[New drugs for small animals in 2018]. / Neue Arzneimittel für Kleintiere 2018.

In 2018, two active pharmaceutical ingredients were released on the German market for small animals: the ectoparasiticide of the isoxazoline group Lotilaner (Credelio®) and the opioid analgesic Tramadol (Tralieve®). Two established veterinary active pharmaceutical ingredients became available for additional species: the nonsteroidal anti-inflammatory drug Meloxicam (Metacam®) from the oxicam group for guinea pigs and the inhalant anesthetic Sevoflurane (Sevoflo®) from the group of halogenated hydrocarbon compounds, which has additionally been authorized for cats. With the combination of Benzylpenicillin-Benzathine and Benzylpenicillin-Procaine, one temporarily non-available combination of active ingredients was reapproved in new drugs. Additionally, one drug with a new pharmaceutical form and one drug with a higher content of the active ingredient have been launched on the market for small animals.

Evaluation of plasma concentration after intravenous and intramuscular penicillin administration over 24 hr in healthy adult horses.

Penicillin is administered intravenously (IV) or intramuscularly (IM) to horses for the prevention and treatment of infections, and both routes have disadvantages. To minimize these shortcomings, a 24-hr hybrid administration protocol (HPP) was developed. Our objective was to determine penicillin plasma concentrations in horses administered via HPP. Venous blood was collected from seven healthy horses administered IV potassium penicillin G at 0 and 6 hr and IM procaine penicillin G at 12 hr. Blood was collected at 2-hr intervals from 0 to 20 hr and at 24 hr. Plasma penicillin concentrations were measured using liquid chromatography and mass spectrometry. Penicillin susceptibility from equine isolates was examined to determine pharmacodynamic targets. The MIC90 of penicillin for 264 isolates of Streptococcus sp. was ≤0.06 µg/ml. For the 24-hr dosing interval, the mean plasma penicillin concentration was >0.07 µg/ml. Five horses (72%) exceeded 0.06 µg/ml for 98% of the dosing interval, and two horses exceeded this value for 52%-65% of the dosing interval. The HPP achieved mean plasma penicillin concentrations in healthy adult horses above 0.07 µg/ml for a 24-hr dosing interval. However, individual variations in plasma concentrations were apparent and deserve future clinical study.

Impact of parenteral antimicrobial administration on the structure and diversity of the fecal microbiota of growing pigs.

While antimicrobials are cost-effective tools for prevention and treatment of infectious disease, the impact of their use on potentially beneficent mucosal microbial communities of growing pigs has not been widely explored. The objective of this study was to characterize the impact of parenteral antibiotics administration on the composition and diversity of the resident fecal microbiota in growing pigs. Five antimicrobial treatment groups, each consisting of four, eight-week old piglets, were administered one of the antimicrobials; Ceftiofur Crystalline free acid (CCFA), Ceftiofur hydrochloride (CHC), Oxytetracycline (OTC), Procaine Penicillin G (PPG) and Tulathromycin (TUL) at label dose and route. Individual fecal swabs were collected immediately before antimicrobial administration (control = day 0), and again on days 1, 3, 7, and 14 after dosing. Genomic DNA was extracted, and the V1-V3 hypervariable region of 16S rRNA gene was amplified and sequenced using Illumina Miseq-based sequencing. Across all groups, the most abundant phyla were Firmicutes, Bacteroidetes, and Proteobacteria. Linear discriminant analysis and stacked area graphs, showed a pronounced, antimicrobial-dependent shift in the composition of fecal microbiota over time from day 0. By day 14, the fecal microbial compositions of the groups receiving CHC and TUL had returned to a distribution that closely resembled that observed on day 0, but differences were still evident. In contrast, animals that received PPG, OTC and CCFA, showed a tendency towards a balanced homeostatic microbiota structure on day 7, but appeared to deviate away from the day 0 composition by day 14. Based on our results, the observed changes in fecal microbiota showed antimicrobial-specific variation in both duration and extent. Understanding the impact of these important antimicrobial-induced changes will be a critical step in optimizing the use of antimicrobials in health management programs in the swine industry.

Acute myocardial infarction in a patient suffering from penicillin-induced laryngeal edema : Kounis syndrome aggravated by adrenaline.

Kounis syndrome or allergic angina is defined as the coincidental occurrence of chest pain and allergic reactions accompanied by clinical and laboratory findings of classical angina pectoris. It is triggered by the action of potent vasoactive and inflammatory mediators, which are released from the mast cells during the allergic reaction. Epinephrine is a life-saving medication in anaphylaxis; however, it can aggravate ischemia and induce coronary vasospasm and arrhythmias. Here, we present a patient with Kounis syndrome that was caused by intramuscular injection of procaine penicillin G, and in whom epinephrine administration for treatment of laryngeal edema had provoked severe myocardial ischemia.

Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial.

BACKGROUND: Parenteral antibiotic therapy for young infants (aged 0-59 days) with suspected sepsis is sometimes not available or feasible in countries with high neonatal mortality. Outpatient treatment could save lives in such settings. We aimed to assess the equivalence of two simplified antibiotic regimens, comprising fewer injections and oral rather than parenteral administration, compared with a reference treatment for young infants with clinical severe infection. METHODS: We undertook the Simplified Antibiotic Therapy Trial (SATT), a three-arm, randomised, open-label, equivalence trial in five communities in Karachi, Pakistan. We enrolled young infants (aged 0-59 days) who either presented at a primary health-care clinic or were identified by a community health worker with signs of clinical severe infection. We included infants who were not critically ill and whose family refused admission. We randomly assigned infants to either intramuscular procaine benzylpenicillin and gentamicin once a day for 7 days (reference); oral amoxicillin twice daily and intramuscular gentamicin once a day for 7 days; or intramuscular procaine benzylpenicillin and gentamicin once a day for 2 days followed by oral amoxicillin twice daily for 5 days. The primary outcome was treatment failure within 7 days of enrolment and the primary analysis was per protocol. We judged experimental treatments as efficacious as the reference if the upper bound of the 95% CI for the difference in treatment failure was less than 5·0. This trial is registered at ClinicalTrials.gov, number NCT01027429. FINDINGS: Between Jan 1, 2010, and Dec 26, 2013, 2780 infants were deemed eligible for the trial, of whom 2453 (88%) were enrolled. Because of inadequate clinical follow-up or treatment adherence, 2251 infants were included in the per-protocol analysis. 820 infants (747 per protocol) were assigned the reference treatment of procaine benzylpenicillin and gentamicin, 816 (751 per protocol) were allocated amoxicillin and gentamicin, and 817 (753 per protocol) were assigned procaine benzylpenicillin, gentamicin, and amoxicillin. Treatment failure within 7 days of enrolment was reported in 90 (12%) infants who received procaine benzylpenicillin and gentamicin (reference), 76 (10%) of those given amoxicillin and gentamicin (risk difference with reference -1·9, 95% CI -5·1 to 1·3), and 99 (13%) of those treated with procaine benzylpenicillin, gentamicin, and amoxicillin (risk difference with reference 1·1, -2·3 to 4·5). INTERPRETATION: Two simplified antibiotic regimens requiring fewer injections are equivalent to a reference treatment for young infants with signs of clinical severe infection but without signs of critical illness. The use of these simplified regimens has the potential to increase access to treatment for sick young infants who cannot be referred to hospital. FUNDING: The Saving Newborn Lives initiative of Save the Children, through support from the Bill & Melinda Gates, and by WHO and USAID.

Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial.

BACKGROUND: Severe infections remain one of the main causes of neonatal deaths worldwide. Possible severe infection is diagnosed in young infants (aged 0-59 days) according to the presence of one or more clinical signs. The recommended treatment is hospital admission with 7-10 days of injectable antibiotic therapy. In low-income and middle-income countries, barriers to hospital care lead to delayed, inadequate, or no treatment for many young infants. We aimed to identify effective alternative antibiotic regimens to expand treatment options for situations where hospital admission is not possible. METHODS: We did this randomised, open-label, equivalence trial in four urban hospitals and one rural field site in Bangladesh to determine whether two alternative antibiotic regimens with reduced numbers of injectable antibiotics combined with oral antibiotics had similar efficacy and safety to the standard regimen, which was also used as outpatient treatment. We randomly assigned infants who showed at least one clinical sign of severe, but not critical, infection (except fast breathing alone), whose parents refused hospital admission, to one of the three treatment regimens. We stratified randomisation by study site and age (<7 days or 7-59 days) using computer-generated randomisation sequences. The standard treatment was intramuscular procaine benzylpenicillin and gentamicin once per day for 7 days (group A). The alternative regimens were intramuscular gentamicin once per day and oral amoxicillin twice per day for 7 days (group B) or intramuscular procaine benzylpenicillin and gentamicin once per day for 2 days, then oral amoxicillin twice per day for 5 days (group C). The primary outcome was treatment failure within 7 days after enrolment. Assessors of treatment failure were masked to treatment allocation. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with ClinicalTrials.gov, number NCT00844337. FINDINGS: Between July 1, 2009, and June 30, 2013, we recruited 2490 young infants into the trial. We assigned 830 infants to group A, 831 infants to group B, and 829 infants to group C. 2367 (95%) infants fulfilled per-protocol criteria. 78 (10%) of 795 per-protocol infants had treatment failure in group A compared with 65 (8%) of 782 infants in group B (risk difference -1.5%, 95% CI -4.3 to 1.3) and 64 (8%) of 790 infants in group C (-1.7%, -4.5 to 1.1). In group A, 14 (2%) infants died before day 15, compared with 12 (2%) infants in group B and 12 (2%) infants in group C. Non-fatal relapse rates were similar in all three groups (12 [2%] infants in group A vs 13 [2%] infants in group B and 10 [1%] infants in group C). INTERPRETATION: Our results suggest that the two alternative antibiotic regimens for outpatient treatment of clinical signs of severe infection in young infants whose parents refused hospital admission are as efficacious as the standard regimen. This finding could increase treatment options in resource-poor settings when referral care is not available or acceptable.

Oral amoxicillin compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with fast breathing when referral is not possible: a randomised, open-label, equivalence trial.

BACKGROUND: WHO recommends referral to hospital for possible serious bacterial infection in young infants aged 0-59 days. We aimed to assess whether oral amoxicillin treatment for fast breathing, in the absence of other signs, is as efficacious as the combination of injectable procaine benzylpenicillin-gentamicin. METHODS: In a randomised, open-label, equivalence trial at five sites in DR Congo, Kenya, and Nigeria, community health workers followed up all births in the community, identified unwell young infants, and referred them to study nurses. We randomly assigned infants with fast breathing as a single sign of illness or possible serious bacterial infection, whose parents did not accept referral to hospital, to receive either injectable procaine benzylpenicillin-gentamicin once per day or oral amoxicillin treatment twice per day for 7 days. A person who was off-site generated randomisation lists using computer software. Trained health professionals gave injections, but outcome assessors were masked to group allocations. The primary outcome was treatment failure by day 8 after enrolment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing on day 4, or recurrence up to day 8. The primary analysis was per protocol and we used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000286044. FINDINGS: From April 4, 2011, to March 29, 2013, we enrolled 2333 infants aged 0-59 days with fast breathing as the only sign of possible serious bacterial infection at the five study sites. We assigned 1170 infants to receive injectable procaine benzylpenicillin-gentamicin and 1163 infants to receive oral amoxicillin. In the per-protocol analysis, from which 137 infants were excluded, we included 1061 (91%) infants who fulfilled predefined criteria of adherence to treatment and adequate follow-up in the injectable procaine benzylpenicillin-gentamicin group and 1145 (98%) infants in the oral amoxicillin group. In the procaine benzylpenicillin-gentamicin group, 234 infants (22%) failed treatment, compared with 221 (19%) infants in the oral amoxicillin group (risk difference -2·6%, 95% CI -6·0 to 0·8). Four infants died within 15 days of follow-up in each group. We detected no drug-related serious adverse events. INTERPRETATION: Young infants with fast breathing alone can be effectively treated with oral amoxicillin on an outpatient basis when referral to a hospital is not possible. FUNDING: Bill & Melinda Gates Foundation grant to WHO.

Changes in the equine fecal microbiota associated with the use of systemic antimicrobial drugs.

BACKGROUND: The intestinal tract is a rich and complex environment and its microbiota has been shown to have an important role in health and disease in the host. Several factors can cause disruption of the normal intestinal microbiota, including antimicrobial therapy, which is an important cause of diarrhea in horses. This study aimed to characterize changes in the fecal bacterial populations of healthy horses associated with the administration of frequently used antimicrobial drugs. RESULTS: Twenty-four adult mares were assigned to receive procaine penicillin intramuscularly (IM), ceftiofur sodium IM, trimethoprim sulfadiazine (TMS) orally or to a control group. Treatment was given for 5 consecutive days and fecal samples were collected before drug administration (Day 1), at the end of treatment (Days 5), and on Days 14 and 30 of the trial. High throughput sequencing of the V4 region of the 16S rRNA gene was performed using an Illumina MiSeq sequencer. Significant changes of population structure and community membership were observed after the use of all drugs. TMS caused the most marked changes on fecal microbiota even at higher taxonomic levels including a significant decrease of richness and diversity. Those changes were mainly due to a drastic decrease of Verrucomicrobia, specifically the "5 genus incertae sedis". Changes in structure and membership caused by antimicrobial administration were specific for each drug and may be predictable. Twenty-five days after the end of treatment, bacterial profiles were more similar to pre-treatment patterns indicating a recovery from changes caused by antimicrobial administration, but differences were still evident, especially regarding community membership. CONCLUSIONS: The use of systemic antimicrobials leads to changes in the intestinal microbiota, with different and specific responses to different antimicrobials. All antimicrobials tested here had some impact on the microbiota, but TMS significantly reduced bacterial species richness and diversity and had the greatest apparent impact on population structure, specifically targeting members of the Verrucomicrobia phylum.

Comminuted fracture of the accessory carpal bone removed via an arthroscopic-assisted arthrotomy.

A 16-year-old American paint horse gelding was presented for evaluation of a left forelimb lameness grade III/V. Radiographs and computed tomography revealed a comminuted fracture of the accessory carpal bone involving the entire articulation with the distal radius and the proximal aspect of the articulation with the ulnar carpal bone. Multiple fragments were present in the palmar pouch of the antebrachiocarpal joint. An arthroscopic-assisted open approach was necessary to remove all fractured fragments. Subsequently the horse was re-admitted for lameness and was treated successfully with antibiotics and long-term supportive bandaging.

Fracture comminutive de l'os du carpe accessoire enlevé à l'aide d'une arthrotomie assistée par arthroscopie. Un cheval American Paint Horse âgé de 16 ans a été présenté pour l'évaluation d'une boiterie de la jambe avant gauche de grade III/V. Les radiographies et la tomodensitométrie ont révélé une fracture comminutive de l'os du carpe accessoire touchant toute l'articulation avec le radius distal et l'aspect proximal de l'articulation avec l'os du carpe cubital. Des fragments multiples étaient présents dans la poche palmaire de l'articulation antébrachio-carpienne. Une approche ouverte assistée par arthroscopie a été nécessaire pour retirer tous les fragments fracturés. Le cheval a ensuite été réadmis pour boiterie et a été traité avec succès à l'aide d'antibiotiques et de pansements de soutien à long terme.(Traduit par Isabelle Vallières).

Depletion of penicillin G residues in heavy sows after intramuscular injection. Part I: tissue residue depletion.

Heavy sows (n = 126) were treated with penicillin G procaine at a 5× label dose (33 000 IU/kg) for 3 consecutive days by intramuscular (IM) injection using three patterns of drug administration. Treatments differed by injection pattern and injection volume. Sets of sows were slaughtered 5, 10, 15, 20, 25, 32, and 39 days after the last treatment; skeletal muscle, kidney, serum, and urine were collected for penicillin G analysis by LC-MS/MS. Penicillin G at withdrawal day 5 averaged 23.5 ± 10.5 and 3762 ± 1932 ng/g in muscle and kidney, respectively. After 15 days of withdrawal, muscle penicillin G residues were quantifiable in only one treated hog (3.4 ng/g) but averaged 119 ± 199 ng/g in kidneys. Using a hypothetical tolerance of 50 ng/g and a natural log-linear depletion model, the withdrawal period required for penicillin depletion to 50 ng/g was 11 days for skeletal muscle and 47 days for kidney.

Depletion of penicillin G residues in heavy sows after intramuscular injection. Part II: application of kidney inhibition swab tests.

Sows (n = 126; 228 ± 30.1 kg) were administered daily IM doses of penicillin G procaine (33 000 IU/kg bw; 5× the label dose) for 3 consecutive days using three different administration patterns. Within treatment, six sows each were slaughtered on withdrawal day 5, 10, 15, 20, 25, 32, and 39. Tissues (injection site, kidney, liver, skeletal muscle) or body fluids (serum and urine) were screened for penicillin G using the KIS test, recently adopted by the USDA Food Safety and Inspection Service. The IM administration patterns had no discernible effect on penicillin G depletion. Residues were depleted more rapidly from liver and skeletal muscle and more slowly from kidney and urine. Kidney was the most sensitive and suitable tissue for detecting penicillin G residues on-site, with two positive results after a 39-day withdrawal period. Urine was the most suitable ante-mortem surrogate to predict the results of kidney tests.

Safety and efficacy of simplified antibiotic regimens for outpatient treatment of serious infection in neonates and young infants 0-59 days of age in Bangladesh: design of a randomized controlled trial.

BACKGROUND: Because access to care is limited in settings with high mortality, exclusive reliance on the current recommendation of 7-10 days of parenteral antibiotic treatment is a barrier to provision of adequate treatment of newborn infections. METHODS: We are conducting a trial to determine if simplified antibiotic regimens with fewer injections are as efficacious as the standard course of parenteral antibiotics for empiric treatment of young infants with clinical signs suggestive of severe infection in 4 urban hospitals and in a rural surveillance site in Bangladesh. The reference regimen of intramuscular procaine-benzyl penicillin and gentamicin given once daily for 7 days is being compared with (1) intramuscular gentamicin once daily and oral amoxicillin twice daily for 7 days and (2) intramuscular penicillin and gentamicin once daily for 2 days followed by oral amoxicillin twice daily for additional 5 days. All regimens are provided in the infant's home. The primary outcome is treatment failure (death or lack of clinical improvement) within 7 days of enrolment. The sample size is 750 evaluable infants enrolled per treatment group, and results will be reported at the end of 2013. DISCUSSION: The trial builds upon previous studies of community case management of clinical severe infections in young infants conducted by our research team in Bangladesh. The approach although effective was not widely accepted in part because of feasibility concerns about the large number of injections. The proposed research that includes fewer doses of parenteral antibiotics if shown efficacious will address this concern.

Successful medical management of intra-abdominal abscesses in 4 adult horses.

Four adult horses with large intra-abdominal abscesses, suspected to be complications of strangles, were treated with systemic antibiotics alone and made a full recovery. The 100% survival rate is significantly better than other reported survival rates. The median duration of treatment (35 days) was shorter than in most previous reports. This study suggests that penicillin G can be used for successful treatment of strangles associated intra-abdominal abscesses in horses.

Gestion médicale réussie d'abcès intra-abdominaux chez 4 chevaux adultes. Quatre chevaux adultes avec des abcès intra-abdominaux de grande taille, suspectés d'être des complications de la gourme, ont été traités seulement à l'aide d'antibiotiques systémiques et se sont rétablis complètement. Le taux de survie de 100 % est significativement meilleur que les autres taux de survie signalés. La durée médiane du traitement (35 jours) a été plus courte que celle indiquée dans la plupart des rapports antérieurs. Cette étude suggère que la pénicilline G peut être utilisée avec succès pour le traitement des abcès intra-abdominaux associés à la gourme chez les chevaux.(Traduit par Isabelle Vallières).