A hypervirulent Acinetobacter baumannii strain has robust anti-phagocytosis ability.

BACKGROUND: Acinetobacter baumannii (A. baumannii) is associated with both hospital-acquired infections (HAP) and community-acquired pneumonia (CAP). In this study, we present a novel CAP-associated A. baumannii (CAP-AB) strain causing severe pneumonia in an afore healthy male patient without underlying conditions. Subsequently, we investigated the pathogenicity and immunogenicity of this CAP-AB strain using a mice pneumonia model. RESULTS: A 58-year-old male patient with no underlying conditions experienced worsening symptoms of a productive cough, sputum, and fever that developed acutely, in just 24 h. The diagnosis was severe community-acquired pneumonia (CAP) and type-1 respiratory failure. An A. baumannii strain was isolated from his sputum and blood cultures. To gain a deeper understanding of the rapid progression of its pathology, we utilized the CAP-associated A. baumannii strain YC128, a previously obtained hospital-acquired pneumonia A. baumannii (HAP-AB) strain YC156, and a highly virulent A. baumannii control strain LAC-4 to construct a mouse pneumonia model, and subsequently compared the mortality rate of the three groups. Following inoculation with 107 CFU of A. baumannii, the mortality rate for the YC128, LAC-4, and YC156 groups was 60% (6/10), 30% (3/10), and 0%, respectively. The bacterial burden within the pulmonary, liver, and spleen tissues of mice in the YC128 group was significantly higher than that of the YC156 group, and slightly higher than that of the LAC-4 group. Pathological analysis of lung tissue using HE-staining revealed that the inflammatory pathological changes in mice from the YC128 group were significantly more severe than those in the YC156 group. Additionally, CT scan images displayed more pronounced inflammation in the lungs of mice from the YC128 group compared to the YC156 group. Local levels of cytokines/chemokines such as IL-1ß, IL-6, TNF-α, and CXCL1 were assessed via RT-qPCR in lung tissues. In comparison with the YC156 strain, the highly virulent YC128 strain induced the expression of proinflammatory cytokines more rapidly and severely. Furthermore, we examined the in vitro anti-phagocytosis ability of YC128 and YC156 strains against mice peritoneal macrophages, revealing that the highly virulent YC128 isolate displayed greater resistance to macrophage uptake in contrast to YC156. Results from Whole Genome Sequencing (WGS) indicated that YC128 harbored a complete type VI secretion system (T6SS) gene cluster, while YC156 lacked the majority of genes within the T6SS gene cluster. The other virulence-related genes exhibited minimal differences between YC128 and YC156. Drawing from previous studies, we postulated that the T6SS is linked to the hypervirulence and robust anti-phagocytic ability of YC128. CONCLUSIONS: This article reports on the isolation of a novel hypervirulent CAP-AB strain, YC128, from a severe CAP patient. The results demonstrate that this CAP-AB strain, YC128, is capable of inducing fatal pneumonia and extrapulmonary dissemination in a mouse pneumonia model. Moreover, this highly virulent CAP-AB strain exhibits significantly stronger anti-phagocytic abilities compared to the HAP-AB YC156 strain. Genome sequencing comparisons reveal that the heightened hypervirulence and enhanced anti-phagocytosis abilities observed in YC128 may be attributed to the presence of the T6SS.

Tau and Aß42 in lavage fluid of pneumonia patients are associated with end-organ dysfunction: A prospective exploratory study.

BACKGROUND: Bacterial pneumonia and sepsis are both common causes of end-organ dysfunction, especially in immunocompromised and critically ill patients. Pre-clinical data demonstrate that bacterial pneumonia and sepsis elicit the production of cytotoxic tau and amyloids from pulmonary endothelial cells, which cause lung and brain injury in naïve animal subjects, independent of the primary infection. The contribution of infection-elicited cytotoxic tau and amyloids to end-organ dysfunction has not been examined in the clinical setting. We hypothesized that cytotoxic tau and amyloids are present in the bronchoalveolar lavage fluid of critically ill patients with bacterial pneumonia and that these tau/amyloids are associated with end-organ dysfunction. METHODS: Bacterial culture-positive and culture-negative mechanically ventilated patients were recruited into a prospective, exploratory observational study. Levels of tau and Aß42 in, and cytotoxicity of, the bronchoalveolar lavage fluid were measured. Cytotoxic tau and amyloid concentrations were examined in comparison with patient clinical characteristics, including measures of end-organ dysfunction. RESULTS: Tau and Aß42 were increased in culture-positive patients (n = 49) compared to culture-negative patients (n = 50), independent of the causative bacterial organism. The mean age of patients was 52.1 ± 16.72 years old in the culture-positive group and 52.78 ± 18.18 years old in the culture-negative group. Males comprised 65.3% of the culture-positive group and 56% of the culture-negative group. Caucasian culture-positive patients had increased tau, boiled tau, and Aß42 compared to both Caucasian and minority culture-negative patients. The increase in cytotoxins was most evident in males of all ages, and their presence was associated with end-organ dysfunction. CONCLUSIONS: Bacterial infection promotes the generation of cytotoxic tau and Aß42 within the lung, and these cytotoxins contribute to end-organ dysfunction among critically ill patients. This work illuminates an unappreciated mechanism of injury in critical illness.

In vitro modelling of bacterial pneumonia: a comparative analysis of widely applied complex cell culture models.

Bacterial pneumonia greatly contributes to the disease burden and mortality of lower respiratory tract infections among all age groups and risk profiles. Therefore, laboratory modelling of bacterial pneumonia remains important for elucidating the complex host-pathogen interactions and to determine drug efficacy and toxicity. In vitro cell culture enables for the creation of high-throughput, specific disease models in a tightly controlled environment. Advanced human cell culture models specifically, can bridge the research gap between the classical two-dimensional cell models and animal models. This review provides an overview of the current status of the development of complex cellular in vitro models to study bacterial pneumonia infections, with a focus on air-liquid interface models, spheroid, organoid, and lung-on-a-chip models. For the wide scale, comparative literature search, we selected six clinically highly relevant bacteria (Pseudomonas aeruginosa, Mycoplasma pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Streptococcus pneumoniae, and Staphylococcus aureus). We reviewed the cell lines that are commonly used, as well as trends and discrepancies in the methodology, ranging from cell infection parameters to assay read-outs. We also highlighted the importance of model validation and data transparency in guiding the research field towards more complex infection models.

Pseudomonas fluorescens pneumonia.

Pseudomonas fluorescens (P. fluorescens) is not generally considered a bacterial pathogen in humans; however, multiple culture-based and culture-independent studies have identified it in the indigenous microbiota of multiple body sites. We herein report a rare case of pneumonia caused by P. fluorescens. A man in his 80 s with chronic obstructive pulmonary disease and diabetes mellitus was diagnosed with stage II rectal cancer. He underwent laparoscopic surgery, and on the 6th postoperative day, he developed a high fever. Chest computed tomography revealed infiltration in the left lower lung. Gram staining of the sputum showed Gram-negative rods phagocytosed by neutrophils, suggesting postoperative nosocomial pneumonia. The patient was started on tazobactam/piperacillin, and his pneumonia quickly improved. Later, only P. fluorescens was detected in a sputum culture. It was susceptible to common antipseudomonal agents. Gram staining of P. fluorescens appears to show a slightly thicker and larger morphology in comparison to Pseudomonas aeruginosa. Although there have been reports of opportunistic infections caused by P. fluorescens in immunosuppressed patients, including those with advanced cancer, most have been bloodstream infections, with very few reports of pneumonia alone. Clinicians should be aware that patients, who are not necessarily immunosuppressed, may develop pneumonia caused by P. fluorescens.

Nursing and healthcare-associated pneumonia due to SARS-CoV-2 Omicron variant.

BACKGROUND: There were many differences in the clinical characteristics between nursing and healthcare-associated pneumonia (NHCAP) and community-acquired pneumonia (CAP) due to the SARS-CoV-2 ancestral strain, Alpha variant and Delta variant. With the replacement of the Delta variant by the Omicron variant, the Omicron variant showed decreased infectivity to lung and was less pathogenic. We investigated the clinical differences between NHCAP and CAP due to the Omicron variant. METHODS: We analyzed 516 NHCAP and 547 CAP patients with COVID-19 pneumonia. Of 516 patients with COVID-19 NHCAP, 330 cases were the Omicron variant (120 cases were BA.1, 53 cases were BA.2, and 157 cases were BA.5 subvariants) and 186 cases were non-Omicron variants. RESULTS: The median age, frequency of comorbid illness, rates of intensive care unit (ICU) stay, and mortality rate were significantly higher in Omicron patients with NHCAP than in those with CAP. Rates of ICU stay and in-hospital mortality were significantly higher in NHCAP patients with non-Omicron variants compared with those in the Omicron variant group. No clinical differences were observed in patients with NHCAP among the Omicron BA.1, BA.2, and BA.5 subvariant groups. CONCLUSIONS: The present study supported that the NHCAP category is necessary not only for bacterial pneumonia but also viral pneumonia. It is necessary to consider prevention and treatment strategies depending on the presence or absence of applicable criteria for NHCAP.

Influenza and Viral Pneumonia.

Influenza and other respiratory viruses are commonly identified in patients with community-acquired pneumonia, hospital-acquired pneumonia, and in immunocompromised patients with pneumonia. Clinically, it is difficult to differentiate viral from bacterial pneumonia. Similarly, the radiological findings of viral infection are in general nonspecific. The advent of polymerase chain reaction testing has enormously facilitated the identification of respiratory viruses, which has important implications for infection control measures and treatment. Currently, treatment options for patients with viral infection are limited but there is ongoing research on the development and clinical testing of new treatment regimens and strategies.

Which trial do we need? Combination antimicrobial therapy for hospital-acquired bacterial pneumonia caused by Pseudomonas aeruginosa.

Meropenem therapy will be open-label, while tobramycin or placebo will be administered in a double-blind fashion. The primary trial endpoint will be a composite hierarchical outcome of 1) 28-day all-cause mortality, 2) ventilator-free days, and 3) modified time to clinical stability, evaluated using a win ratio methodology (see below). Secondary trial outcomes will include frequency of safety events (acute kidney injury), resolution of circulatory shock, recurrent HABP, and emergence of meropenem resistance both during treatment and in cases of recurrent infection. Using simulation studies to inform sample size calculations, we estimate that recruitment of 130 patients per treatment arm would provide at least 80% power to detect a win ratio of 1.50 while preserving a two-sided type 1 error rate of 0.05.

Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

BACKGROUND: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation. METHODS: A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses. RESULTS: In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%--55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid. CONCLUSIONS: The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR.

Exploring the microbial landscape: uncovering the pathogens associated with community-acquired pneumonia in hospitalized patients.

Objectives: This study aimed to investigate the etiology, clinical features, and outcomes of community-acquired pneumonia (CAP) in adults. Understanding the causative pathogens is essential for effective treatment and prevention. Design: Between 2016-2018, 518 hospitalized adults with CAP and 241 controls without symptoms were prospectively enrolled. Urine samples were collected for pneumococcal urinary antigen tests and nasopharyngeal swabs for viral and bacterial analysis, combined with routine diagnostic care. Results: Among the included CAP patients, Streptococcus pneumoniae was the most common pathogen, detected in 28% of patients, followed by Haemophilus influenzae in 16%. Viruses were identified in 28%, and concurrent viruses and bacteria were detected in 15%. There was no difference in mortality, length of stay, or symptoms at hospitalization when comparing patients with bacterial, viral, or mixed etiologies. Among the control subjects without respiratory symptoms, S. pneumoniae, H. influenzae, or Moraxella catarrhalis were detected in 5-7%, and viruses in 7%. Conclusion: Streptococcus pneumoniae emerged as the predominant cause of CAP, followed closely by viruses and H. influenzae. Intriguingly, symptoms and outcome were similar regardless of etiology. These findings highlight the complexity of this respiratory infection and emphasize the importance of comprehensive diagnostic and treatment strategies.Clinical Trial Registration: ClinicalTrials.gov, identifier [NCT03606135].

Investigation of etiology of community-acquired pneumonia in hospitalized patients in a tertiary hospital of São Paulo City, Brazil.

BACKGROUND: Community-Acquired Pneumonia (CAP) is the primary cause of hospitalization in the United States and the third leading cause of death in Brazil. The gold standard for diagnosing the etiology of CAP includes blood culture, Gram-stained sputum, and sputum culture. However, these methods have low sensitivity. No studies investigating the etiology of CAP have been conducted in Brazil in the last 20-years, and the empirical choice of antimicrobials is mainly based on the IDSA guidelines. This is the first national study with this aim, and as a result, there's potential for the Brazilian consensus to be impacted and possibly modify its guidelines rather than adhering strictly to the IDSA's recommendations. METHODS: The aim of this study is to identify the main microorganisms implicated in CAP by employing a multiplex Polymerase Chain Reaction (mPCR) at the foremost public hospital in Brazil. All patients who were admitted to the emergency department and diagnosed with severe CAP underwent an mPCR panel using nasopharyngeal and oropharyngeal swabs, with the aim of detecting 13 bacterial and 21 viral pathogens. RESULTS: A total of 169 patients were enrolled in the study. The mPCR panel identified an etiological agent in 61.5% of patients, with viruses being the most common (42.01%), led by Rhinovirus, followed by Influenza and Coronavirus (non-SARS-CoV-2). Bacterial agents were identified in 34.91% of patients, with S. pneumoniae being the most common, followed by H. influenzae, M. catarrhalis, and S. aureus. Additionally, we found that the prescription for 92.3% of patients could be modified, with most changes involving de-escalation of antibiotics and antiviral therapy. CONCLUSION: Our study revealed different etiological causes of CAP than those suggested by the Brazilian guidelines. Using molecular diagnostic tests, we were able to optimize treatment by using fewer antibiotics.

Evaluation of the BioFire® FilmArray® Pneumonia plus Panel for Detecting Bacterial Etiological Agents of Lower Respiratory Tract Infections in an Oncologic Hospital. Comparison with Conventional Culture Method.

Conventional methods used to determine pneumonia pathogens are characterized by low sensitivity and long turnaround times. Introducing new tests with better parameters in patients at higher risk of infections is highly anticipated. The results of the conventional quantitative culture method (CM) in determining the bacterial etiology of pneumonia were compared with the results of the Pneumonia plus Panel test (PNP; BioFire® Diagnostics, USA) in 79 samples of bronchoalveolar lavage (BAL). Materials were collected from 79 patients with suspected pneumonia treated in an oncologic hospital due to solid tumors. Only 16/79 BAL samples (20.3%) were true positive (TP) for bacterial etiology in CM vs. 27/79 samples (34.2%) true positive in the PNP test. The total agreement between methods of interpreting the result (positive or negative) was 84.8%. The most prevalent pathogens in both methods were Staphylococcus aureus, followed by Escherichia coli, Pseudomonas aeruginosa, and Haemophilus influenzae. The PNP test identified several respiratory pathogens that were not grown in culture. The semiquantitative value reported by the PNP test was higher than that reported by culture. The PNP test vs. combined test (PNP test and CM methods) demonstrated positive predictive value (PPV) and negative predictive value (NPV) values of 100.0% and 98.1%, and the sensitivity and specificity were 96.4% and 100.0%. The PNP test is a good tool for determining the etiology of bacterial pneumonia and may support the care of an oncologic patient. However, further large-sample studies are needed to research in strictly defined groups of oncologic patients.

Monoclonal antibodies against lipopolysaccharide protect against Pseudomonas aeruginosa challenge in mice.

Pseudomonas aeruginosa is a common cause of hospital-acquired infections, including central line-associated bloodstream infections and ventilator-associated pneumonia. Unfortunately, effective control of these infections can be difficult, in part due to the prevalence of multi-drug resistant strains of P. aeruginosa. There remains a need for novel therapeutic interventions against P. aeruginosa, and the use of monoclonal antibodies (mAb) is a promising alternative strategy to current standard of care treatments such as antibiotics. To develop mAbs against P. aeruginosa, we utilized ammonium metavanadate, which induces cell envelope stress responses and upregulates polysaccharide expression. Mice were immunized with P. aeruginosa grown with ammonium metavanadate and we developed two IgG2b mAbs, WVDC-0357 and WVDC-0496, directed against the O-antigen lipopolysaccharide of P. aeruginosa. Functional assays revealed that WVDC-0357 and WVDC-0496 directly reduced the viability of P. aeruginosa and mediated bacterial agglutination. In a lethal sepsis model of infection, prophylactic treatment of mice with WVDC-0357 and WVDC-0496 at doses as low as 15 mg/kg conferred 100% survival against challenge. In both sepsis and acute pneumonia models of infection, treatment with WVDC-0357 and WVDC-0496 significantly reduced bacterial burden and inflammatory cytokine production post-challenge. Furthermore, histopathological examination of the lungs revealed that WVDC-0357 and WVDC-0496 reduced inflammatory cell infiltration. Overall, our results indicate that mAbs directed against lipopolysaccharide are a promising therapy for the treatment and prevention of P. aeruginosa infections.

Changes in the prevalence of pathogens causing hospital-acquired bacterial pneumonia and the impact of their antimicrobial resistance patterns on clinical outcomes: A propensity-score-matched study.

BACKGROUND: This study aimed to evaluate changes in the prevalence of pathogens causing hospital-acquired bacterial pneumonia (HABP) and their antimicrobial resistance patterns in recent years, and to identify risk factors for 28-day all-cause mortality (ACM) in patients with HABP. METHODS: A propensity-score-matched study was performed by randomly allocating patients with ventilator-associated and non-ventilator-associated bacterial pneumonia admitted to two university hospitals between 2011 and 2021. RESULTS: In total, 17,250 patients with HABP were enrolled. The annual incidence of Staphylococcus aureus HABP decreased during the study period, while that of Klebsiella pneumoniae HABP increased significantly each year. Over the same period, the resistance rate of S. aureus to methicillin decreased from 88.4% to 64.4%, while the non-susceptibility rate of K. pneumoniae to carbapenems increased from 0% to 38%. HABP caused by A. baumannii [adjusted odds ratio (aOR) 1.50, 95% confidence interval (CI) 1.25-1.79], K. pneumoniae (aOR 1.28, 95% CI 1.16-1.40) and Stenotrophomonas maltophilia (aOR 1.32, 95% CI 1.05-1.66) was a risk factor for 28-day ACM. Patients with HABP caused by methicillin-resistant S. aureus and carbapenem-non-susceptible A. baumannii or K. pneumoniae had a significantly lower probability of survival. HABP with preceding coronavirus disease 2019 (COVID-19) was associated with high 28-day ACM (aOR 5.40, 955 CI 3.03-9.64) and high incidence of bacteraemic pneumonia (aOR 40.55, 95% CI 5.26-312.79). CONCLUSIONS: This study showed shifting trends in HABP-causing pathogens in terms of annual incidence and resistance rates to major therapeutic antimicrobial agents. HABP-causing bacterial pathogens, their antimicrobial resistance phenotypes, and preceding COVID-19 were significantly associated with progression of HABP to bloodstream infection and 28-day ACM in infected patients.

Validation of JRS atypical pneumonia score in patients with community-acquired Chlamydia psittaci pneumonia.

INTRODUCTION: The Japanese Respiratory Society (JRS) atypical pneumonia score is a useful tool for the rapid presumptive diagnosis of atypical pneumonia. We investigated the clinical features of community-acquired pneumonia (CAP) due to Chlamydia psittaci and validated the JRS atypical pneumonia score in patients with C. psittaci CAP. METHODS: This study was conducted at 30 institutions and assessed a total of 72 sporadic cases with C. psittaci CAP, 412 cases with Mycoplasma pneumoniae CAP, and 576 cases with Streptococcus pneumoniae CAP. RESULTS: Sixty-two of 72 patients with C. psittaci CAP had a history of avian exposure. Among the six parameters of the JRS score, matching rates of four parameters were significantly lower in the C. psittaci CAP than the M. pneumoniae CAP in the following parameters: age <60 years, no or minor comorbid illness, stubborn or paroxysmal cough, and absence of chest adventitious sounds. The sensitivity of the diagnosis of atypical pneumonia in patients with C. psittaci CAP was significantly lower than the M. pneumoniae CAP (65.3% and 87.4%, p < 0.0001). When the diagnostic sensitivity was analyzed for different ages, the diagnostic sensitivities for the C. psittaci CAP were 90.5% for non-elderly patients and 30.0% for elderly patients. CONCLUSIONS: The JRS atypical pneumonia score is a useful tool for distinguishing between C. psittaci CAP and bacterial CAP in patients aged <60 years, but not in patients aged ≥60 years. A history of avian exposure in middle-aged patients with normal white blood cell count may be suggestive of C. psittaci pneumonia.

Childhood Pneumonia: What's Unchanged, and What's New?

Childhood pneumonia is still a significant clinical and public health problem. India contributes the highest number of deaths due to pneumonia, accounts for about 20% of global mortality among under five children. Various etiologic agents including bacteria, viruses and atypical organism are responsible for childhood pneumonia. Recent studies suggest that viruses are one of the major causes of childhood pneumonia. Among viruses, respiratory syncytial virus has got great attention and several recent studies are reporting it as an important organism for pneumonia. Lack of exclusive breast feeding during first six months, improper timing of start and content of complimentary feeding, anemia, undernutrition, indoor pollution due to tobacco smoking and use of coal and wood for cooking food and lack of vaccinations are important risk factors. X-ray chest is not routinely performed to diagnose pneumonia while use of lung ultrasound is increasing to detect consolidation, pleural effusion, pneumothorax and pulmonary edema (interstitial syndrome). Role of C-reactive protein (CRP) and procalcitonin is similar, to differentiate between viral and bacterial pneumonia, however duration of antibiotics is better guided by procalcitonin. Newer biomarkers like IL-6, presepsin and triggering receptor expressed on myeloid cells 1 are needed to be evaluated for their use in children. Hypoxia is significantly associated with childhood pneumonia. Therefore, use of pulse oximetry should be encouraged for early detection and prompt treatment of hypoxia to prevent adverse outcomes. Among the available tools for risk of mortality assessment in children due to pneumonia, PREPARE score is the best but external validation will be needed.

Optimizing antibiotic dosing regimens for nosocomial pneumonia: a window of opportunity for pharmacokinetic and pharmacodynamic modeling.

INTRODUCTION: Determining antibiotic exposure in the lung and the threshold(s) needed for effective antibacterial killing is paramount during development of new antibiotics for the treatment of nosocomial pneumonia, as these exposures directly affect clinical outcomes and resistance development. The use of pharmacokinetic and pharmacodynamic modeling is recommended by regulatory agencies to evaluate antibiotic pulmonary exposure and optimize dosage regimen selection. This process has been implemented in newer antibiotic development. AREAS COVERED: This review will discuss the basis for conducting pharmacokinetic and pharmacodynamic studies to support dosage regimen selection and optimization for the treatment of nosocomial pneumonia. Pharmacokinetic/pharmacodynamic data that supported recent hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia indications for ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol will be reviewed. EXPERT OPINION: Optimal drug development requires the integration of preclinical pharmacodynamic studies, healthy volunteers and ideally patient bronchoalveolar lavage pharmacokinetic studies, Monte-Carlo simulation, and clinical trials. Currently, plasma exposure has been successfully used as a surrogate for lung exposure threshold. Future studies are needed to identify the value of lung pharmacodynamic thresholds in nosocomial pneumonia antibiotic dosage optimization.