Where have all the susceptible gonococci gone? A historical review of changes in MIC distribution over the past 75 years.

BACKGROUND: Does the emergence of antimicrobial resistance in Neisseria gonorrhoeae include the erasure of highly susceptible strains or does it merely involve a stretching of the MIC distribution? If it was the former this would be important to know as it would increase the probability that the loss of susceptibility is irreversible. METHODS: We conducted a historical analysis based on a literature review of changes of N. gonorrhoeae MIC distribution over the past 75 years for 3 antimicrobials (benzylpenicillin, ceftriaxone and azithromycin) in five countries (Denmark, Japan, South Africa, the United Kingdom and the United States). RESULTS: Changes in MIC distribution were most marked for benzylpenicillin and showed evidence of a right shifting of MIC distribution that was associated with a reduction/elimination of susceptible strains in all countries. In the case of ceftriaxone and azithromycin, where only more recent data was available, right shifting was also found in all countries but the extent of right shifting varied and the evidence for the elimination of susceptible strains was more mixed. CONCLUSIONS: The finding of right shifting of MIC distribution combined with reduction/elimination of susceptible strains is of concern since it suggests that this shifting may not be reversible. Since excess antimicrobial consumption is likely to be responsible for this right shifting, this insight provides additional impetus to promote antimicrobial stewardship.

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

BACKGROUND: Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. METHODOLOGY/PRINCIPAL FINDINGS: Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13%) and 0.35% (95% CI: 0.06-1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. CONCLUSIONS/SIGNIFICANCE: Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in good physical condition after withdrawing anti-neurosyphilis regimen. We did not see an exacerbation of neutropenia in patients with the readministration of benzylpenicillin.

The Treatment of Possible Severe Infection in Infants: An Open Randomized Safety Trial of Parenteral Benzylpenicillin and Gentamicin Versus Ceftriaxone in Infants <60 days of Age in Malawi.

BACKGROUND: The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment for infants with sepsis in low-income settings, and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 low-income settings, Staphylococcus aureus, Klebsiella spp. and Escherichia coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was >50% of all isolates, and 44% of Gram-negative isolates were gentamicin resistant. However, ceftriaxone may cause neonatal jaundice, and gentamicin may cause deafness. Therefore, we compared parenteral benzylpenicillin plus gentamicin with ceftriaxone as first-line treatment, assessing outcome and adverse events. METHODS: This was an open randomized trial carried out in the Queen Elizabeth Central Hospital, Blantyre, Malawi, from 2010 to 2013. Infants <60 days of age with possible severe sepsis received either benzylpenicillin and gentamicin or ceftriaxone. Adverse events and outcomes were recorded until 6 months post discharge. RESULTS: Three-hundred forty-eight infants were included in analyses. Outcome in the benzylpenicillin and gentamicin and ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae were 14.5% and 11.2%, respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% versus 5%, P = 0.03. Thirteen (6%) survivors had bilateral hearing loss. There was no difference between the treatment groups. By 6 months post discharge, 11 more infants had died, and 17 more children were found to have sequelae. CONCLUSIONS: Ceftriaxone and gentamicin are safe for infants in our setting. Infants should receive long-term follow-up as many poor outcomes occurred after hospital discharge.

Penicillin Encephalopathy: An Unlikely Adversary in the Treatment of Neurosyphilis--Case Report and Review of the Literature.

UNLABELLED: Penicillin encephalopathy is a rare, potentially reversible phenomenon of drug-induced neurotoxicity. CASE: A 65-year-old female with a history of HIV was admitted with a three-day history of worsening headache, confusion, and lethargy. On examination she was awake but confused. Cerebrospinal fluid (CSF) and serum venereal disease research laboratory (VDRL) test returned positive and the patient was started on intravenous penicillin G with probenecid. On the second day of therapy, she developed myoclonic jerking, consistent with penicillin neurotoxicity. Repeat labs also showed new onset renal failure. Penicillin and probenecid therapy were stopped with a resolution of symptoms. Subsequently, therapy without probenecid was reinstituted uneventfully. DISCUSSION: Herein, we describe a female who developed penicillin neurotoxicity after initiation of intravenous penicillin therapy with probenecid for neurosyphilis. It is important that penicillin-induced toxicity be considered if characteristic myoclonic movements accompany encephalopathy. The presence of coexistent renal compromise should heighten the vigilance of clinicians.

Detecting drug-herbal interaction using a spontaneous reporting system database: an example with benzylpenicillin and qingkailing injection.

PURPOSE: The study aims to quantify anaphylaxis signal for combined exposure of benzylpenicilin and qingkailing injection (QI) compared with individual exposure of the two drugs and the background risk based on all other exposures in SRS database. METHODS: Data used in this study were collected during 2003-2014 from China Guangdong Provincial Center of ADR Monitoring. We studied the suspected ADR reports using a case/non-case design. The cases were defined as the reactions coded by WHO-preferred terms of anaphylactic shock or anaphylactoid reaction. Reporting odds ratios (RORs) were used as a measure of disproportionality and were adjusted for age and gender to reduce confounding effects. An observed-to-expected ratio Ω was also used for interaction detection. RESULTS: The crude RORs (95 % CIs) for anaphylaxis in patients who used only benzylpenicillin or QI and those who used the two drugs concomitantly compared with patients who used neither of the two drugs were 2.50 (2.34-2.68), 1.59 (1.46-1.73), and 6.22 (3.34-11.58), respectively. The adjusted RORs (95 % CIs) were 2.48 (2.31-2.65), 1.54 (1.41-1.67), and 6.01 (3.22-11.20), respectively, after being adjusted for age and gender. The measured Ω, Ω0, Ω025, and Ω975 was 1.03, 1.09, 0.14, and 1.71, respectively. CONCLUSIONS: Case reports in the database are suggestive of a safety signal which indicates that an interaction between benzylpenicillin and QI resulting in excess risk of anaphylaxis may occur. SRS databases have a potential for signaling unknown drug-herbal interactions. More effort is needed to expand this potential.

Hypersensitivity reactions to penicillins: studies in a group of patients with negative benzylpenicillin G skin test.

BACKGROUND: Although skin tests are usually employed to evaluate current penicillin allergy status, a negative result does not exclude hypersensitivity. There is a need for accurate in vitro tests to exclude hypersensitivity. A radioallergosorbent test (RAST) is a potentially good supplementary approach, but there is little information on the suitability of this method to diagnose penicillin hypersensitivity in subjects with a negative skin test to benzylpenicillin. METHODS: A total of 133 patients with a negative skin test to benzylpenicillin G (PG) and all of whom developed allergic reactions to PG were studied. RAST was used to detect eight kinds of specific IgE antibodies to penicillins in serum, which included four kinds of major and minor antigenic determinants to four penicillin drugs. The combination sites for the specific IgE antibodies were studied by RAST inhibition test. RESULTS: The rate of positive reactions for the specific IgE antibodies was 59.40% (79/133). Of the eight kinds of antigenic determinants, the positive rates for specific IgE against the major and minor determinants were 39.10% (52) and 42.86% (57) respectively. Of the four drugs, positive cases only to PG were 10 (7.5%), were significantly fewer than the cross-reacting positive cases (36) to PG (P < 0.01). In the RAST inhibition studies all drugs exhibited good inhibitory potencies, and in some instances the side-chain of the penicillins could induce specific responses with a variable degree of cross-reactivity among the different penicillins. CONCLUSION: Radioallergosorbent test is a good complementary test in persons who are skin-test negative with PG, and the sensitivity of RAST increases with increasing specificity of IgE antibodies to be detected. 6-APA and the groups, making part of the different side-chains on penicillins, all contributed to the cross-reactivity.

Continuous-infusion penicillin home-based therapy for serious infections due to penicillin-susceptible pathogens.

To evaluate the feasibility of continuous-infusion (CI) penicillin in the treatment of serious bacterial infections, consecutive adult patients with deep-seated infections due to penicillin-susceptible pathogens were treated with CI aqueous penicillin G in a home-based programme, and their treatment outcomes were reviewed. Thirty-one patients with microbiologically proven infections completed the planned course of treatment. Twenty of 31 (65%) were followed for at least 2 months thereafter, and all remained free of relapse. One patient had fever attributable to penicillin hypersensitivity, two patients developed catheter-site infections and one patient developed catheter-related bacteraemia. Thus, CI penicillin is feasible for the home-based treatment of a variety of deep-seated infections with minimal toxicity.

Reacciones tardías en las pruebas cutáneas con penicilina: correlación con la anamnesis / Late reactions to penicillin skin tests: correlation with history

Antecedentes y objetivos: La utilidad de las pruebas cutáneas en el diagnóstico de la alergia a las penicilinas está bien demostrada; sin embargo, no siempre existe una buena relación entre la anamnesis y el resultado de estas pruebas. Casos clínicos: Se presentan tres pacientes en los que la anamnesis, ya por el tiempo de aparición de la reacción, ya por el tipo de lesión, sugiere una hipersensibilidad inmediata o acelerada con posible participación de la IgE; las pruebas cutáneas fueron positivas de forma muy tardía, entre 2 y 3 semanas después de su aplicación. Conclusión: No siempre existe un patrón clínico que permita predecir el resultado de las pruebas cutáneas por lo que aconsejamos realizar el estudio alergológico aún cuando la sospecha de hipersensibilidad sea baja

Background and objectives: The useful of skin tests in diagnosis of penicillin allergy is well known; however, there is not always a good correlation between history and results from these tests. Cases: Three cases are presented in which the history, due to the time of appearance or the type of lesions, suggests an potentially IgE-mediated immediate or accelerated hypersensitivity; skin tests were positive very late, between 2 and 3 weeks after their application. Conclusion: There is not always a clinic pattern which permits to predict results of skin tests, so we recommend to perform the allergy study even with a low index of suspicion

Severe immune haemolysis after standard doses of Penicillin.

Summary Penicillin causes immune haemolytic anaemia by the 'drug-adsorption' mechanism and typically occurs after prolonged exposure to large doses of the drug. Withdrawal of the drug is associated with improved red cell survival and gradual cessation of haemolysis. Although this complication is uncommon, it can be potentially serious. An unusual case is described herein. The patient was exposed to a short course (9 days) of standard dose penicillin but suffered acute severe haemolysis about 1 week after cessation of therapy. A high titre anti-penicillin antibody (1 : 512) not cross-reacting with cephalosporins, was demonstrated. The delay in the development of immune haemolysis vis-à-vis penicillin therapy may be due to the patient being immunologically naive to the drug. Penicillin may persist for weeks in circulation, coating red cells and providing continued antigenic stimulation for the development of anti-penicillin antibody.

Inhibitory effect of jujuboside A on penicillin sodium induced hyperactivity in rat hippocampal CA1 area in vitro.

AIM: To study the effect of jujuboside A (JuA), one constituent of Chinese herbal medicine Ziziphus jujuba Mill Var spinosa (Bunge) Hu,on the penicillin sodium induced hyperactivity in rat CA1 neurons in vitro. METHODS: Hippocampal slices were obtained from the Sprague-Dawley rat brain and populational signals were measured from CA1 neurons of hippocampal slices using the extracellular recording technique. RESULTS: Penicillin sodium of 500, 1000, and 2000 kU/L were found to excite hippocampal CA1 neurons in a concentration-dependent manner in vitro. This excitatory effect of penicillin sodium could be inhibited by phenobarbital sodium of 0.02 - 0.05 g/L and JuA of 0.05 - 0.10 g/L. CONCLUSION: A high dose of JuA can inhibit the hyperactivity of hippocampal CA1 area induced by penicillin sodium. The inhibition of the amplitude of the first population spike (PS) and the latency of PS are more pronounced than the slope of the field excitatory post-synaptic potential.

Obstacles to penicillin use in treating pneumococcal infection.

OBJECTIVES: To determine the pattern of penicillin use in the treatment of pneumococcal pneumonia, and factors contributing to the use of alternative antibiotics. METHODS: This study included all adult inpatients of St. Vincent's Hospital and Medical Center who had documented pneumococcal pneumonia between December 1998 and October 1999. St. Vincent's is a 600 bed tertiary teaching hospital in New York City. Patients who had Streptococcus pneumoniae isolated from a respiratory tract specimen were identified through microbiology laboratory records. A retrospective chart review of these patients was conducted, and those identified with clinical pneumonia were included in this study. Antibiotic use, patient demographics, resistance data, and clinician awareness of the antibiotic susceptibility results were noted. RESULTS: Sixty adult patients hospitalized with documented pneumococcal pneumonia were identified. Thirteen (21.6%) of the 60 patients received penicillin or ampicillin. Susceptibility results were not noted in the medical record in 21 (35.0%) of the 60 patients, and none received penicillin. High rates of reported penicillin allergy in 8 (13.3%) of the 60 patients, and reluctance to use penicillin when isolates demonstrated intermediate susceptibility in 8 (13.3%) of the 60 patients were observed. CONCLUSIONS: Several remediable obstacles to penicillin use were identified in this study. An increased awareness of susceptibility results by physicians and education of practitioners could have increased the use of penicillin as therapy to two-thirds of these patients.

Drug-induced linear IgA disease with antibodies to collagen VII.

Linear IgA disease (LAD) is characterized by circulating and tissue-bound IgA antibodies against heterogeneous antigens in the cutaneous basement membrane zone. In most cases the cause is unknown, but a minority of cases has been drug induced. We report a 76-year-old man who developed an acute blistering eruption following high-dose penicillin treatment for pneumococcal septicaemia. Indirect immunofluorescence demonstrated dermal binding IgA antibodies, and Western blotting of serum showed reactivity with a 250 kDa dermal antigen corresponding to collagen VII of anchoring fibrils. Indirect immunoelectron microscopy showed antibody labelling in the lamina densa and sublamina densa zone. This is one of the few cases of drug-induced LAD in which the target antigen profile has been characterized, and the first in which the antigen has been shown to correspond to collagen VII.

[Antibiotic-induced hemorrhagic cystitis]. / Antibiotikaudløst haemoragisk cystitis.

Two cases of haemorrhagic cystitis following treatment with methicillin and penicillin G are presented. Two males, aged 24 and 45 years, presented identical symptoms including haematuria, dysuria and pollakisuria. The condition has in rare instances been described as caused by antibiotic treatment; in all cases a penicillin was involved. All symptoms promptly vanished when the antibiotic treatment was stopped, and the reactions were possibly allergic since cross-reactions between different penicillins have been described in earlier cases.

Basic aspects related to penicillin-allergy skin testing: on the variability of the hapten-paratope interaction.

Ampicillin and benzylpenicillin conjugated to human serum albumin were used as immunogens in order to obtain antihaptenic IgG responses in outbred guinea pigs according to different schedules, all involving complete Freund's adjuvant. The individual responses were characterized by ELISA and by ELISA inhibition using ampicillin, benzylpenicillin, and carbenicillin peptidic conjugates for coating and for inhibition. In several instances, drastically reduced cross-reactivity and even its absence were observed, although the penicillin antigens differ only in the side-chain. The notion that the invariantly present thiazolidine ring will always provide significant binding to antibodies against all penicillins differing only in the side-chain has to be dropped. The experiments were performed in relation to newer findings of clinical penicillin-allergy skin testing which suggest that benzylpenicillin-based reagents alone are not able to detect or predict all reactions against semisynthetic penicillins. The experimental evidence here obtained corroborates this conclusion.

Drug-specific immune responses induced by immunization with drugs in guinea pigs and mice.

In order to develop a system for evaluating the allergenicity of drugs in clinical use, we tested drugs for the ability to induce drug-specific immune responses in guinea pigs and mice. Test drugs were benzylpenicillin, procainamide, hydralazine, isoniazid, alpha-methyldopa, D-penicillamine, captopril, sulfamethoxazole and 2,4-dinitrochlorobenzene (DNCB), which are known to induce allergic responses in man including hypersensitivity reactions and drug-induced auto-immune responses. Guinea pigs were immunized with an emulsion of complete Freund's adjuvant (CFA) and 25 mg of each drug. Mice were immunized with an emulsion of CFA and 2 mg of each drug or a mixture of aluminum hydroxide gel and 2 mg of each drug. In order to examine drug-specific immune responses, we employed detection of antibodies by enzyme-linked immunosorbent assay (ELISA) and passive cutaneous anaphylaxis tests, active systemic anaphylaxis (ASA) tests and delayed type hypersensitivity (DTH) tests. In guinea pigs, drug-specific antibodies were detected following immunization with benzylpenicillin, procainamide, hydralazine, isoniazid, captopril, sulfamethoxazole or DNCB. Some of these drugs were also positive in DTH tests and/or ASA tests. In mice, however, only DNCB gave positive results. Therefore, our system involving immunization of guinea pigs with CFA emulsion of a drug and detection of drug-specific immune responses is considered to be an effective test method for evaluating drug allergenicity.

[Use of vilozen and ketotifen combination for increasing the effectiveness and prevention of complications of antibiotic therapy of streptococcal infections]. / Primenenie kombinatsii vilozena i ketotifena dlia povysheniia éffektivnosti i profilaktiki oslozhnenii antibiotikoterapii streptokokkovykh infektsii.

The clinical efficacy of a vilozen and ketotifen (zaditen) combination in the treatment of streptococcal infections along with the routine therapy was studied. The use of the combination was shown advisable in the complex therapy and prevention of relapses in patients with streptococcal infections. The combined pharmacotherapy promoted better clinical indices, normalization of the immune status and a reduction in the incidence of allergic reactions to antibiotics and a decrease in sensitization to bacterial allergens.

[Is penicillin G the drug of choice in gas gangrene? Results of a prospective documentation of clinical, microbiological and animal experiment data]. / Ist Penicillin-G das Mittel der Wahl beim Gasödem? Ergebnisse aus prospektiver Dokumentation klinischer, mikrobiologischer und tierexperimenteller Daten.

Between 1978 and 1990 98 patients with gas gangrene were treated in the departments of general surgery and traumatology of the University of Kiel. The microbiological results of tissue samples and results of animal infectious experiments were correlated to the clinical outcome. It could be shown, that gas gangrene due to C.perfringens alone had a higher mortality than gas gangrene due to polymicrobial infection. In trauma patients, however, the rate of amputations was lower in cases of clostridial monoinfections (25%), than in patients with mixed infections (48%). The results of animal experiments with guinea pigs which were infected by patients' infectious material showed a correlation to the clinical outcome. This correlation could not bee shown using isolated and cultured clostridia. Therefore and because of the quantity of mixed infections it is necessary to use broad spectrum antibiotics for treatment in cases of gas gangrene and for perioperative antibiotic prophylaxis. Penicillin-G alone can not more be recommended for this purpose.

Limulus lysate positivity and Herxheimer-like reactions in leptospirosis: a placebo-controlled study.

Jarisch-Herxheimer reactions are characteristic of some spirochetal diseases and have been reported in leptospirosis, but their pathogenesis and relationship to endotoxin remain unclear. Serial limulus amebocyte lysate assays (LAL) for endotoxin were performed on 40 patients with proven leptospirosis who were monitored for reactions after receiving either intravenous penicillin (24) or saline placebo (16). No Herxheimer-like reactions were observed, although 78% of patients had at least one positive LAL. Serum creatinine, serum bilirubin, and white blood cell counts were significantly higher (P less than .01) in simultaneously drawn LAL-positive specimens than in negative ones. Delayed hepatic clearance of endotoxin due to liver dysfunction may explain the high LAL positivity rate, since assay results correlated with severity of disease but not with the presence or absence of spirochetes. Fear of a Herxheimer-like reaction should not dissuade clinicians from administering antibiotics to patients with leptospirosis.

A prospective study of neutropenia induced by high doses of beta-lactam antibiotics.

A prospective study on the effect of beta-lactam antibiotics on granulopoiesis was carried out in 29 consecutive patients with bacterial endocarditis. Fourteen patients received a high dose of benzylpenicillin, up to 18 g/day, but in only three of them could the treatment be fulfilled as planned, for a mean time of 25 days. In 11 benzylpenicillin treated patients treatment had to be discontinued because of fever, rash or neutropenia. Neutropenia appeared in seven patients after 14-24 (mean 22) days. No superinfection occurred during the neutropenic phase which lasted 2-12 days. Patients with neutropenia differed significantly from others in having a lowered pretreatment neutrophil count (3.2 vs 10.4). In 15 patients treated with other beta-lactams, three cases of fever and rash and one case of neutropenia were seen in patients treated with cloxacillin 12 g daily. It was concluded that a daily dose of 18 g of benzylpenicillin is too high for longer treatment periods and that patients with initial low counts of neutrophils have an increased risk of developing neutropenia.