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Antimicrobial stewardship programs are important for reducing antimicrobial resistance because they can readjust antibiotic prescriptions to local guidelines, switch intravenous to oral administration, and reduce hospitalization times. Pharmacokinetics-pharmacodynamics (PK-PD) empirically based prescriptions and therapeutic drug monitoring (TDM) programs are essential for antimicrobial stewardship, but there is a need to fit protocols according to cost benefits. The cost benefits can be demonstrated by reducing toxicity and hospital stay, decreasing the amount of drug used per day, and preventing relapses in infection. Our aim was to review the data available on whether PK-PD empirically based prescriptions and TDM could improve the cost benefits of an antimicrobial stewardship program to decrease global hospital expenditures.A narrative review based on PubMed search with the relevant studies of vancomycin, aminoglycosides, beta-lactams, and voriconazole.TDM protocols demonstrated important cost benefit for patients treated with vancomycin, aminoglycosides, and voriconazole mainly due to reduce toxicities and decreasing the hospital length of stay. In addition, PK-PD strategies that used infusion modifications to meropenem, piperacillin-tazobactam, ceftazidime, and cefepime, such as extended or continuous infusion, demonstrated important cost benefits, mainly due to reducing daily drug needs and lengths of hospital stays.TDM protocols and PK-PD empirically based prescriptions improve the cost-benefits and decrease the global hospital expenditures.

Aim: The aims of the study are to evaluate the activity of sulbactam, meropenem, and polymyxin B alone and in combination against six isolates of extremely drug resistant Acinetobacter baumannii an...

Fosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in both in vitro and clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa strains has not been tested. The objective of this study was to determine the synergism and optimal intravenous dosing regimens of fosfomycin with meropenem against MDR and MBL-producing P. aeruginosa strains. The MICs of both antimicrobials were determined by the checkerboard method and analyzed by two synergism tests with 19 clones of P. aeruginosa isolates, 10 of which were MBL producers. A pharmacodynamic (PD) analysis was performed for meropenem (administered at 1 g every 8 h [q8h], 1.5 g every 6 h [q6h], and 2 g q8h) and fosfomycin (administered at 4 g q8h, 4 g q6h, 6 g q8h, and 8 g q8h) regimens with a dose reduction for renal impairment by determining the probability of target attainment (PTA) for target PD indices of meropenem (the percentage of the time in a 24-h duration at which the free drug concentration remains above the MIC [fT>MIC], ≥40%) and fosfomycin (the ratio of the area under the free drug concentration-versus-time curve over 24 h and the MIC [fAUC/MIC], ≥40.8). The combination reduced the MIC50 and MIC90 by 8-fold. Seven (44%) isolates with MICs in the intermediate or resistant ranges became sensitive to meropenem. For the MBL-producing isolates, the combination resulted in 40% of isolates becoming sensitive to meropenem. The meropenem regimens reached a PTA of ≥90% (MIC = 4 μg/ml) in 6 (32%) isolates when they were used as monotherapy and 13 (68%) isolates when they were combined with fosfomycin. None of the fosfomycin monotherapy regimens reached the PTA of ≥90% (MIC = 16 μg/ml). When combined with meropenem, the fosfomycin regimens reached the PTA of ≥90% in 14 (74%) isolates. The increase in pharmacodynamic activities resulting from the synergistic action of meropenem with fosfomycin demonstrates the potential relevance of this combination to fight infections caused by MDR and MBL-producing P. aeruginosa strains.

Orientador: Prof.ª Dr.ª Maria Cristina Bronharo Tognim Coorientador: Prof.ª Dr.ª Silvana Martins Caparroz Assef Tese (doutorado em Biociências e Fisiopatologia)--Universidade Estadual de Maringá, 2019 Resumo: Os bacilos Gram negativos multirresistentes (MDR) como Pseudomonas aeruginosa produtoras de metalo-?-lactamase (Pa-MBL) e Klebsiella pneumoniae produtoras de Klebsiella pneumoniae carbapenemase (Kp-KPC) continuam causando altas taxas de morbimortalidade em todo o mundo, e ainda faltam antimicrobianos efetivos e acessíveis para combatê-los. Vários estudos clínicos mostraram que a terapia combinada com antimicrobianos conhecidos, incluindo meropenem (MEM), fosfomicina (FOF) e gentamicina (GEN), foi mais efetiva que a monoterapia, mas não definiram posologias. Esse estudo avaliou o sinergismo de (MEM + FOF) contra Pa-MBL e (MEM + GEN) contra Kp-KPC e comparou o alcance farmacodinâmico dos regimes em monoterapia ou terapia combinada, propondo posologias adequadas, conforme descrito nos dois artigos: a) "Pharmacodynamic attainment of the synergism of meropenem and fosfomycin combination against Pseudomonas aeruginosa producing metallo-?-lactamase"; b) "Resgate do meropenem combinado com gentamicina contra Klebsiella pneumoniae produtora de KPC-2". As concentrações inibitórias mínimas (MIC) foram determinadas por microdiluição, e o sinergismo por checkerboard das associações de MEM + FOS contra 19 isolados clínicos de P. aeruginosa (10 MBL e 9 não MBL), e MEM + GEN contra 18 isolados clínicos Kp-KPC. Análises farmacodinâmicas (AF) foram realizadas por simulação de Monte Carlo dos regimes plenos de MEM (1 g q8h; 1,5 g q6h, 2 g q8h) infundidos (Inf) em 0,5 h ou 3 h e regimes de FOF (4 g q8h; 4 g q6h; 6 g q8h; 8 g q8h) inf 0,5 h, contra as MICs dos isolados de P. aeruginosa obtidos com sais puros e em associação, assim como regimes de MEM (1 g q8h; 1.5 g q6h, 2 g q8h) inf 0.5 ou 3 h contra as MICs dos isolados de Kp-KPC obtidos de MEM puro ou combinado com GEN. Regimes adequados foram considerados aqueles com probabilidade de alcançar o alvo (PTA) ?90%. A AF do regime de GEN (490 mg q24h) foi realizada por estimativa da concentração em um paciente crítico virtual. Os índices farmacodinâmicos e valores alvos utilizados para os regimes de MEM, FOF e GEN foram %fT>MIC ?40%, fAUC24h/MIC ?40.8, Cmax/MIC ?10, respectivamente, e as posologias foram ajustados para a disfunção renal conforme o clearance de creatinina. A combinação de MEM + FOF contra isolados de P. aeruginosa reduziu as MIC50 e MIC90 para 1/8 das MIC50 e MIC90 puras. Sete (44%) dos isolados de P. aeruginosa classificados como intermediários ou resistentes ao meropenem, tornaram-se sensíveis a esse agente, sendo que quatro desses eram Pa-MBL. A AF das posologias plenas, regimes de MEM em monoterapia atingiram PTA ?90% (MIC = 4 mg/L) para 6 (32%) isolados, e quando combinados MEM + FOF atingiram PTA ?90% na mesma MIC para 13 (68%) isolados. Nenhum regime de FOF em monoterapia alcançou PTA ?90% (MIC = 16 mg/L), entretanto, quando combinados com MEM, todos os regimes alcançaram PTA adequada na mesma MIC para 14 (74%) isolados. Em relação aos isolados de Kp-KPC, as MIC50 e MIC90 do MEM após a combinação MEM + GEN foram reduzidas em 1/32 e 1/8, respectivamente, das MIC50 e MIC90 puras, e para a GEN a combinação com MEM reduziu as MIC50 e MIC90 para 1/4 das MIC50 e MIC90 puras. Dos isolados resistentes ao MEM, oito (44%) tornaram-se sensíveis quando combinados com GEN. O sinergismo ocorreu em 94% dos testes, e nenhum antagonismo foi verificado. A AF mostrou que os regimes de MEM + GEN otimizados, ampliaram a cobertura da PTA ?90% (MIC = 4 mg/L) de 3 (17%) isolados para 16 (89%) isolados e na (MIC = 16 mg/L). O dois estudos realizados demonstraram de modo evidente a ação sinérgica das combinações antimicrobianas de MEM + FOF contra isolados de Pa-MBL, assim como na associação de MEM + GEN contra isolados de Kp-KPC avaliadas, constatada pela redução nas MIC50 e MIC90, bem como a mudança de categoria resistente para sensível, e a ampliação das coberturas farmacodinâmicas verificadas após as respectivas combinações, demonstrando assim o potencial das combinações em posologias máximas diárias e otimizadas de MEM + FOF para tratar infecções por Pa-MBL, como também, MEM + GEN para tratar infecções por Kp-KPC Abstract: Multidrug-resistant (MDR) Gram negative bacillus, such as Metallo-beta-Lactamase-producing Pseudomonas aeruginosa (MBL-Pa) and Klebsiella Pneumoniae Carbapenemase-producing Klebsiella pneumoniae (KPC-Kp), continue to cause high morbidity and mortality rates worldwide, and effective and accessible antimicrobials are still lacking to combat them. Several clinical studies have shown that combination therapy with known antimicrobials, including meropenem (MEM), fosfomycin (FOF) and gentamicin (GEN), was more effective than monotherapy, but did not define dosages. This study evaluated the synergism of (MEM + FOF) against MBL-Pa and (MEM + GEN) against KPC-Kp and compared the pharmacodynamic reach of the monotherapy and combination therapy regimens and proposed suitable dosages, as described in the two articles: a) "Pharmacodynamic attainment of the synergism of meropenem and fosfomycin combination against Pseudomonas aeruginosa producing metallo-?-lactamase"; b) "Rescue of meropenem in combination with gentamicin against KPC-2-producing Klebsiella pneumoniae". Minimum inhibitory concentrations (MICs) were determined by microdilution, and the synergism of associations by checkerboard of MEM + FOF against 19 clinical isolates of P. aeruginosa (MBL, 10; not MBL, 9), and MEM + GEN against 18 clinical isolates of Kp-KPC. Pharmacodynamic analyzes (PA) were performed by Monte Carlo simulation of the full regimens of MEM (1 g q8h, 1.5 g q6h, 2 g q8h) infused (Inf) in 0.5 h or 3 h and and regimens of FOF (4 g q8h, 4 g q6h, 6 g q8h, 8 g q8h) inf 0.5 h, against the MICs of P. aeruginosa isolates obtained with pure salts and in association, as well as regimens of MEM (1 g q8h; 1.5 g q6h, 2 g q8h) inf 0.5 or 3 h against the MICs of Kp-KPC isolates obtained from MEM pure or combined with GEN. Appropriate regimens were considered those with probability of target attainment (PTA) ?90%. The PA of the GEN regimen (490 mg q24h) was performed by estimating the concentration in a virtual critical patient. The pharmacodynamic indexes and target values used for MEM, FOF, and GEN regimens were %fT>MIC ?40%, fAUC24h/MIC ?40.8, Cmax/MIC ?10, respectively, and the dosages were adjusted for renal dysfunction according to creatinine clearance. MEM + FOF combination against P. aeruginosa isolates reduced the MIC50 and MIC90 to 1/8 of the respective pure MICs. Seven (44%) isolates of P. aeruginosa classified as intermediate or resistant to meropenem have become sensitive to this agente, and four of which were Pa-MBL. The PA of full doses, MEM regimens in monotherapy reached PTA ?90% (MIC = 4 mg/L) for 6 (32%) isolates, and when combined MEM + FOF reached PTA ?90% in the same MIC for 13 (68 %) isolated. No monotherapy FOF regimen achieved PTA ?90% (MIC = 16 mg/L), however, when combined with MEM, all regimens achieved adequate PTA in the same MIC for 14 (74%) isolates. Regarding Kp-KPC isolates, the MIC50 and MIC90 of the MEM after the MEM + GEN combination were reduced to 1/32 and 1/8, respectively, of the pure MIC50 and MIC90; and for GEN, the combination with MEM reduced the MIC50 and MIC90 to 1/4 of the pure MIC50 and MIC90. Of the isolates resistant to MEM, eight (44%) became sensitive when combined with GEN. Synergism occurred in 94% of the tests, and no antagonism was found. The PA showed that the combined regimes of MEM + GEN and optimized, increased coverage PTA ?90% (MIC = 4 mg/L) of 3 (17%) isolates for 16 (89%) isolates, and in (MIC = 16 mg/L). The two studies performed in this thesis clearly demonstrated the synergistic action of antimicrobial combinations of MEM + FOF against Pa-MBL isolates, as well as the association of MEM + GEN against Kp-KPC isolates evaluated, observed by the reduction in the MIC50 and MIC90, as well as the change from resistant to sensitive category, and the expansion of pharmacodynamic coverage verified after the respective combinations, thus demonstrating the potential of combinations in maximal dosages daily and optimized of MEM + FOF to treat Pa-MBL infections, as well as MEM + GEN to treat Kp-KPC infections

Fosfomycin is widely used for the treatment of uncomplicated urinary tract infection (UTI), and it has recently been recommended that fosfomycin be used to treat infections caused by multidrug-resistant (MDR) Gram-negative bacilli. Whether urine acidification can improve bacterial susceptibility to fosfomycin oral dosing regimens has not been analyzed. The MIC of fosfomycin for 245 Gram-negative bacterial isolates, consisting of 158 Escherichia coli isolates and 87 Klebsiella isolates which were collected from patients with urinary tract infections, were determined at pH 6.0 and 7.0 using the agar dilution method. Monte Carlo simulation of the urinary fosfomycin area under the concentration-time curve (AUC) after a single oral dose of 3,000 mg fosfomycin and the MIC distribution were used to determine the probability of target attainment (PTA). Fosfomycin was effective against E. coli (MIC 90 ≤ 16 μg/ml) but not against Klebsiella spp. (MIC 90 > 512 μg/ml). Acidification of the environment increased the susceptibility of 71% of the bacterial isolates and resulted in a statistically significant decrease in bacterial survival. The use of a regimen consisting of a single oral dose of fosfomycin against an E. coli isolate with an MIC of ≤64 mg/liter was able to achieve a PTA of ≥90% for a target pharmacodynamic index (AUC/MIC) of 23 in urine; PTA was not achieved when the MIC was higher than 64 mg/liter. The cumulative fractions of the bacterial responses (CFR) were 99% and 55% against E. coli and Klebsiella spp., respectively, based on simulated drug exposure in urine with an acidic pH of 6.0. A decrease of the pH from 7.0 to 6.0 improved the PTA and CFR of the target pharmacodynamic index in both E. coli and Klebsiella isolates.

KPC-producing Klebsiella pneumoniae causes serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producing K. pneumoniae . The activities of combination antimicrobials were also determined by the checkerboard method. The MIC 50 and MIC 90 of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval ( f T>MIC). The monotherapy MIC 50 s and MIC 90 s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC 50 s and to 1/8 to 1/16 the MIC 90 s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC 50 and MIC 90 had better chances of achieving ≥90% probability of target attainment (PTA) of 70% f T>MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40% f T>MIC for MIC 50 but not MIC 90 . The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producing K. pneumoniae .

Background First detected in the United States in 1996, Klebsiella pneumoniae carbapenemase (KPC) has spread internationally among gram-negative bacteria, especially K pneumoniae . These microorganisms can cause serious infections in hospitalized patients, and there are few therapeutic options, culminating in increased mortality. The objective of this study was to describe the occurrence of outbreaks that were caused by KPC-producing K pneumoniae , emphasizing the interventions that were implemented to contain the outbreaks. Methods PubMed, Web of Knowledge, and Literatura Latino Americana em Ciencias da Saude databases were searched for articles that were published between 2001 and 2012 according to the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Results Of the 586 studies identified, 13 were selected for the final sample. Most studies showed that the containment of KPC outbreaks is possible in hospital settings through several actions, particularly use of surveillance cultures and the establishment of contact precautions. Conclusions The results show that limiting the cross-transmission of these and other KPC-producing bacteria is possible in a hospital setting. However, such isolates need to be detected early with the aid of culture surveillance and contained early using appropriate actions immediately to prevent an outbreak.