalized Patients

Penicillin allergy testing is underutilized in inpatients despite its potential to immediately impact antibiotic treatment. Although most tested patients are able to tolerate penicillin, limited availability and awareness of this tool leads to the use of costly and harmful substitutes. We established an inpatient service at a large academic hospital to identify and test patients with a history of penicillin allergy with the goals of removing inaccurate diagnoses, reducing the use of beta-lactam alternatives, and educating patients and clinicians about the procedure. Eligible inpatients were flagged daily through the electronic medical record and prioritized via a specialized algorithm. A trained clinical pharmacist performed penicillin skin tests and challenges preemptively or by provider request. Clinical characteristics and antibiotic use were analyzed in tested patients. A total of 1203 applicable charts were detected by our system leading to 252 direct evaluations over 18 months. Overall, 228 subjects (90.5%) had their penicillin allergy removed. Of these, 223 were cleared via testing and 5 by discovery of prior penicillin tolerance. Among patients testing negative, 85 (38%) subsequently received beta-lactams, preventing 504 inpatient days and 648 outpatient days on alternative agents. Penicillin allergy testing using a physician-pharmacist team model effectively removes reported allergies in hospitalized patients. The electronic medical record is a valuable asset for locating and stratifying individuals who benefit most from intervention. Proactive testing substantially reduces unnecessary inpatient and outpatient use of beta-lactam alternatives that may otherwise go unaddressed.

The Negative Impact of Persistent Penicillin Allergy Labeling

Rationale Although 8-20% of patients have penicillin allergy labels (PAL), less than 1% of the population are truly allergic. The extent to which a PAL persists in the EMR despite documented penicillin tolerance is currently unknown. Methods The synthetic derivative (de-identified version) of the electronic medical record (EMR) was mined for patients >18 years or older with >3 visits linked to Vanderbilt ambulatory care from January 2000 to August 2014. Key outcomes including antibiotic utilization and presence of C. difficile infection were compared between cases with (n=11,504) and controls (n=31,084) without PAL. Cases were examined for the persistence of the PAL despite documented tolerance. Categorical variables were analyzed by Pearson Chi-squared test and continuous data by Wilcoxon signed rank test. Results Most PAL (67%) were already labeled upon entry into the EMR, and 96% remained persistently labeled. Cases were more likely to develop C. difficile infection (1.2% vs 0.9%, p=0.001). The proportion of prescription encounters for levofloxacin (15% vs 12%), vancomycin (5% vs 4%), clindamycin (8% vs 4%), and aztreonam (1% vs <0.1%) were overrepresented in PAL cases versus unlabeled controls (all p<0.001). Of 11216 PAL, 4321 (39%) had EMR documentation of having received and tolerated a penicillin, however despite this 4045/4321 (94%) retained the PAL. Conclusions In this largely ambulatory population, PALs persist within the EMR despite proven tolerance and are associated with higher risk antibiotic treatments and C. difficile infection. Major reform of the EMR to utilize systematic approaches of documenting, reconciling, and removing the PAL is urgently needed.

Penicillin allergy: optimizing diagnostic protocols, public health implications, and future research needs.

Unverified penicillin allergy is being increasingly recognized as a public health concern. The ideal protocol for verifying true clinically significant IgE-mediated penicillin allergy needs to use only commercially available materials, be well tolerated and easy to perform in both the inpatient and outpatient settings, and minimize false-positive determinations. This review concentrates on articles published in 2013 and 2014 that present new data relating to the diagnosis and management of penicillin allergy. Penicillin allergy can be safely evaluated at this time, in patients with an appropriate clinical history of penicillin allergy, using only penicilloyl-poly-lysine and native penicillin G as skin test reagents, if an oral challenge with amoxicillin 250 mg, followed by 1 h of observation, is given to all skin test negative individuals. Millions of individuals falsely labeled with penicillin allergy need to be evaluated to safely allow them to use penicillin-class antibiotics and avoid morbidity associated with penicillin avoidance. Further research is needed to determine optimal protocol(s). There will still be a 1-2% rate of adverse reactions reported with all future therapeutic penicillin-class antibiotic use, even with optimal methods used to determine acute penicillin tolerance. Only a small minority of these new reactions will be IgE-mediated.

Risk of redocumenting penicillin allergy in a cohort of patients with negative penicillin skin tests

Even though electronic documentation of allergies is critical to patient safety, inaccuracies in documentation can potentiate serious problems. Prior studies have not evaluated factors associated with redocumenting penicillin allergy in the medical record despite a proven tolerance with a penicillin skin test (PST). Assess the prevalence of reinstating inaccurate allergy information and associated factors thereof. We conducted a retrospective observational study from August 1, 2012 to July 31, 2013 of patients who previously had a negative PST. We reviewed records from the hospital, long-term care facilities (LTCF), and primary doctors' offices. Vidant Health, a system of 10 hospitals in North Carolina. Patients with proven penicillin tolerance rehospitalized within a year period from the PST. We gauged hospital reappearances, penicillin allergy redocumentation, residence, antimicrobial use, and presence of dementia or altered mentation. Of the 150 patients with negative PST, 55 (37%) revisited a Vidant system hospital within a 1-year period, of whom 21 were LTCF residents. Twenty (36%) of the 55 patients had penicillin allergy redocumented without apparent reason. Factors associated with penicillin allergy redocumentation included age >65 years (P = 0.011), LTCF residence (P = 0.0001), acutely altered mentation (P < 0.0001), and dementia (P < 0.0001). Penicillin allergy was still listed in all 21 (100%) of the LTCF records. At our hospital system, penicillin allergies are often redocumented into the medical record despite proven tolerance. The benefits of PST may be limited by inadequately removing the allergy from different electronic/paper hospital, LTCF, primary physician, and community pharmacy records.

Serine/Threonine Protein Kinase Stk Is Required for Virulence, Stress Response, and Penicillin Tolerance in Streptococcus pyogenes

Genes encoding one or more Ser/Thr protein kinases have been identified recently in many bacteria, including one (stk) in the human pathogen Streptococcus pyogenes (group A streptococcus [GAS]). We report that in GAS, stk is required to produce disease in a murine myositis model of infection. Using microarray and quantitative reverse transcription-PCR (qRT-PCR) studies, we found that Stk activates genes for virulence factors, osmoregulation, metabolism of α-glucans, and fatty acid biosynthesis, as well as genes affecting cell wall synthesis. Confirming these transcription studies, we determined that the stk deletion mutant is more sensitive to osmotic stress and to penicillin than the wild type. We discuss several possible Stk phosphorylation targets that might explain Stk regulation of expression of specific operons and the possible role of Stk in resuscitation from quiescence.

Use of commercial anti–penicillin IgE fluorometric enzyme immunoassays to diagnose penicillin allergy

The intermittent unavailability of penicilloyl-polylysine since September 2000 has focused interest on commercial anti-penicillin IgE fluorometric enzyme immunoassay (FEIA) tests to evaluate penicillin allergy. There has been no published comparison of commercial anti-penicillin IgE FEIAs and penicillin skin testing performed in the United States. To determine whether the current commercial anti-penicillin IgE FEIAs can replace or augment penicillin skin testing and oral challenges when evaluating individuals with a history of penicillin allergy for future therapeutic penicillin tolerance. A prospective convenience sample of 150 individuals with a history of penicillin allergy were evaluated between January 23, 2007, and August 4, 2009, with both penicillin skin tests and commercial anti-penicillin IgE FEIAs to penicillin G, penicillin V, and amoxicillin. All individuals with a negative penicillin skin test result underwent oral penicillin class antibiotic challenges. All individuals with a positive anti-penicillin IgE FEIA result also underwent oral penicillin class antibiotic challenges. Six individuals (4.0%; 95% confidence interval [CI], 0.9% to 7.1%) had positive penicillin skin test results, and none had positive FEIA results. Four individuals (2.7%; 95% CI, 0.1% to 5.3%) had positive FEIA results, and none had positive penicillin skin test results. Three individuals (2.0%; 95% CI, -0.2% to 4.2%) had positive oral challenge results, 1 with hives at 6 hours after challenge and 2 with delayed-onset (at >24 hours) nonurticarial rashes, and none had positive FEIA results. The current commercial anti-penicillin IgE FEIAs are not useful in diagnosing penicillin allergy in patients with remote histories of penicillin allergy. Penicillin skin testing and, if the results are negative, an oral challenge remain the criterion standard tests to determine therapeutic penicillin tolerance.

213: Antibiotic resistance and penicillin tolerance in clinical isolates of group B streptococci

213: Antibiotic resistance and penicillin tolerance in clinical isolates of group B streptococci

Loss of penicillin tolerance by inactivating the carbon catabolite repression determinant CcpA in Streptococcus gordonii

Antibiotic tolerance is a phenomenon allowing bacteria to withstand drug-induced killing. Here, we studied a penicillin-tolerant mutant of Streptococcus gordonii (Tol1), which was shown to be deregulated in the expression of the arginine deiminase operon (arc). arc was not directly responsible for tolerance, but is controlled by the global regulator CcpA. Therefore, we sought whether CcpA might be implicated in tolerance. The ccpA gene was characterized and subsequently inactivated by PCR ligation mutagenesis in both the susceptible wild-type (WT) and Tol1. The minimal inhibitory concentration and time-kill curves for the strains were determined and the outcome of penicillin treatment in experimental endocarditis assessed. ccpA sequence and expression were similar between the WT and Tol1 strains. In killing assays, the WT lost 3.5 +/- 0.6 and 5.3 +/- 0.6 log(10) cfu/mL and Tol1 lost 0.4 +/- 0.2 and 1.4 +/- 0.9 log(10) cfu/mL after 24 and 48 h of penicillin exposure, respectively. Deletion of ccpA almost totally restored Tol1 kill susceptibility (loss of 2.5 +/- 0.7 and 4.9 +/- 0.7 log(10) cfu/mL at the same endpoints). In experimental endocarditis, penicillin treatment induced a significant reduction in vegetation bacterial densities between Tol1 (4.1 log(10) cfu/g) and Tol1DeltaccpA (2.4 log(10) cfu/g). Restitution of ccpA re-established the tolerant phenotype both in vitro and in vivo. CcpA, a global regulator of the carbon catabolite repression system, is implicated in penicillin tolerance both in vitro and in vivo. This links antibiotic survival to bacterial sugar metabolism. However, since ccpA sequence and expression were similar between the WT and Tol1 strains, other factors are probably involved in tolerance.

Bovine kidney tissue/biological fluid correlation for penicillin

Penicillin is one of the most commonly misused drugs in steers and dairy cows. In the US, at slaughter the tolerance is 50 ng/g in kidney and other edible tissues. If the tolerance is exceeded, the carcass may not be used for human food. A preslaughter test for penicillin in an easily accessible biological fluid is needed to predict if the concentration of penicillin is below tolerance in the kidney before the bovine is slaughtered. In this study, 12 steers were injected three times with the approved dose (7000 IU) of penicillin at 12-h intervals. Blood and urine samples were collected at intervals after the final dose of penicillin. At each sampling point, one kidney biopsy sample was collected by laparoscopic surgery in the live animal. Another kidney sample was collected at slaughter. Correlations between plasma and kidney concentrations and between urine and kidney concentrations were determined. These correlations predict with 95% confidence that 99% of the animals will have kidney tissue below penicillin tolerance when the plasma concentration of penicillin is below 0.4 ng/mL and/or the urine penicillin concentration is below 140 ng/mL.

Cloning and characterization of the lytB gene of Campylobacter jejuni.

LytB of Escherichia coli is an essential gene involved in penicillin tolerance and the stringent response. The lytB gene of Campylobacter jejuni was cloned and characterized. It could complement a temperature-sensitive E. coli lytB mutant. The C. jejuni lytB gene encodes a protein of 277 amino acids that has 34, 36 and 40% amino acid identity with the LytB proteins of E. coli, Haemophilus influenzae, and Synechocystis sp. PCC6803, respectively. The lytB gene is situated between the aroA gene and a gene that encodes ribosomal protein S1.

Vancomycin-Tolerance among Clinical Isolates of Streptococcus pneumoniae in Mississippi during 1999-2001

In recent years, infection with Streptococcus pneumoniae has been a serious worldwide health concern. Antimicrobial-resistant S pneumoniae is increasing in incidence worldwide, posing a potentially serious threat. Resistance to beta-lactams, macrolides, and trimethoprim-sulfamethoxazole represents a major problem in the treatment of pneumococcal infections Our laboratory conducted a survey of local resistance patterns in S pneumoniae. Clinical isolates from two separate respiratory seasons were collected from representative geographic areas in Mississippi (totaling 28 hospitals) and were tested for antimicrobial resistance to penicillin, amoxicillin, ceftriaxone, cefuroxime, azithromycin, clindamycin, tetracycline, trimethoprim-sulfamethoxazole, levofloxacin, gatifloxacin, moxifloxacin, and vancomycin using reference methods. Vancomycin-tolerant strains of S pneumoniae were initially identified as those in which the vancomycin MIC was 0.5 microg/mL. Strain tolerance was confirmed by time kill studies For the 1999-2000 respiratory season, 318 isolates were available for testing; for 2001-2002, 166 isolates were available. Of the 484 total isolates tested, two isolates were identified as having increased tolerance to vancomycin. A greater than 2 log10 difference in viability between the tolerant isolates and the nontolerant isolates of S pneumoniae was observed in time kill studies Two vancomycin-tolerant isolates of S pneumoniae were identified and characterized. Antibiotic tolerance is defined as the ability of bacteria to survive but not proliferate in the presence of an antibacterial agent. Tolerance to vancomycin is particularly significant when the incidence of penicillin tolerance or resistance is high. In addition, tolerance to vancomycin is not detected by routine in vitro susceptibility testing.