Clinical efficacy of renal dosing adjustments of ceftazidime-avibactam in patients affected by carbapenem-resistant Gram-negative infections: A systematic review and meta-analysis of observational studies.

AIMS: The aim of this study is to assess clinical efficacy of ceftazidime-avibactam for the management of carbapenem-resistant Gram-negative infections in renal patients receiving recommended dosing adjustments compared to those treated with scheduled full-dose. METHODS: Two authors independently searched PubMed-MEDLINE and Scopus database from inception to 31 December 2021, to retrieve randomized controlled trials or observational studies comparing clinical efficacy of ceftazidime-avibactam in patients affected by carbapenem-resistant Gram-negative infections receiving recommended renal dosing adjustments compared to those treated with scheduled full-dose. Data were independently extracted by the 2 authors, and the quality of included studies was independently assessed according to ROBINS-I tool for observational studies. Mortality rate was selected as primary outcome. Meta-analysis was conducted by including only studies at low or moderate risk of bias providing adjustment for confounders. RESULTS: In total, 1794 articles were screened, and 11 observational studies (1 prospective and 10 retrospective) were included. Serious or critical risk of bias was found in 4 studies, while the other 7 were classified at moderate risk of bias and included in the meta-analysis. Renal dosing adjustments of ceftazidime-avibactam were associated with higher risk of mortality (odds ratio 1.79; 95% confidence interval 1.18-2.72). CONCLUSION: Renal dosing adjustment of ceftazidime-avibactam seems to be associated with a higher risk of mortality in patients affected by carbapenem-resistant Gram-negative infections. However, residual confounder associated with baseline conditions cannot be excluded. Further prospective studies including larger samples are warranted to definitively address this unmet clinical need.

Intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multi-drug-resistant Gram-negative organisms: A real-life experience.

AIM: To investigate the efficacy of intravenous (IV) fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) acute and subacute infections with multi-drug-resistant (MDR) Gram-negative bacteria (GNB), and risk factors associated with 90-day mortality. METHODS: A retrospective, observational, monocentric study enrolled patients treated with IV fosfomycin in combination regimens (≥72 h) for proven DTT-MDR-GNB infection. Multi-variate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving fosfomycin was performed to control for confounding factors. RESULTS: In total, 70 patients were included in this study: 54.3% had carbapenem-resistant isolates, 31.4% had ceftazidime/avibactam-resistant isolates and 28.6% had ceftolozane/tazobactam-resistant isolates. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), osteomyelitis (17.1%) and intra-abdominal infections. All-cause 30- and 90-day mortality were 15.7% and 31.4%, respectively (18.9% and 50% considering acute DTT-MDR-GNB infections alone). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock and ceftolozane/tazobactam resistance. The relationship between resistance to ceftolozane/tazobactam and 90-day mortality was confirmed to be significant after adjustment by propensity score analysis (hazard ratio 5.84, 95% confidence interval 1.65-20.68; P=0.006). CONCLUSIONS: Fosfomycin seems to be a promising salvage, combination treatment in DTT-MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are needed urgently to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of DTT-MDR-GNB infections.

A case of treatment of multidrug-resistant intracranial Klebsiella pneumoniae infection by multichannel colistin sulfate.

The management of severe neurologic infections due to multidrug-resistant (MDR) Klebsiella pneumoniae infection remains a challenge. Limited antibiotic treatment regimens make treatment of severe MDR K. pneumoniae infection more difficult. We describe a patient who developed severe meningitis and ventriculitis after craniotomy caused by MDR K. pneumoniae and was effectively treated with the administration of multichannel applications (intravenous, intrathecal and aerosol inhalation) of colistin sulfate. This case provides clinical evidence that the intrathecal, intravenous and aerosol inhalation of colistin sulfate by multichannel application can be a last resort in refractory intracranial infection by MDR K. pneumoniae.

Difficult-to-treat resistant gram-negative blood stream infections - the beginning of a superbug era - a prospective observational study.

INTRODUCTION: Carbapenem resistant gram-negative bacterial infections are a growing concern worldwide. However, India is already in the era of a shortage of effective antibiotics for the management of these infections. Moreover, Difficult-to-Treat Resistance (DTR) gram-negative infections, which are not much studied, further complicate the scenario. This study emphasized the incidence and outcomes of DTR infections. METHODOLOGY: This is a single-center prospective observational study. The study included hospitalised patients aged ≥18 years with gram-negative bacterial bloodstream infections (GNBSI). Blood cultures with the growth of contaminants and/or single positive culture taken from the femoral site were excluded. Incidences of DTR infections and outcomes in the form of 30-day mortality were analysed. RESULTS: Two hundred forty patients with GNBSI episodes were recorded. The Incidence of DTR GNBSI was 37.9% (91/240). Multivariate analysis found that Hospital-acquired infections, ICU admission and mechanical ventilation were independent risk factors for DTR GNBSI. The most common DTR GNB isolates were Klebsiella pneumoniae (31/49, 63.3%) and Acinetobacter baumannii (26/52, 50%). The adjusted relative risk of mortality was remarkably high in DTR GNBSI (aRR 3.9; 95% CI 1.9-7.9) as compared to CR+/DTR- GNBSI (aRR 0.3; 95% CI 0.1-1.0) and ESCR/CS GNBSI (aRR 1.1; 95% CI 0.5-2.4). CONCLUSION: DTR GNB infections are growing concern in India and this need to be evaluated in multicentric studies. Moreover, DTR GNBSI was associated with significantly higher mortality and there is need of further empowerment of antibiotic stewardship practices.

A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative bloodstream infections and/or ventilator-associated pneumonia.

OBJECTIVES: To describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative (CR-GN) bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP). METHODS: Critically ill patients with different degrees of renal function who were treated with CI ceftazidime-avibactam for documented CR-GN infections, and who underwent therapeutic drug monitoring from April 2021 to March 2022, were retrospectively assessed. Ceftazidime and avibactam concentrations were determined at steady-state, and the free fraction (fCss) was calculated. The joint PK/PD target of ceftazidime-avibactam was considered as optimal when both Css/MIC ratio for ceftazidime ≥4 (equivalent to 100%fT>4xMIC) and Css/CT ratio for avibactam >1 (equivalent to 100% fT>CT of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two was achieved, and suboptimal if neither of the two was achieved). The relationship between ceftazidime-avibactam PK/PD targets and microbiological outcome was assessed. RESULTS: Ten patients with documented CR-GN infections (5 BSIs, 4 VAP, 1 BSI+VAP) were retrieved. The joint PK/PD targets of ceftazidime-avibactam were optimal and quasi-optimal in eight and two cases, respectively. Microbiological failure occurred in two patients (one with VAP, one with BSI+VAP), one of whom developed ceftazidime-avibactam resistance. Both underwent renal replacement therapy, and failed despite attaining optimal joint PK/PD target and receiving fosfomycin co-treatment. CONCLUSION: CI administration may enable optimal joint PK/PD targets of ceftazidime-avibactam to be achieved in most critical renal patients with CR-GN infections, and may help to minimize the risk of microbiological failure.

Azithromycin: An Underappreciated Quinolone-Sparing Oral Treatment for Pseudomonas aeruginosa Infections.

Outpatient treatment of Pseudomonas aeruginosa infections is challenged by increasing rates of resistance to fluoroquinolones, the only class of antibiotics which offers an established oral route of administration against this organism. Azithromycin does not demonstrate activity against P. aeruginosa when evaluated under standard methods of susceptibility testing with bacteriologic media. However, growing evidence shows that azithromycin is very active against P. aeruginosa when using physiologic media that recapitulate the in vivo milieu and is supported by animal models of infection and various clinical settings, including cystic fibrosis. We present three cases of outpatient management of P. aeruginosa otolaryngological infections successfully treated with oral azithromycin, 500 mg daily ranging from 3-8 weeks, where use of fluoroquinolones was not possible due to either resistance or patient intolerance. We review the previous data supporting this clinical approach, in the hope that this will alert clinicians to this treatment option and to inspire a more thorough clinical trial evaluation of azithromycin in this environment of growing medical need.

Resistant gram-negative infections in a pediatric intensive care unit: a retrospective study in a tertiary care center.

AIM: Healthcare-associated infections cause increased morbidity and mortality in intensive care units. In this study, it was aimed to compare infections with multi-drug resistance and extended drug resistance, while evaluating the characteristics of resistant Gram-negative infections in the pediatric intensive care unit in our university hospital. MATERIAL AND METHODS: In this study, pediatric patients who were found to have Gram-negative infections during hsopitalization in the pediatric intensive care unit in our faculty between January 2011 and December 2015, were evaluated retrospectively. RESULTS: One thousand thirty patients were internalized in our unit in the study period. The incidence for healthcare-associated infection was found as 17.2% and the incidence density was found as 32.7 per 1000 patient days. The incidence for healthcare-related infection per 1000 device days and the rate for device use were calculated as 66.9 and 0.59, respectively. One hundred thirty Gram-negative infection episodes were found in 79 patients whose median age was 22 (1-205) months. The most common infections included ventilator-related pneumonia (n=78, 60%) and bloodstream infections (n=38, 29.2%). The most common causative agents included Pseudomonas aeruginosa (n=50, 38.5%), Kleibsiella pneumonia (n=32, 24.6%) and Acinetobacter baumannii (n=28, 21.5%). Among A. baumannii isolates, the rates for resistance against piperacillin-tazobactam and meropenem were found as 96.4% and 89.3%, respectively. Empirical use of carbapenems, aminoglycosides, and fluoroquinolones, the presence of total parenteral nutrition and history of Gram-negative bacterial infections prior to pediatric intensive care unit admission were significantly more common among extended-drug Gram-negative bacterial infections. The late mortality rate was found to be higher in presence of extended drug resistance. History of Gram-negative infection was found to be an independent risk factor in terms of extended drug resistance. CONCLUSION: Healthcare-associated infections are an important health problem and it is important for infection control committees of hospitals to determine and apply strategies according to hospital colonization in prevention.

AMAÇ: Saglik bakimi iliskili enfeksiyonlar yogun bakim birimlerinde yüksek hastalik ve ölüme neden olmaktadir. Bu çalismada, üniversite hastanemiz çocuk yogun bakim birimindeki dirençli gram negatif enfeksiyonlarin özellikleri degerlendirilirken; çok ilaca dirençli ve genisletilmis ilaç direnci olan enfeksiyonlarin karsilastirilmasi amaçlanmistir. GEREÇ VE YÖNTEMLER: Bu çalismada Ocak 2011­Aralik 2015 yillari arasinda, fakültemiz çocuk yogun bakim biriminde yatisi sirasinda gram negatif enfeksiyon saptanan çocuk hastalar geriye dönük olarak degerlendirildi. BULGULAR: Çalisma döneminde birimimize 1 030 hasta yatirildi; saglik bakimi iliskili enfeksiyon sikligi %17,2, siklik yogunlugu 1 000 hasta günü basina 32,7 idi. 1 000 cihaz günü basina saglik bakimi iliskili enfeksiyon sikligi ve cihaz kullanim orani sirasiyla 66,9 ve 0,59 olarak hesaplandi. Yas ortancasi 22 (1­205) ay olan 79 hastada, 130 gram negatif enfeksiyon atagi saptandi. En sik saptanan enfeksiyonlar, ventilatör iliskili pnömoni (n=78, %60) ve kan akim enfeksiyonu (n=38, %29,2) idi. En sik etkenler Pseudomonas aeruginosa (n=50, %38,5), Kleibsiella pneumonia (n=32, %24,6) ve Acinetobacter baumannii (n=28, %21,5) idi. A. baumannii izolatlari arasinda piperasilin-tazobaktam ve meropenem direnci sirasi ile %96,4 ve %89,3 saptandi. Ampirik karbapenem, aminoglikozid ve florokinolon kullanimi, total parenteral nütrisyon varligi, yogun bakim öncesi geçirilmis gram negatif enfeksiyon öyküsü anlamli olarak daha yüksekti. Geç dönem ölüm hizi genisletilmis ilaç direnci varliginda daha yüksek saptandi. Geçirilmis gram negatif enfeksiyon öyküsü, genisletilmis ilaç direnci açisindan bagimsiz risk etmeni olarak bulundu. ÇIKARIMLAR: Saglik bakimi iliskili enfeksiyonlar önemli bir saglik sorunudur ve önlemede mümkünse her hastanenin kendi enfeksiyon kontrol kurulunun hastane kolonizasyonuna göre stratejiler belirleyip uygulamasi önemlidir.

Antimicrobial resistance and treatment: an unmet clinical safety need.

INTRODUCTION: Infections due to multidrug-resistant (MDR) bacteria are burdened by high mortality rates. The development of new compounds to face the global threat of resistance is urgently needed. Combination regimens including "old" high-dose antimicrobials are currently limited by the risk of toxicity, resistance selection, and reduced efficacy. Following the Infectious Diseases Society of America call to develop 10 new antibacterials by 2020, new molecules are currently under development or have become available for use in clinical practice. AREAS COVERED: We have reviewed safety characteristics and tolerability of old antimicrobials that are currently employed in combination regimens as well as new antimicrobials, including beta-lactams/beta-lactamase inhibitors, new cephalosporins, quinolones, and aminoglycosides. EXPERT OPINION: The availability of new compounds that show in vitro efficacy against MDR represents a unique opportunity to face the threat of resistance and to optimize the current use of antimicrobials, potentially reducing toxicity. Agents that are potentially active against MDR Gram-negatives are ceftozolane/tazobactam, new carbapenems and cephalosporins, the combination of avibactam with ceftazidime, and plazomicin. Further data from clinical trials and post-marketing studies for drugs targeting MDR pathogens are crucial to confirm their efficacy and safety.

Intravenous Colistin Use for Multidrug-Resistant Gram-Negative Infections in Pediatric Patients.

BACKGROUND: The emergence of infections due to multidrug-resistant Gram-negative bacilli (MDR-GNB) has led to the resurrection of colistin use. The data on colistin use and drug-related adverse effects in children are scarce. AIMS: In this study, we aimed to evaluate the clinical efficacy and safety of colistin use in critically ill pediatric patients. STUDY DESIGN: This study has a retrospective study design. METHODS: Sixty-one critically ill children were identified through the department's patient files archive during the period from January 2011 to November 2014. RESULTS: Twenty-nine females and thirty-two males with a mean±standard deviation (SD) age of 61±9 months (range 0-216, median 12 months) received IV colistin due to MDR-GNB infections. Bacteremia (n=23, 37.7%) was the leading diagnosis, followed by pneumonia (n=19, 31%), clinical sepsis (n=7, 11.4%), wound infection (n=6, 9.8%), urinary tract infection (n=5, 8.1%) and meningitis (n=1, 1.6%). All of the isolates were resistant to carbapenems; however, all were susceptible to colistin. The isolated microorganisms in decreasing order of frequency were: Acinetobacter baumanni (n=27, 44.2%), Pseudomonas aeruginosa (n=17, 27.8%), Klebsiella pneumoniae (n=6, 9.8%), K. pneumoniae and Stenotrophomonas maltophilia (n=1, 1.6%), K. pneumoniae and A. baumanni (n=1, 1.6%), K. oxytoca (n=1, 1.6%) and Enterobacter cloacae (n=1, 1.6%). In seven patients, no microorganisms were detected; however, five of these patients were colonized by carbapenem-resistant K. pneumoniae. The mean duration of colistin therapy was 12 days (range 3-45). Colistin was administered concomitantly with one of the following antibiotics: carbapenem (n=50, %82), ampicillin-sulbactam (n=5, 8%), quinolones (n=5, 8%), rifampicin (n=1, 1.6%). Carbapenem was the most frequently used antibiotic. Nephrotoxicity was observed in only 1 patient, and we did not observe neurotoxicity in this study. All the patients received intravenous colistin (colisthimethate) at a dosage of 5 mg/kg daily by dividing it in three equal doses. Seven (11.4%) patients died during the study period. CONCLUSION: Colistin appears to be a safe and efficacious drug for treating MDR-GNB infections in children.