What are the optimal pharmacokinetic/pharmacodynamic targets for ß-lactamase inhibitors? A systematic review.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) indices are widely used for the selection of optimum antibiotic doses. For ß-lactam antibiotics, fT>MIC, best relates antibiotic exposure to efficacy and is widely used to guide the dosing of ß-lactam/ß-lactamase inhibitor (BLI) combinations, often without considering any PK/PD exposure requirements for BLIs. OBJECTIVES: This systematic review aimed to describe the PK/PD exposure requirements of BLIs for optimal microbiological efficacy when used in combination with ß-lactam antibiotics. METHODS: Literature was searched online through PubMed, Embase, Web of Science, Scopus and Cochrane Library databases up to 5 June 2023. Studies that report the PK/PD index and threshold concentration of BLIs approved for clinical use were included. Narrative data synthesis was carried out to assimilate the available evidence. RESULTS: Twenty-three studies were included. The PK/PD index that described the efficacy of BLIs was fT>CT for tazobactam, avibactam and clavulanic acid and fAUC0-24/MIC for relebactam and vaborbactam. The optimal magnitude of the PK/PD index is variable for each BLI based on the companion ß-lactam antibiotics, type of bacteria and ß-lactamase enzyme gene transcription levels. CONCLUSIONS: The PK/PD index that describes the efficacy of BLIs and the exposure measure required for their efficacy is variable among inhibitors; as a result, it is difficult to make clear inference on what the optimum index is. Further PK/PD profiling of BLI, using preclinical infection models that simulate the anticipated mode(s) of clinical use, is warranted to streamline the exposure targets for use in the optimization of dosing regimens.

Effects of genotype and environment on forage yield, nutritive value and morphology of lablab (Lablab purpureus (L.) sweet).

The goal of the study is to determine the effect of genotype and environment on forage yield, forage nutritive value and to determine the relation between morphology and forage yield and nutritive value of lablab. Thirteen genotypes (one local and 12 improved) were replicated 3 times in a randomized complete block trial across three locations in Ethiopian lowlands namely, Bechi, Kite and Tepi. All forage samples were analyzed for dry matter (DM), crude protein (CP), and in vitro dry matter digestibility (IVDMD) using a combination of conventional nutritional analyses and near infrared reflectance spectroscopy. There was a significant (P < 0.001) effect of genotype, location and genotype*location on forage yield of DM, forage yield of CP, forage yield of IVDMD, CP, and IVDMD. The difference between means of minimum and maximum genotypes was 12.9 t/ha of DM, 3.12 t/ha CP, 8.22 t/ha IVDMD, 57 g/kg of CP and 56 g/kg of IVDMD. The correlation between plant morphology and forage yield and nutritive value was weak (r ≤ 0.41) in all locations and the combined data. Both genotype and location should be considered by the farmers when they decide to grow lablab for forage production. Morphological traits of lablab are not suitable to evaluate forage yield and nutritive value. Enhancing the awareness of farmers about the effect genetic-environment interaction effect of forage yield and nutritive value and the relation between morphology and yield and nutritive value would improve the uptake of lablab in mixed the farming system leading to more sustainable agricultural production.

Acacia nilotica leaf meal - potential supplement to 25% dorper crosses of local sheep fed a basal diet of natural pasture hay.

This research was conducted to evaluate the replacement potential of Acacia nilotica dried leaf meal for Noug Seed Cake (NSC) to supplement low quality grass hay in the diet of crossbred sheep (25% Dorper). In doing so, four treatments were set up in such a way that 0%, 33%, 67%, and 100% NSC is replaced with dried leaf of Acacia nilotica from a conventional supplement while the treatments were kept isonitrogenous. The experiment was set up in a Randomized Complete Block Design, with initials weight used as the blocking factor. Twenty animals were allocated to the four treatments. The experiment consisted of hundred days of feeding trial followed by evaluation of carcass components at the end. In addition, the experimental feed ingredient was studied in vitro for gas production, methane (CH4) production, fractional rate of degradation (Kd), and in vitro dry matter digestibility (IVDMD). In view of chemical composition, grass hay contained lower crude protein (CP = 3.2% DM) and high cell wall contents that makes it lower quality feed. On the other hand, Acacia nilotica leaf meal was moderate in quality (CP = 14.3% DM) that can support moderate level of ruminant production. In an in vitro study, Acacia nilotica was found to have lower (P < 0.01) levels of CH4, total gas, kd, and IVDMD compared to the other feed ingredients. This indicates that tannin have an effect on Acacia nilotica feed. Partial and complete replacement of NSC with Acacia nilotica leaf meal significantly increased total dry matter intake (TDMI) (P < 0.001). Average daily gain (ADG) and dressing percentage was also higher for leaf meal supplemented groups. Hot carcass weight was in the range of 14.8-17.8 kg, which is higher than the national average carcass weight for Ethiopian sheep, and it was also found to be higher when NSC was partially (33%) as well as completely replaced by the leaf meal. In general, NSC can be replaced either partially or completely with Acacia nilotica leaf meal in the diet of 25% Dorper crosses while weight gain as well as carcass yield is promoted. The maximum inclusion level of Acacia nilotica was 61.3% or 319.2 g per day for 25% Dorper cross sheep fed natural pasture hay as a basal diet.

Noug Seed (Guizotia abyssinica) Cake Substituted with Dried Mulberry (Morus indica) and Vernonia amygdalina Mixed Leaves' Meal on Growth Performances of Bonga Sheep at Teppi, Ethiopia.

This study was conducted to evaluate noug seed (Guizotia abyssinica) cake substituted with dried mulberry and Vernonia mixed leaves' meal on feed intake, body weight change, and digestibility of Bonga sheep fed on Rhodes grass hay at Teppi Agricultural Research Center, Ethiopia. The experiment was conducted using 25 yearling lambs with an average initial body weight of 20.83 ± 1.66 kg. Five lambs were allotted per treatment in randomized complete block design. Treatments were isonitrogenous supplements of 100% concentrate (49.5% NSC, 49.5% ground maize grain, and 1% salt) offered at 400 g DM/head/day (T1), 25, 50, 75, and 100 of NSC CP substituted by dried mulberry and Vernonia mixed leaves' meal in T2 = 429.8 g/day, T3 = 459.5 g/day, T4 = 489.3 g/day, and T5 = 519 g/day, respectively. The sheep were fed Rhodes grass hay adlibitum and had free access to water and salt block. Intake and growth trail lasted for 90 days followed by 10 days of digestibility trial. The CP, NDF, and ADF contents of Rhodes grass hay were 7.9, 74.8, and 46.8 percent. The CP content of NSC, ground maize grain, dried mulberry, and Vernonia leaves was 32.4, 8.3, 18.5, and 22.5%, respectively. Total DM intake (g/day) was significantly higher for lambs in T3 (771.4) than in T1 (722.8) and T5 (642.8) but similar to T2 (754.9) and T4 (759.7). The CP intake was highest (P < 0.001) for sheep in T2 and T3, but lowest in T5. The apparent DM digestibility for T1 (70.8%), T2 (68.8%), and T3 (69.1%) was significantly higher than for T5 (64.4%), while T4 (67.9%) and T5 were not significantly different. The attained average daily gain (g/day) of sheep in T1 (87.7), T2 (82.0), T3 (83.4), and T4 (75.2) was higher (P < 0.01) than in T5 (56.0). The result of this study indicated that dried mulberry and Vernonia mixed leaves' meal can substitute NSC as a protein supplement up to 75% inclusion level resulting in optimum DM and nutrient intakes and body weight gain of yearling Bonga sheep. This study also highlights the positive potential of dried mulberry and Vernonia mixed leaves' meal as a supplement to ruminants on a basal diet of fibrous feeds.

A Chicken Production Intervention and Additional Nutrition Behavior Change Component Increased Child Growth in Ethiopia: A Cluster-Randomized Trial.

BACKGROUND: Chicken production in the context of nutrition-sensitive agriculture may benefit child nutrition in low-income settings. OBJECTIVES: This study evaluated effects of 1) a chicken production intervention [African Chicken Genetic Gains (ACGG)], and 2) the ACGG intervention with nutrition-sensitive behavior change communication (BCC) [ACGG + Agriculture to Nutrition (ATONU)], on child nutrition and health outcomes and hypothesized intermediaries. METHODS: Forty ACGG villages received 25 genetically improved chickens and basic husbandry guidance; of these, 20 ACGG + ATONU villages in addition received a nutrition-sensitive behavior change and homegardening intervention; 20 control clusters received no intervention. We assessed effects of the interventions on height-for-age z scores (HAZ), weight-for-age z scores (WAZ), and weight-for-height z scores (WHZ) at 9 (midline) and 18 mo (endline) through unadjusted and adjusted ordinary least squares (OLS) regressions. We examined the interventions' effects on hypothesized intermediaries including egg production and consumption, dietary diversity, women's empowerment, income, child morbidities, anemia, and chicken management practices through OLS and log binomial models. RESULTS: Data included 829 children aged 0-36 mo at baseline. ACGG + ATONU children had higher midline HAZ [mean difference (MD): 0.28; 95% CI: 0.02, 0.54] than controls. The ACGG group had higher HAZ (MD: 0.28; 95% CI: 0.05, 0.50) and higher WAZ (MD: 0.18; 95% CI: 0.01, 0.36) at endline than controls; after adjusting for potential baseline imbalance, effects were similar but not statistically significant. At endline, differences in ACGG + ATONU children's HAZ and WAZ compared with controls were similar in magnitude to those of ACGG, but not statistically significant. There were no differences in anthropometry between the intervention groups. ACGG + ATONU children had higher dietary diversity and egg consumption than ACGG children at endline. Both interventions showed improvements in chicken management practices. The interventions did not increase anemia, diarrhea, fever, or vomiting, and the ACGG + ATONU group at midline showed reduced risk of fever. CONCLUSIONS: A chicken production intervention with or without nutrition-sensitive BCC may have benefited child nutrition and did not increase morbidity.This trial was registered at clinicaltrials.gov as NCT03152227.