Treatment Of Hospital-acquired Pneumonia Research Articles

Quantitative Study of Antibiotic Usage in Pneumonia Patients: Systematic Literature Review

Pneumonia caused more than 2,56 million deaths in 2017 worldwide. With the high number of pneumonia sufferers, the use of antibiotics will also increase. This study aims to describe the quantity of antibiotic use in pneumonia patients using the Systematic Literature Review method. The literature search was conducted through the PubMed, Sciencedirect, Mendeley, BMC, and Google Scholar databases. The literature used is a journal of the last 10 years that discusses the use of antibiotics in pneumonia patients calculated by the ATC/DDD system. Of the total 19 journals included in the study, 8 journals were from Indonesia. A total of 5 journals discussed antibiotics used in CAP (Community-Acquired Pneumonia), 2 journals in HAP (Hospital-Acquired Pneumonia), 2 journals in VAP (Ventilator-Associated Pneumonia), 2 journals were non-specific, and the remainder covered several types of pneumonia. The class of antibiotics with the highest DDD value is fluoroquinolones, with an average use of 41,81 DDD/100 patient-days; 17,29 DDD/100 bed days; and 0,0696 DDD/1000 inhabitants per day, and third-generation cephalosporins, with an average use of 15,86 DDD/100 patient-days and 28,31 DDD/100 bed days. The antibiotic with the highest DDD value was levofloxacin, with an average use of 31,29 DDD/100 patient-days; 12,22 DDD/100 bed days; and 0,0612 DDD/1000 inhabitants per day, and ceftriaxone, with an average use of 12,51 DDD/100 patient-days and 26,33 DDD/100 bed days. The most widely used antibiotics in the treatment of CAP and HAP are third-generation cephalosporins, while penicillin is the most commonly used in VAP.

Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa.

Hospital-acquired pneumonia (HAP) is a leading cause of morbidity and mortality, commonly caused by Pseudomonas aeruginosa. Meropenem is a commonly used therapeutic agent, although emergent resistance occurs during treatment. We used a rabbit HAP infection model to assess the bacterial kill and resistance pharmacodynamics of meropenem. Meropenem 5 mg/kg administered subcutaneously (s.c.) q8h (±amikacin 3.33-5 mg/kg q8h administered intravenously[i.v.]) or meropenem 30 mg/kg s.c. q8h regimens were assessed in a rabbit lung infection model infected with P. aeruginosa, with bacterial quantification and phenotypic/genotypic characterization of emergent resistant isolates. The pharmacokinetic/pharmacodynamic output was fitted to a mathematical model, and human-like regimens were simulated to predict outcomes in a clinical context. Increasing meropenem monotherapy demonstrated a dose-response effect to bacterial kill and an inverted U relationship with emergent resistance. The addition of amikacin to meropenem suppressed the emergence of resistance. A network of porin loss, efflux upregulation, and increased expression of AmpC was identified as the mechanism of this emergent resistance. A bridging simulation using human pharmacokinetics identified meropenem 2 g i.v. q8h as the licensed clinical regimen most likely to suppress resistance. We demonstrate an innovative experimental platform to phenotypically and genotypically characterize bacterial emergent resistance pharmacodynamics in HAP. For meropenem, we have demonstrated the risk of resistance emergence during therapy and identified two mitigating strategies: (i) regimen intensification and (ii) use of combination therapy. This platform will allow pre-clinical assessment of emergent resistance risk during treatment of HAP for other antimicrobials, to allow construction of clinical regimens that mitigate this risk.IMPORTANCEThe emergence of antimicrobial resistance (AMR) during antimicrobial treatment for hospital-acquired pneumonia (HAP) is a well-documented problem (particularly in pneumonia caused by Pseudomonas aeruginosa) that contributes to the wider global antimicrobial resistance crisis. During drug development, regimens are typically determined by their sufficiency to achieve bactericidal effect. Prevention of the emergence of resistance pharmacodynamics is usually not characterized or used to determine the regimen. The innovative experimental platform described here allows characterization of the emergence of AMR during the treatment of HAP and the development of strategies to mitigate this. We have demonstrated this specifically for meropenem-a broad-spectrum antibiotic commonly used to treat HAP. We have characterized the antimicrobial resistance pharmacodynamics of meropenem when used to treat HAP, caused by initially meropenem-susceptible P. aeruginosa, phenotypically and genotypically. We have also shown that intensifying the regimen and using combination therapy are both strategies that can both treat HAP and suppress the emergence of resistance.

Cefiderocol (Fetroja) as a Treatment for Hospital-Acquired Pneumonia.

With increasing resistance to conventional antibiotic treatments, especially among gram-negative bacilli, the search for new antibiotics has become critical on a global scale. Among infections with multidrug-resistant bacteria is hospital-acquired pneumonia (HAP), which is nosocomial pneumonia in patients who have been hospitalized for more than 48 hours. HAP carries a high mortality rate and continues to be a challenge with regard to adequate treatment. The typical multidrug-resistant gram negatives found in HAP include Pseudomonas aeruginosa, Klebsiella pneumoniae,and Acinetobacter baumannii. Many new antibiotics have been studied and tested against these pathogens as possible solutions, and the search continues. Cefiderocol, a novel siderophore cephalosporin, is effective against these pathogens. Cefiderocol is an iron-chelating agent that makes use of iron pumps on the membrane of bacteria via a catechol moiety on the C3 side chain of the molecule. This allows for easy access into the cytoplasm, where it can inhibit peptidoglycan synthesis by binding to penicillin-binding proteins. Cefiderocol displays linear pharmacokinetics and is mainly excreted through the kidneys. It is well tolerated in healthy individuals but may need adjustments of dosage in patients with impaired renal function. Studies have shown that both healthy subjects and those with impaired renal function experienced some adverse effects, including nausea, diarrhea, abdominal pain, and increased creatinine kinase; however, these adverse effects were limited and experienced in placebo groups. It has demonstrated efficacy in treating infections caused by many multidrug-resistant gram-negative pathogens and has demonstrated high stability against many classes of b-lactamases. There have been multiple phase 3 trials, such as the CREDIBLE-CR trial and the APEKS-NP trial, that demonstrated efficacy in treated nosocomial pneumonia caused by multidrug-resistant gram negatives, such as carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa, compared to the best available treatment. While clinical data remainlimited, a few studies are showing clinical efficacy and few adverse effects. Cefiderocol demonstratedeffectivityin treating multidrug-resistant gram-negative pneumonia in patients with multiple comorbidities, such as chronic kidney disease, chronic-obstructive pulmonary disease, and diabetes mellitus. Cefiderocol shows promise as a novel antimicrobial agent in treating multidrug-resistant gram-negative in HAP.

Colistin plasma concentrations are not associated with better clinical outcomes in patients with pneumonia caused by extremely drug-resistant Pseudomonas aeruginosa.

The objective of this study was to examine the relationship between colistin plasma concentrations and clinical outcomes in patients with hospital-acquired pneumonia (HAP) caused by extensively drug-resistant Pseudomonas aeruginosa (XDR-PA). A prospective observational cohort study was conducted at a tertiary care hospital. Patients diagnosed with HAP caused by XDR-PA between January 2010 and September 2018 were included. Steady-state plasma concentrations (Css,avg) of colistin were measured by high performance liquid chromatography (HPLC). Based on the pharmacokinetic/pharmacodynamic data of colistin in animal models, previous clinical data, and the minimum inhibitory concentration (MIC) of the most prevalent strain in our center, an area under the ROC curve (AUC)/MIC24h between 30 and 60 mg·h/L was considered optimal. The primary outcome was 30-day mortality, and the secondary outcomes were clinical cure and colistin-associated nephrotoxicity. Seventy-five patients were included. The median Css,avg was 1.1 (0.56-1.75) mg/L and only 23 (30.7%) patients achieved an AUC/MIC24h of 30-60 mg·h/L and the 30-day mortality was 30.7%. In multivariate analysis, sequential organ failure assessment score [adjusted hazard ratio (95% confidence interval, CI) 1.19 (1.07-1.32)] and high AUC/MIC24h (hazard ratio 1.55, 95% CI 1.17-2.04, P = 0.002) were associated with increased risk of death and clinical failure. Based on the maximally selected standardized log-rank statistic, the Css,avg cutoff point that best predicted mortality was 1.5 mg/L. Nephrotoxicity at the end of treatment was 38.7%. High colistin exposure was not associated with improved clinical outcomes in the setting of HAP caused by XDR-PA. These data suggest that caution is required with intravenous colistin for the treatment of HAP caused by XDR-PA.IMPORTANCEIn some cases, colistin is the only treatment option for infections caused by the very drug-resistant Pseudomonas aeruginosa. However, in the past decade, there have been questions concerning its pharmacokinetics and concentration at the site of infection. In this scenario, its use in a difficult-to-treat infection like pneumonia is currently debatable. This is a clinical pharmacokinetic study of colistin in patients with multidrug-resistant P. aeruginosa pneumonia. Our findings demonstrate that colistin exposure is associated with worse clinical outcomes rather than better clinical outcomes, implying that other therapeutic options should be explored in this clinical setting.

The role of clinical pulmonary infection score and some infection biomarkers in diagnosis and follow up in hospital acquired pneumonia

Aims: Early diagnosis and treatment affect mortality in hospital-acquired pneumonia (HAP). Therefore, clinicians need some objective parameters for guiding treatment. The aim of this study was to determine the course of ‘‘clinical pulmonary infection score’’ (CPIS), C-reactive protein (CRP) and procalcitonin (PCT) in patients under treatment as well as the relationship of these parameters with each other and mortality. Methods: This single-center, prospective, cross-sectional study focused on cases of HAP in hospitalized patients. In patients with HAP; CPIS, CRP and PCT assays were assessed on the first day. Appropriate treatment was initiated according to Turkish Thoracic Society HAP Task Force recommendations. On the 3rd day, CPIS evaluation and on the 4th day CRP and PCT analysis were repeated. All the patients’ one month mortality rates were recorded. Results: Among the 25 patients, there were 14 females. The mean age was 66±15 years. The mean duration for HAP development was 9.4±8.2 days. With a cutt-off value of 65 for age CPIS, CRP, PCT, length of hospital stay and mortality rate was not found different (p>0.05), however as the age increased HAP development duration significantly decreased (r=-0.416, p=0.03). We demonstrated a significant change between the first and the follow-up values of fever (p=0.046), leukocyte (p<0.001), PaO2/FiO2 (p=0.016), secretion presence (p<0.001), culture positivity (p<0.001) as well as total CPIS (p=0.030). However, there wasn’t a significant difference in CRP and PCT levels. We couldn’t show any relation between CPIS domains, total CPIS, CRP, PCT, HAP development duration and mortality rates. Conclusion: Monitoring HAP treatment according to CPIS was found better than CRP and PCT. However, these parameters had no effect on mortality. For more accurate comments, studies with more patients are needed.

Clinical efficacy of Buzhong Yiqi decoction in the treatment of hospital-acquired pneumonia with multi-drug resistant bacteria: a prospective, randomized, multicenter controlled trial.

To evaluate the efficacy and safety of Buzhong Yiqi decoction (, BZYQ) in the treatment of hospital-acquired pneumonia (HAP) with multi-drug-resistant bacteria (MDRB). This 28-day study was conducted at 5 clinical centers in Shanghai. The eligible patients were randomly assigned (1:1) into the intervention group (BZYQ plus conventional Western Medicine therapy) and control group (conventional Western Medicine therapy). The primary outcomes were the clinical response, clinical pulmonary infection score (CPIS), and microbiologic response. The secondary outcomes were the 28-day all-cause mortality (ACM), Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, ventilator weaning rate, length of mechanical ventilation (MV), length of hospital stay, and changes of infection indicators. Altogether 83 subjects in the intervention group and 85 subjects in the control group were analyzed. The clinical success rate (48.2%) and the pathogen eradication rate (59.0%) of the intervention group were all better than those of the control group (32.9% and 38.9%, respectively) with statistically significant differences (<0.05). The CPIS score of the intervention group (8.9 ± 1.7) was lower than that of the control group (9.6 ± 2.5) (<0.05). The length of MV in the intervention group [(13.7 ± 6.4) d] was significantly shorter than that of the control group [ (17.2 ± 7.2) d] (<0.05). The 28-day ACM of the intervention group (13.33%) was lower than that of the control group (21.2%) with no statistically significant difference (>0.05). The differences between two groups in ventilator weaning rate, length of hospital stay, and APACHE Ⅱ score were not statistically significant (> 0.05). The intervention group displayed decreases in white blood cell count, C-reactive protein, neutrophil percentage, and procalcitonin at day 28 compared with baseline (<0.05). No serious adverse events occurred in either group during the 28-day follow-up. BZYQ may be an effective therapeutic option for the management of HAP with MDRB.

Validated spectrofluorimetric assay of two co-administered drug mixtures containing hydroxychloroquine with either moxifloxacin or ofloxacin as a drug regimen for hospital-acquired pneumonia in covid-19 patients.

Moxifloxacin and ofloxacin are two broad-spectrum quinolone antibiotics. They are among the most widely used antibiotics nowadays in controlling the covid-19 pandemic. Hydroxychloroquine is an FDA-approved drug for the treatment of covid-19. This work describes a simple, green, selective, and sensitive spectrofluorimetric method for the assay of moxifloxacin and ofloxacin in presence of hydroxychloroquine as two co-administered mixtures used in the treatment of hospital-acquired pneumonia in the covid-19 patients. Simultaneous assay of hydroxychloroquine and moxifloxacin was carried out in methanol by direct spectrofluorimetric method (method I) at 375 nm and 550 nm respectively after excitation at 300 nm. The direct spectrofluorimetric assay was rectilinear over concentration range of (50.0-400.0) and (300.0-2500.0) ng/ml for hydroxychloroquine and moxifloxacin with LOD of 6.4 and 33.64 ng/ml and LOQ of 19.4 and 102.6 ng/ml for the two drugs respectively. While the assay of hydroxychloroquine and ofloxacin was carried out by measuring the first derivative synchronous amplitude for hydroxychloroquine at the zero crossing point of ofloxacin and vice versa at Δ λ = 140 nm (method II). Hydroxychloroquine was measured at 266 nm while ofloxacin at 340 nm over concentration range of (4.0-40.0 ng/ml) for hydroxychloroquine and (200.0-2000.0 ng/ml) for ofloxacin with LOD of 0.467 ng/ml and 25.3 ng/ml and LOQ of 1.42 ng/ml and 76.6 ng/ml for the two drugs respectively. the two methods were validated following ICH guidelines and were applied to the analysis of the two drugs in plasma with good percent recoveries (109.73-93.17 %).

P24 Auditing antibiotic course lengths for the management of community-acquired pneumonia and hospital-acquired pneumonia against current NICE guidance

Abstract Background Protracted antibiotic course lengths for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) contribute to increased risk of antibiotic resistance.1 Optimizing antibiotic course length in line with the current national guidance improves patient safety and overall cost savings.1 NICE guidelines state that antibiotic treatment should be stopped at day 5 if patients were afebrile for &amp;lt;48 hours with one or no sign of clinical instability, defined as systolic blood pressure &amp;lt; 90 mmHg, heart rate &amp;gt; 100/minute, respiratory rate &amp;gt; 24/minute, arterial oxygen saturation &amp;lt; 90% or oxygen partial pressure &amp;gt; 60 mmHg in room air.2 Objectives To assess the current prescribing practice for antibiotic course lengths of CAP and HAP across medical specialties at RCHT. Methods A list of patients discharged from medical specialities (respiratory, cardiology, nephrology, gastroenterology, endocrinology and geriatrics) between 1 August and 1 September 2022 with the coded indication of CAP or HAP was requested from the RCHT Informatics Team. Inclusion criteria were any hospitalized patient aged ≥18 years, with a CAP/HAP diagnosis with pulmonary infiltrate on chest X-ray plus at least one symptom including cough, fever, dyspnoea and chest pain. Patients were excluded if having chronic immunosuppression; HIV positive; living in a nursing/care home, onsite subacute care unit or intensive therapy unit (ITU) or palliative care unit within last 14 days; having taken antibiotics 30 days before admission; requiring a longer duration of therapy because of an uncommon cause; requiring a chest tube or having had a condition complicated by extrapulmonary infection.1 For each patient, the patient’s vital signs at day 5 of antibiotic course and the total antibiotic course lengths were recorded. Results A total of 27 patients were assessed for eligibility; of these, 22 patients (81%) met the inclusion criteria, and 5 patients were excluded. Among those excluded, two recently stepped down from ITU, two lived in a nursing/care home and one had taken antibiotics 30 days before admission. Of the 22 patients, 10 patients (45%) received 5 or 6 days of antibiotics for CAP/HAP. The remaining 12 patients (55%) received courses between 7 to 10 days despite meeting the criteria for stopping antibiotics at 5 days. The mean and median of antibiotic course length including all specialities were 6.5 and 6.3 days, respectively. Conclusions This audit demonstrates that almost half of patients with CAP /HAP are being managed with antibiotic courses of fewer than 7 days. Further prescriber and pharmacy team education sessions on appropriate course lengths are needed. There is consideration for an alert notification on EPMA which reminds prescribers to check patient’s vital signs on day 5 when prescribed an antibiotic for the treatment of CAP and HAP. Recommendation would be to reaudit with a longer data collection timeframe and larger sample size.

Effect of Folic Acid Treatment for Patients with Traumatic Brain Injury (TBI)-Related Hospital Acquired Pneumonia (HAP): A Retrospective Cohort Study.

Hospital Acquired Pneumonia (HAP) is one of the most common complications and late causes of death in TBI patients. Targeted prevention and treatment of HAP are of great significance for improving the prognosis of TBI patients. In the previous clinical observation, we found that folic acid treatment for TBI patients has a good effect on preventing and treating HAP. We conducted this retrospective cohort study to demonstrate what we observed by selecting 293 TBI patients from two medical centers and analyzing their hospitalization data. The result showed that the incidence of HAP was significantly lower in TBI patients who received folic acid treatment (44.1% vs. 63.0%, p = 0.012). Multivariate logistic regression analysis showed that folic acid treatment was an independent protective factor for the occurrence of HAP in TBI patients (OR = 0.418, p = 0.031), especially in high-risk groups of HAP, such as the old (OR: 1.356 vs. 2.889), ICU (OR: 1.775 vs. 5.996) and severe TBI (OR: 0.975 vs. 5.424) patients. At the same time, cohort studies of HAP patients showed that folic acid also had a good effect on delaying the progression of HAP, such as reducing the chance of tracheotomy (26.1% vs. 50.8%, p = 0.041), and reduced the length of hospital stay (15 d vs. 19 d, p = 0.029) and ICU stay (5 d vs. 8 d, p = 0.046). Therefore, we believe that folic acid treatment in TBI patients has the potential for preventing and treating HAP, and it is worthy of further clinical research.

Pharmacokinetic/pharmacodynamic analysis of high‐dose tigecycline, by Monte Carlo simulation, in plasma and sputum of patients with hospital‐acquired pneumonia

To Investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of high-dose tigecycline in plasma and sputum of patients with hospital-acquired pneumonia (HAP), and provide a therapeutic regimen of multidrug-resistant bacteria (MDRB) infections. Blood/sputum samples were collected at intervals after tigecycline had reached a steady-state. Tigecycline concentrations in specimens were determined by high-performance liquid chromatography (HLPC), PK parameters were evaluated by WinNonlin software using a non-compartment model. The probability of target attainments (PTAs) at different minimal inhibitory concentrations (MICs) were calculated for achieving the PK/PD index with Crystal Ball software by 10,000-patient Monte Carlo Simulation. In plasma, the maximum concentration (Cmax ) and area under the concentration-time curve from 0 to 12 h (AUC0-12h ) were 2.21 ± 0.17 mg/L and 15.29 ± 1.13 hmg/L, respectively. In sputum, they were 2.48 ± 0.21 mg/L and 19.46 ± 1.82 hmg/L, respectively. The mean lung penetration rate was 127.27%. At the MIC ≤4mg/L, the PTAs in plasma and sputum were 100.00%. When the MIC increased to 8mg/L, the PTAs in plasma and sputum mostly were < 90.00% according to two criteria. In this study, we explored PK/PD of high-dose tigecycline in plasma and sputum. From a PK/PD perspective, high-dose tigecycline had greater therapeutic outcomes in HAP treatment caused by MDRB. Antimicrobial-drug concentrations should be determined to optimize their clinical use.

PB2261: LINEZOLID AS A SAFE ANTIMICROBIAL AGENT IN THROMBOCYTOPENIC PATIENTS UNDERGOING CHEMOTHERAPY FOR HEMATOLOGIC MALIGNANCIES

Background: Febrile neutropenia (FN) is a common event in patients undergoing high-dose chemotherapy (HD-CT) for hematologic malignancies. Linezolid (LZ) is the first-in-class oxazolidinone antimicrobial agent active against gram-positive bacteria, often administered during FN as treatment for hospital-acquired pneumonia, gram-positive bacteriemia and soft-skin tissue infection. LZ induced thrombocytopenia or delayed platelet recovery are adverse events of concern in patients receiving HD-CT. As of today, few data are available on the safety of LZ in this specific setting. Aims: To retrospectively analyze a cohort of thrombocytopenic patients treated with LZ for FN in a single center, evaluating bleeding risk and impact on PLT recovery time. Methods: The analysis included patients diagnosed with Acute Leukemia (AL), High Grade Lymphomas (HGL) and Multiple Myeloma (MM) treated at our institution, between 2016 and 2021, with LZ for a FN episode during induction chemotherapy or ASCT conditioning. To be enrolled, PLT count at the start of LZ therapy had to be < 50×109/L. Results: A total of 40 FN episodes treated with LZ were identified. 22 occurred during induction therapy for AL and 18 during ASCT conditioning regimens. The median PLT count at the start of LZ therapy was 19×109/L in both groups (range 5-49×109/L in the AL cohort, 5-35×109/L in the ASCT group), while the median treatment duration was 8 days in both groups (range 2-15 days in the AL cohort, 3-12 days in the ASCT cohort). Only one clinically relevant bleeding event was observed in the AL group, while 0 bleeding events were observed in the ASCT group. Resolution of infection (defined as fever resolution, normalization of CRP and blood culture negativization) after the introduction of LZ therapy was observed in 17 (77%) AL patients and 15 (83%) ASCT patients. In the AML group PLT recovery (defined as a stable PLT count ≥20×109/L without the need for PLT transfusion) was observed in 18 (81%) patients with a median time to recovery of 22 days from the start of the chemotherapeutic regimen (range 18-41). PLT recovery was observed in 10 (71%) ASCT patients with a median time to recovery of 35 days from the stem cell infusion (range 13-136). 4 out of 18 patients in the ASCT group started LZ therapy after PLT recovery, and 3 out of 18 patients in the same group died due to the infectious complication that prompted the start of LZ therapy. Median PLT recovery time was not significantly different between patients enrolled in this study and historical controls from our center (AML: median 20 days, p>0.1. ASCT: median 22.5 days, p>0.1). Summary/Conclusion: Our observations support the use of LZ in this setting, as only one relevant bleeding event was observed among the two groups, and no impact on PLT recovery time was noted after comparison with historical data. Our study suggests that LZ is a safe and effective antimicrobial therapy in patients undergoing HD-CT for hematological malignancies. This data needs to be prospectively confirmed in a larger cohort of patients in a multicenter study.

Polymyxin B/Tigecycline Combination vs. Polymyxin B or Tigecycline Alone for the Treatment of Hospital-Acquired Pneumonia Caused by Carbapenem-Resistant Enterobacteriaceae or Carbapenem-Resistant Acinetobacter baumannii.

IntroductionIt is not clear whether polymyxin B/tigecycline (PMB/TGC) combination is better than PMB or TGC alone in the treatment of hospital-acquired pneumonia (HAP) caused by carbapenem-resistant organisms (CROs).MethodsWe conducted a multicenter, retrospective cohort study in patients with HAP caused by CROs. The primary outcome was 28-day mortality, and the secondary outcomes included clinical success and the incidence of acute kidney injury (AKI). Multivariate Cox regression analysis was performed to examine the relationship between antimicrobial treatments and 28-day mortality by adjusting other potential confounding factors.ResultsA total of 364 eligible patients were included in the final analysis, i.e., 99 in the PMB group, 173 in the TGC group, and 92 in the PMB/TGC combination group. The 28-day mortality rate was 28.3% (28/99) in the PMB group, 39.3% (68/173) in the TGC group, and 48.9% (45/92) in the PMB/TGC combination group (p = 0.014). The multivariate Cox regression model showed that there was a statistically significant lower risk of 28-day mortality among participants in the PMB group when compared with the PMB/TGC combination group [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31–0.81, p = 0.004] and that participants in the TGC group had a lower risk of 28-day mortality than in the PMB/TGC combination group but without statistical significance. The incidence of AKI in the PMB group (52.5%) and the PMB/TGC combination group (53.3%) was significantly higher than that in the TGC group (33.5%, p = 0.001).ConclusionThe appropriate PMB/TGC combination was not superior to appropriate PMB therapy in the treatment of HAP caused by carbapenem-resistant Enterobacteriaceae/carbapenem-resistant Acinetobacter baumannii (CRE/CRAB) in terms of 28-day mortality.

Clinical Value of Metagenomics Next-Generation Sequencing in Bronchoalveolar Lavage Fluid for Patients with Severe Hospital-Acquired Pneumonia: A Nested Case-Control Study.

BackgroundMetagenomics next-generation sequencing (mNGS) is more efficient in identifying pathogens responsible for pneumonia. However, whether these patients ultimately benefit from this improvement remains unknown.MethodsIn this retrospective, nested, case–control study, patients with severe hospital-acquired pneumonia (HAP) who had undergone mNGS of bronchoalveolar lavage fluid while in our intensive care unit from March 2017 to December 2020 (n = 33) were matched in a ratio of 1 to 2 (n = 66) by sex, age, comorbidities, immune status, Acute Physiology and Chronic Health Evaluation II score, severity of pulmonary infection, and use of extracorporeal life support with patients who had undergone conventional microbiological testing only. The primary outcome was 90-day mortality; secondary outcomes being length of intensive care unit stay, duration of mechanical ventilation support, 7-day and 28-day mortality, and efficacy of treatment of pulmonary infection.ResultsIn the CMT group, 17 patients (25.8%) had negative results, whereas only one (3.0%) had negative results in the mNGS group (P < 0.001). After receipt of microbiology results, antibiotics were altered in 23/33 patients (70.0%) in the mNGS group, but in only 29/66 (43.9%) in the CMT group (P = 0.016). Pulmonary infection-related findings improved in 20/33 patients (60.6%) in the mNGS group in the subsequent 7 days, but in only 25/66 (37.9%) in the CMT group (P = 0.032). However, the 28-day (33.3% vs 31.2%, P = 1.0) and 90-day (48.5% vs 45.5%, P = 0.78) mortality rates did not differ significantly between the two groups. These findings were supported by Cox-regression and Kaplan–Meier survival curve analyses.ConclusionmNGS is helpful in the treatment of severe HAP but does not improve medium or long-term survival rates, especially in patients with severe comorbidities.

Risk Factors and Algorithms for the Empirical Treatment of Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) continue to be major concerns for morbidity and mortality, especially in patients treated in the intensive care unit. With the rise in multidrug-resistant organisms, HAP and VAP treatment is challenged by the need for early appropriate treatment, with broad-spectrum agents, while still being aware of the principles of antibiotic stewardship. The two major society guidelines proposed a series of risk factors in their most recent guidelines to help identify patients who can most benefit from narrow- or broad-spectrum initial empiric antibiotic therapy. The guidelines reveal differences in the proposed risk factors and treatment approaches, as well as major similarities.

Cefiderocol.

Cefiderocol is a new siderophore cephalosporin with potent in vitro activity against gram-negative bacilli including Enterobacterales that produce all kinds of carbapenemases and non-fermenting Gram-negative with difficult-to-treat resistance. As a β-lactam, its efficacy is optimized in extended-per-fusion and requires dose adjustment in renal dysfunction and hyperclearance. Its efficacy has been validated in three clinical trials, one of them in the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia. The clinical trial aimed at difficult-to-treat gram-negatives achieved the clinical and microbiological target, but the increase in mortality observed in the cefiderocol arm makes it necessary to demonstrate efficacy in real clinical practice. Cefiderocol is a good option among the new β-lactams for the treatment of pneumonia caused by Gram-negative bacilli carbapenem-resistant.

Clinical Efficacy of Doripenem in Treating Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia: A Systematic Review and Meta-Analysis

This meta-analysis investigated whether the clinical efficacy of doripenem is comparable to that of alternative antibiotics for treating hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). The PubMed, Web of Science, Cochrane Library, Ovid MEDLINE, and EBSCO databases were searched for literature published before October 20, 2021. Clinical studies comparing the efficacy of doripenem with that of other antibiotics in HAP/VAP treatment were included. Primary outcomes included all-cause mortality at 28 to 30 days, whereas the secondary outcome was the clinical cure rate. In total, 5 clinical studies were included in this meta-analysis. All-cause mortality did not differ significantly between doripenem and the comparators. For VAP alone, no statistical differences were observed between doripenem and the comparators. For Pseudomonas aeruginosa-related pneumonia, mortality did not differ between doripenem and the comparators. The clinical cure rates were 60.7% and 57.3% for doripenem and the comparators, respectively; a similar trend was observed in the subgroup analysis for VAP. For HAP/VAP due to P. aeruginosa, the clinical cure rates for doripenem and the comparators did not differ. Doripenem was comparable to other antibiotics in the treatment of HAP and VAP.

1313. Disease Burden and Real-world Clinical Practice for the Treatment of Hospital-Acquired Bacterial Pneumonia Using a Japanese Large-scale Claims Database: A Retrospective Cohort Study

BackgroundWith an aging population and increasing healthcare utilization, the frequency of hospital-acquired pneumonia (HAP) is expected to increase. Since HAP is life threatening, appropriate diagnosis and treatment are required; however, large-scale Japanese data focusing on patient profiles and treatment patterns is lacking.MethodsThe demographics and treatment patterns of HAP were examined using a large-scale Japanese claims database from Jan. 2016 to Apr. 2018. The HAP population included patients who received injection antibiotics ≧3 consecutive days after admission, but not within 2 days after admission, and those whose reason for hospitalization was not pneumonia but had a diagnosis of pneumonia after hospitalization (based on ICD-10 codes).Results2,968 HAP patients (mean age 77 years, 64.9% male) contributing 2,979 total HAP episodes were included. The 12-month pre-index mean Charlson Comorbidity Index (CCI) score was 4.0±3.1 (mean±SD), CCI scores ≧4 comprised 44.0%. Most HAP episodes (77.6%) occurred ≧5 days after hospitalization. During the 12month pre-index period including outpatients, 84.9% of patients had some type of pneumonia record, 9.1% had VAP (ventilator associated pneumonia) records, and 7.4% had anti-MRSA prescription records. For post-index HAP treatment, ampicillin/sulbactam (36.4%, 8.2±3.8 days) and piperacillin/tazobactam (22.0%, 8.8±4.4 days) were frequently prescribed as the first antibiotic prescription. Ceftriaxone (19.4%) and meropenem (9.8%) were also frequently prescribed. Examinations prescribed during HAP: 30.5% blood culture tests, 28.2% sputum examinations and 29.2% urine antigen tests. The overall mortality rate of HAP in overall hospitalization post-index was 22.0%, in which 14.4% of deaths occurred within 30 days. The mean (±SD) length of overall hospital stay was 49.9 (±34.2) days (11.3 days for HAP period), with 12.4% ICU use and 17.6% ventilator use. The median total cost during hospitalization was ¥1,924,848.18 (&19,248).ConclusionThe data revealed patient characteristics, treatment patterns, mortality rates and healthcare costs in Japanese HAP patients. This database approach should prove useful for discussing antibiotics usage trends in highly aging Japan.Disclosures Masahiro Kimata, PhD, MSD K.K., Tokyo, Japan (Employee) Yosuke Aoki, MD, PhD, MSD K.K., Tokyo, Japan (Other Financial or Material Support, Honorarium for Lecturing)SHIONOGI & Co., Ltd (Grant/Research Support, Other Financial or Material Support, Honorarium for Lecturing) Adachi Noriaki, n/a, MSD K.K., Tokyo, Japan (Employee) Takeshi Akiyama, MSc, MSD K.K., Tokyo, Japan (Independent Contractor) Akiko Harada, n/a, MSD K.K., Tokyo, Japan (Employee)

Aerosolized antibiotics in the treatment of hospital-acquired pneumonia/ventilator-associated pneumonia

Aerosolized antibiotics are being increasingly used to treat respiratory infections, especially those caused by drug-resistant pathogens. Their use in the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia in critically ill patients is especially significant. They are also used as an efficient alternative to overcome the issues caused by systemic administration of antibiotics, including the occurrence of drug-resistant strains, drug toxicity, and insufficient drug concentration at the target site. However, the rationale for the use of aerosolized antibiotics is limited owing to their insufficient efficacy and the potential for underestimated risks of developing side effects. Despite the lack of availability of high-quality evidence, the use of aerosolized antibiotics is considered as an attractive alternative treatment approach, especially in patients with multidrug-resistant pathogens. In this review, we have discussed the effectiveness and side effects of aerosolized antibiotics as well as the latest advancements in this field and usage in the Republic of Korea.

Pharmacokinetics, pharmacodynamics, and safety of single- and multiple-dose intravenous ceftobiprole in healthy Chinese participants.

BackgroundCeftobiprole is a novel β-lactam cephalosporin with activity against Gram-positive and -negative bacteria. The aim of the present study was to investigate the pharmacokinetics (PK), pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerance of ceftobiprole in Chinese participants, to evaluate this dosage regimen for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) in China.MethodsThe use of ceftobiprole was investigated in a single-center, open-label, single- and multiple-dose study using 12 healthy Chinese participants (6 males and 6 females). Ceftobiprole plasma and urine concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry assay. The PK/PD characteristics of 500 mg ceftobiprole every 8 h at 1.5-, 2-, 3-, or 4-h infusion time were analyzed by Monte Carlo simulations (MCS).ResultsThe maximum plasma concentration of ceftobiprole was observed 2 h after dosage; its terminal half-life was about 3 h. Ceftobiprole was predominantly eliminated in urine, and the cumulative excretion in 24 h was >90%. There was no accumulation after multiple dosing. Both single and multiple doses were well tolerated, with no severe or serious adverse events (AEs). PK/PD analysis indicated that Staphylococcus pneumoniae (S. pneumoniae) and Staphylococcus aureus (S. aureus) were sensitive to ceftobiprole. About half of extended-spectrum β-lactamase (ESBL) non-producing Enterobacteriaceae are sensitive to ceftobiprole, according to PK/PD results of ceftobiprole. For Pseudomonas aeruginosa (P. aeruginosa), no regimen was found to be effective against strains.ConclusionsThe PK/PD results indicated that 500 mg ceftobiprole every 8 h at 2-h infusion time is expected to achieve good microbiological efficacy in the treatment of CAP and HAP in China.

Clinical Efficacy of Cefoperazone-Sulbactam versus Piperacillin-Tazobactam in the Treatment of Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia.

ObjectiveThe aim of this study was to compare the usefulness of cefoperazone-sulbactam and that of piperacillin-tazobactam in the treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).MethodsThis retrospective study included the adult patients receiving cefoperazone-sulbactam or piperacillin-tazobactam against HAP/VAP in nine hospitals in Taiwan from March 1, 2018 to May 30, 2019. Primary outcome was clinical cure rate.ResultsA total of 410 patients were enrolled. Among them, 209 patients received cefoperazone-sulbactam and 201 patients received piperacillin-tazobactam. Overall, cefoperazone-sulbactam group had similar distribution of age, sex, or SOFA scores as piperacillin-tazobactam group. However, cefoperazone-sulbactam had higher comorbidity score and disease severity than piperacillin-tazobactam group (Charlson score: 6.5 ± 2.9 vs 5.7 ± 2.7, p < 0.001; APACHE II score: 21.4 ± 6.2 vs 19.3 ± 6.0, p = 0.002). Regarding clinical outcomes, no significant difference in clinical cure and failure rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical cure rate: 80.9% vs 80.1% and clinical failure rate: 17.2% vs 18.4%, p = 0.943). Moreover, no significant difference in clinical effectiveness and ineffectiveness rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical effective rate: 80.9% vs 80.6% and clinical ineffective rate: 17.7% vs 18.9%, p = 0.711). The all-cause mortality rates of the cefoperazone-sulbactam and piperacillin-tazobactam groups were similar (23.9% vs 20.9%, p = 0.48). After adjustment of Charlson score and APACHE II score, the similarities in these clinical outcomes did not change in overall patients and patients with HAP or VAP.ConclusionFor treating adult patients with nosocomial pneumonia, cefoperazone-sulbactam was as effective as piperacillin-tazobactam.