### Diagnosis An infection in the lung. Accurately diagnosing [[pneumonia]] is problematic as individual signs and symptoms are often neither sensitive or specific. The best are > "egophony (LR+ = 6.17, 95% CI = 1.34 to 18.0), dullness to percussion (LR+ = 2.62, 95% CI = 1.14 to 5.30)," and fever. [^1] I will note as I have retired and have been a patient, as well as taking my mother to the doctor, that physical exam skills really stink. I have never seen nor received so many half-assed, perfunctory cardiopulmonary exams that serve no diagnostic purpose but are, I suspect, only done to boost billing codes. Besides blood and sputum cultures, there are a variety of diagnostic tests depending on which pathogen is a concern. Gram stains have always been questionable for making a diagnosis, but I can't give them up. For CAP: > "Gram stain of sputum samples was useful in guiding the microbiological diagnosis of CAP in 23% of patients. The Gram stain and culture of sputum samples obtained from patients who have received antibiotic treatment was unreliable. The presence of gram-positive diplococci and gram-negative coccobacilli was highly specific for the culture of S. pneumoniae and H. influenzae, respectively." [^2] > "SGS was highly specific to diagnose S. pneumoniae and H. influenzae infections in patients with CAP. With good- quality specimens, SGS can provide clinically actionable information for pathogen-directed antibiotic therapies." [^3] vs > "In a meta-analysis examining respiratory specimen Gram stain for diagnosis of ventilator-associated [[pneumonia]], absence of bacteria on Gram stain had a high negative predictive value, but a positive Gram stain correlated poorly with organisms recovered in culture." [^4] Guidelines say do sputum culture in patients with severe disease as well as in all inpatients empirically treated for MRSA or *P*. *aeruginosa*. Blood culture recommended in patients with severe disease as well as in all inpatients empirically treated for MRSA or *P*. *aeruginosa*. My take? A quality sputum gram stain is one of many pieces of information needed to determine what the cause of the [[pneumonia]] is/might be. I tend not to think in terms of VAP, HAP, CAP which are CRAP (except you should follow the treatment guidelines). I think of pneumonias as differentiated by risks, CXR pattern, gram stain, and culture. A sputum culture is no worse than a BAL for a microbiologic diagnosis. [^5] 30% of patients with clinical CAP and a negative CXR will have a positive CT. [^6] Are we going to CT everyone? Nope. But it is important to remember the limitations of some studies. > "...a CXR has no diagnostic value in patients without respiratory signs or symptoms, if a reliable medical history can be obtained." [^7] But a bedside ultrasound may be the way to go. [^8] If I were younger I would have learned the technique. *[[Legionella]]* and Pneumococcal urine antigens are often routinely ordered, but guidelines suggest only if a severe disease or risk. > "A total of 474 episodes of CAP were included. [[Streptococcus]] pneumoniae was the causative pathogen in 171 cases (36.1%). It was detected exclusively by urinary antigen test in 75 cases (43.8%). Sixty-nine patients had CAP caused by a pathogen other than S pneumoniae. Specificity was 96%, positive predictive value ranged from 88.8% to 96.5%, and the positive likelihood ratio ranged from 14.6 to 19.9." [^9] So not a bad test. And it may allow you to narrow antibiotics. HAHAHAHAHAHAHAHAHA. Like anyone does that when the cultures come back. I kill me. The Pneumococcal antigen can be positive for a prolonged time after disease: > "18 (52.9%) of the 34 patients in the first month after [[pneumonia]] diagnosis. In 12 of these positive cases, the test was still positive in the second month, in six patients after 4 months, and in two cases 6 months after the diagnosis of [[pneumonia]]." [^10] While the guidelines suggest *[[Legionella]]* and Pneumococcal antigen on everyone, they have low yield: > "Recommended indications for SP and LP urinary antigen testing in the IDSA/ATS CAP guidelines have poor sensitivity and specificity for identifying patients with positive tests...No clinical characteristics were strongly associated with positive SP UATs, while features associated with positive LP UATs were hyponatremia, fever, [[diarrhea]], and recent travel." [^11] And then there are these respiratory panels; mostly used in the ICU. Admit?  Use the CURB 65 Score - One point each: - Confusion of new onset (defined as an AMTS of 8 or less) - Blood Urea nitrogen greater than 7 mmol/l (19 mg/dL) - Respiratory rate of 30 breaths per minute or greater - Blood pressure less than 90 mmHg systolic or diastolic blood pressure 60 mmHg or less - Age 65 or older Mortality goes up with the score: - 0---0.6% - 1---2.7% - 2---6.8% - 3---14.0% - 4---27.8% - 5---27.8% Disposition - 0-1: Treat as an outpatient - 2: Consider a short stay in hospital or watch very closely as an outpatient - 3-5: Requires hospitalization  ### Epidemiologic Risks So many variations, depending on the organism, the host, and the exposures. PPI's are a risk in the first month after starting them, he says with a tortured sentence structure. [^12] In the elderly, the use of antipsychotics increases the risk of CAP in a dose-dependent manner. [^13] I am glad MY voices tell me good things. Post-obstructive [[pneumonia]] may be more common; it tends to be slow in onset and have a cavity. [^14] *[[Legionella]]* and *Mycoplasma* *pneumoniae* infections increase when it is humid and in the week following thunderstorms. [^15] Multiple studies have demonstrated that *[[Legionella]]* rates go up after rains. [^16] Drowning. 90% aspirate and when cultured grow *[[Aeromonas]]* species > *[[Staphylococcus]]* *aureus* > *[[Pseudomonas]]* species = *[[Haemophilus]]* *influenzae* > *[[Streptococcus]]* *pneumoniae*, Klebsiiella *pneumoniae*, *[[Enterobacter]]* *cloacae*, *Acinetobacter* species, and *Stenotrophomonas* *maltophilia*. [^17] Environmental disasters spew soil pathogens into the air for people to inhale.  For example, after tornadoes, *[[Alcaligenes]]* *xylosoxidans*, *[[Burkholderia]]* species, *[[Aspergillus]]*, *[[Pseudomonas]]* *putida*, and *[[Enterobacter]]* *aerogenes* are found in patients with [[pneumonia]] after a tornado. [^18] Curiously, obesity is protective for survival. [^19] Prescription opiates increase risk. [^20] Any opiates as well. Over 40% of patients with CAP will have undiagnosed diabetes or pre-diabetes. [^21] When you give the patient with CHF antibiotics for their CHF, you are doing harm: > "ADHF patients who received IVAB without evidence of infection had longer lengths of stay, required more diuretics, and were more likely to be readmitted compared with ADHF patients not exposed to IVAB." [^22] ### Microbiology The lung does have a low-density microbiome that can be altered in disease. [^23] If stool transplant is barf-o-genic, wait until they try sputum transplants. 50% of the time we get no diagnosis and the cause has changed over the decades. For example, *Pneumococcus* has become uncommon for a variety of reasons, going from 90% of cases to 10%. [^24] As the French say, the more things change, the more things change. Common causes include( I bet as PCR is more widely used this list will change [^26] [^27] ): **Viral** [^25] Influenza, RSV, [[adenovirus]], picornaviruses, and coronaviruses. Rhinovirus is the most common isolated in a 2015 NEJM review. [^28] Mimivirus, a virus so damn big -- 3rd biggest ever -- it can be seen as gram-positive cocci. Really. ( [^29] [^30] 25% of patients will have a mixed viral/bacterial cause and may have an increased death rate. [^31] And about 40% of those being admitted with a viral cause will get a bacterial super-infection, usually, but not always, with S. pneumoniae. [^32] In one adult cohort, the viral cause of [[pneumonia]] as Respiratory Syncytial virus 6.1%, Human metapneumovirus 4.5% patients, and influenza in 6.5% of patients. [^33] There are always new pathogens cropping up, be it SARS in Asia or coronavirus a Saudi Arabia. [^34] One day a new pathogen will arise and sweep the world killing us all. Written before [[COVID]] or bird flu. > "Clinical manifestations of human metapneumovirus [[pneumonia]] include high fever, wheezing in 43%, and respiratory failure in 31% of patients. An elevated number of white blood cells as well as increased levels of C-reactive protein, creatine phosphokinase, and both aspartate and alanine transaminases." [^35] **Bacterial** S. [[pneumonia]] is still number one. At least 13.5% of patients with invasive disease will have some sort of hypogammaglobulinemia. [^36] Other bacteria, in alphabetical order, include *Actinomycosis*, *C*. *[[pneumonia]]*, *C*. *psittaci*, *[[Coxiella]]* *burnetti*, *K*. *[[pneumonia]]*, *[[Legionella]]* spp (probably under-diagnosed; PCR if used routinely can markedly increase the diagnosis, in one study it was from 1 in 9 to 1 in 20 cases of [[pneumonia]] [^38], *Mycobacterium* spp, *Mycoplasma* *pneumoniae*, *Nocardia* spp, *P*. *aeruginosa*, *S*. *aureus* (for CAP, MRSA accounts for only 2.5% of causative organisms). [^37] Maybe normal flora: > "The novel finding in this study is that bacteria that are gener- ally reported as NRF appears to play a causative role in 25.8% of cases of CAP. In 17.5% of adults hospitalized for CAP who provided a high-quality sputum, [[pneumonia]] appeared to be caused by NRF alone and, in 8.3%, by coinfection with NRF and a respiratory virus. In an additional 19.1% of patients whose sputum yielded RBP, coinfection with NRF may have played a contributory role..." [^39] When the CXR shows patchy infiltrates, dry cough, and the sputum has WBC but no organisms seen, think atypical and when you think atypical, think *[[Legionella]]*. Think *[[Legionella]]* if low sodium (under 133) low platelets (under 177K) and elevated LDH (over 225). [^40] Going to use a procalcitonin? Think again: > "sensitivity and specificity of serum procalcitonin were 0.55 (95% confidence interval [CI], .37-.71; I2 = 95.5%) and 0.76 (95% CI, .62-.86; I2 = 94.1%), respectively. Thus, a procalcitonin level is unlikely to provide reliable evidence either to mandate administration of antibiotics or to enable withholding such treatment in patients with CAP. [^42] More like amateur-calcitonin, am I right? Most of the time ESBL *E*. *coli* and *K*. *[[pneumonia]]* in ventilated patients are colonization but when found in infection-related ventilator-associated events it doesn't stop the use of unneeded carbapenems. [^41] But. > "E. coli [[pneumonia]] isolates from critically ill patients indicate that they belong to the extraintestinal pathogenic E. coli pathovar but have distinguishable lung-specific traits." [^43] *Acinetobacter*, usually a hospital-acquired pathogen, can cause community-acquired [[pneumonia]], associated with poor hosts (they serve Bud light) and warm, wet environments. [^44] When should you worry about MRSA as a cause of CAP? Probably never. *S*. *aureus* causes less than 2% of community-acquired [[pneumonia]] (except as a complication of influenza), yet 30% of patients get put on anti-Staphylococcal antibiotics. Go figure. > "MRSA [[pneumonia]] was observed more frequently in patients with a previous history of MRSA infection (OR = 6.05; P < 0.001), a PSI score ≥120 (OR = 2.40; P = 0.015), intravenous antibiotic treatment within 30 days of [[pneumonia]] (OR = 2.23; P = 0.018)." [^45] A negative nares for MRSA had a high specificity and negative predictive value (almost 100%) for ruling out MRSA [[pneumonia]], particularly for CAP/HCAP. [^46] So MRSA nasal negative? Don't give [[vancomycin]]. If the cultures and nasal swab are negative for MRSA it is reasonable to stop antibiotics. [^47] This is especially true for HAP/ VAP. [^48] Intubation, tracheotomy, and 2 bronchoscopies increase the risk of pneumococcal [[pneumonia]]. [^49] Around 14% will be co-infected with bacteria and a virus; they do poorly. [^50] **Parasite** Usually as part of a Loeffler's syndrome as worms pass through the lung often with eosinophilia. Roundworms *[[Ascaris]]* *lumbricoides*, *Strongyloides* *stercoralis*, and hookworms *[[Ancylostoma]]* *duodenale* and *Necator* *americanus*, *Trichinella* *spiralis* and Schistosomiasis. **Fungal** *[[Aspergillus]]*, *Coccidiomycosis*, *[[Cryptococcus]]*, *Histoplasma*, and *PJP*. In one series, 12% of VAPs were due to *[[Aspergillus]]*. [^51] In the non-neutropenic ICU patients, respiratory cultures have 50% sensitivity (50%) and 20%--70% specificity. Perhaps the galactomannan in bronchoalveolar lavage fluid specimens may be the way to go. A negative galactomannan in high-risk hematology patients probably excludes invasive *[[Aspergillus]]* in the ICU. [^52] *[[Candida]]* almost NEVER causes [[pneumonia]] and can almost always be ignored, even in a BAL. > "We concede, by the present data, that it is convincingly proven that [[Candida]] species are at most a very rare cause of [[pneumonia]]." [^53] with 0.07% of positive BAL's will actually be the real *[[Candida]]* deal. Like most fungal infections, the diagnosis is slow to be made as people do not consider it, even in endemic areas. [^54]Take a damn exposure history and know what is in your community. **Community-Acquired Lobar ('typical') [[Pneumonia]]** *S*. *[[pneumonia]]* isstill number one, patients with this disease have a marked increased risk for acute MI, CHF, and arrhythmia. [^55] *K*. *[[pneumonia]]* (especially ETOH abusers), *[[Legionella]]* spp., *S*. *aureus* (after influenza or other viral URI; always suspect R sided [[endocarditis]] when there is *S*. *aureus* in the sputum). In one study they found an etiology in 90% of patients, with *S*. *[[pneumonia]]* in combination with a virus about 25% of the time. [^56] **Post Influenza** *S*. *[[pneumonia]]*, *[[Haemophilus]]* *influenza*, and *S*. *aureus*. In 2007 MRSA was the most common post influenza [[pneumonia]]. [^57] **Community-Acquired Interstitial ('atypical') [[Pneumonia]]** *C*. *[[pneumonia]]*, *C*. *psittaci*, *[[Coccidioides]]* *immitis* (29% of people presenting with [[pneumonia]] in Arizona had cocci) *[[Coxiella]]* *burnetti*, *Mycoplasma* *pneumoniae*, *[[Legionella]]* spp (is increased shortly after hot, humid, thundershower weather), Influenza, PJP. **Aspiration [[Pneumonia]]** If rasty dentition (i.e. no WAY would you kiss that person) and chronic loss of consciousness from drugs, ETOH, seizures or trauma) then anaerobes and *Streptococci*. They usually present as chronic lung abscess and [[empyema]]. People with good dentition (i.e. kissable) do not have a big load of anaerobes in their mouth. If the patient has no teeth, they have no anaerobes. Repeat that last sentence until you understand it. And if a toothless person has an anaerobic lung abscess, they likely have a tumor in their airway. Most other aspirations are chemical and do not require antibiotics, but try to stop anyone from giving them. Can't do it.  Seriously.  An aspiration event is not not not not an aspiration [[pneumonia]] and whether community, hospital or ventilator no study or guideline that I can find nothing suggesting that anaerobes are important in acute aspiration events; anaerobes are never isolated. Treating anaerobes because of an acute aspiration event is so stupid it makes my teeth hurt. See the Rant of Lung Abscess for more. The 2019 NEJM review on aspiration is horrible and I think totally doesn't get it. Ignore it. And that ain't my opinion, it's backed by SCIENCE [^58]: > "Prophylactic antimicrobial therapy for patients with acute aspiration pneumonitis does not offer clinical benefit and may generate antibiotic selective pressures that results in the need for escalation of antibiotic therapy among those who develop aspiration [[pneumonia]]." [^59] As per the guidelines: > "We suggest not routinely adding anaerobic coverage for suspected aspiration [[pneumonia]] unless lung abscess or [[empyema]] is suspected". Which is kind of stupid with the suspected. What, you don't have a CXR to help you see the lung abscess and [[empyema]]? **Cavitary [[Pneumonia]]** Mixed anaerobes PLUS *Streptococci* (lung abscess), *S*. *aureus*, *Mycobacterium* (Tb and atypical), *Actinomycosis*, *Nocardia*, *[[Aspergillus]]*, *Mucormycosis*, *Coccidiomycosis*, *[[Cryptococcus]]*, *Histoplasma*, PJP (on inhaled [[Pentamidine]]. Yeah, we did that in the bad old days of [[AIDS]]). **Miliary**. Usually, think TB, remember that miliary disease is often due to hematogenous spread of organisms that lodge in the interstitium of the lung and multiply. Many pathogens can cause a miliary pattern, [^60] and since the disease is not in the alveoli, sputum and bronchoscopy will not get the diagnosis. You need a biopsy. **Hospital-Acquired or Ventilator Acquired [[Pneumonia]]** Mostly gram-negative rods of the *[[Pseudomonas]]* variety or *S*. *aureus* (especially if a tracheostomy). Occasionally *[[Legionella]]* spp. NOT anaerobes. Ever. So quit using [[metronidazole]]. About a third are due to viruses, mostly rhinovirus and metapneumovirus. **Immunoincompetent** [[Cytomegalovirus]], PJP, *Nocardia*, *Mycobacterium* (Tb and atypical), *[[Aspergillus]]*, *Mucormycosis* are added to the list that includes all the above. The occasional asymptomatic nodule, often on PET scan, due to NMTB. As the title says > "Surgical resection is sufficient for incidentally discovered solitary pulmonary nodule caused by nontuberculous mycobacteria in asymptomatic patients." [^61] ### Empiric Therapy One presumes you have taken a careful risk, travel and exposure history. Oh, I know you didn't. But humor me. Then you have categorized the [[pneumonia]] pattern and, pending cultures, you embark of a course of antibiotics. What follows is from the IDSA Guidelines 2019. [^62] Follow the guidelines and make sure they are not updated. When compared to patients who do not receive antibiotics as recommended by the guidelines, those who get therapy by the IDSA have decreased 48 hour [^63] and long term mortality. [^64] AKA they died. Home or admit? To decide, use the [[pneumonia]] severity index. You really should use the calculator, it will improve care and survival. [^65] [Here is an online severity index calculator](https://www.mdcalc.com/calc/33/psi-port-score-[[pneumonia]]-severity-index-cap). Do not forget the vaccines at discharge; everyone does but it works. By the way, if the patient is getting better, they only need one CXR. [^66] As you read the recommendations remember in systemic reviews, for all CAP inpatient/outpatient disease, given as monotherapy or in combination with a beta-lactam, a quinolone leads to more clinical cure than macrolide for all kinds of [[pneumonia]]. [^67] BUT. [[Azithromycin]] and other macrolides with a beta-lactam demonstrated decreased mortality when the cause is *Pneumococcus*, and *Pneumococcus* is the most common cause of CAP. BUT, for all patients, monotherapy with a beta-lactam is non-inferior and maybe better. [^68] Specific examples follow. From the IDSA guidelines: #### Outpatient treatment **Treatment of CAP in healthy outpatients** No co-morbidities and no recent antibiotics: A macrolide OR [[doxycycline]]). Recent antibiotics: [[moxifloxacin]], [[levofloxacin]], or gemifloxacin alone, [[erythromycin]]), [[Azithromycin]], or [[clarithromycin]] PLUS high-dose [[amoxicillin]] OR [[erythromycin]]), [[Azithromycin]], or [[clarithromycin]] PLUS high-dose [[amoxicillin]]./clavulanate. Recent antibiotics: [[moxifloxacin]], [[levofloxacin]], gemifloxacin alone OR [[erythromycin]]), [[Azithromycin]], [[clarithromycin]] PLUS a beta-lactam. Suspected aspiration with infection: [[amoxicillin]]-clavulanate OR [[clarithromycin]]. I prefer [[amoxicillin]] OR a third-generation cephalosporin PLUS [[metronidazole]]. Post Influenza with bacterial superinfection: (third-generation cephalosporins OR penicillin/beta-lactamase inhibitors PLUS [[vancomycin]]) OR [[moxifloxacin]], [[levofloxacin]], or gemifloxacin. How long to treat? Shorter is better than longer, recent studies with a long-acting [[Azithromycin]] [^84] suggest a single dose will do. Usually, it is 5,7,10 or 14, based on the number of fingers we have or the number of days in the week. I think if we had 8 fingers and 12 day weeks, then patients would be getting some multiple of 8 and 12 days of therapy. [^85] For uncomplicated CAP, 5 days suffice, and maybe even 3 days total. [^86] And, as should come to no surprise to anyone, patients are more adherent with their compliance (or is it compliant with their adherence?) if given a once a day antibiotic. [^87] Depending on the population, up to 66% of *Mycoplasma* *pneumoniae*, can be macrolide-resistant. A macrolide twice daily, but only if local pneumococcal resistance to macrolides is estimated to be <25%. The overall prevalence of pneumococcal macrolide resistance in the United States is estimated to be >30%. Sometimes guidelines suggest not getting cultures. But how are you to know what the prevalence of resistance is if you don't do culture? **Among patients with significant comorbid chronic illness** Co-morbidities (COPD, Diabetes, Renal or Congestive Heart Failure, or Malignancy) No recent antibiotics: [[erythromycin]]), [[Azithromycin]], [[clarithromycin]] OR [[moxifloxacin]], [[levofloxacin]], or gemifloxacin. But [[doxycycline]]) use is associated with decreased mortality if they have *Pneumococcus*. [^69]  Except if you are really worried about *Mycoplasma* *[[pneumonia]]*: Resistance to macrolides can be as high at 69% (but may make no difference in outcome) in some series and is associated with a prolonged fever if you use a macrolide. Go figure. Treat a patient with an antibiotic that does not work and the patient doesn't do as well. Presence of co-morbidities such as chronic heart, lung, liver or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; or use of antimicrobials within the previous 3 months (in which case an alternative from a different class should be selected. A beta-lactam plus a macrolide. I was always a fan of the immunomodulating effects of macrolides as well as their suppression of virulence factors ie protein, although the data is thin. This is the best option. In a meta-analysis, >"...macrolide-based regimens were associated with a significant 22% reduction in mortality compared with non macrolides; however, this benefit did not extend to patients studied in RCTs or patients that received guideline-concordant antibiotics. Our findings suggest guideline concordance is more important than choice of antibiotic when treating CAP." [^70] Of course, there is Newton's second law of medical literature.  For every study there is an equal and opposite study: >"Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was non-inferior to strategies with a beta-lactam--macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality." [^71] [^72] But: [[clarithromycin]] for acute exacerbations of chronic obstructive pulmonary disease or community-acquired [[pneumonia]] may be associated with increased cardiovascular events. Damned if you do, damned if you do. OR A respiratory quinolone aka not ciprofloxicin. And who knew quinolones could breathe? And you can give the quinolone po with no change in outcome. [^74] And if there is invasive *Pneumococcal* disease, the use of [[levofloxacin]] when resistant has increased mortality. [^75] > In regions with a high rate of infection with high-level (mic > 16 mg/mL) macrolide-resistant [[Streptococcus]] pneumoniae, consider the use of alternative agents listed above in (2) for patients without co-morbidities. #### Inpatients, non-ICU treatment As of 2019, the concept of healthcare-associated [[pneumonia]] was abandoned in place of > "Emphasis on local epidemiology and validated risk factors to determine need for MRSA or P. aeruginosa coverage. Increased emphasis on de-escalation of treatment if cultures are negative." About time. It was a stupid concept and led to the overuse of antibiotics. A beta-lactam plus a macrolide. I think this is definitely the best option and the data all point to a decrease in mortality with the combination, especially if bacteremia, and who can predict bacteremia upfront? [^76] [^77] [^78] [[Doxycycline]] may be equal to the quinolone, [^79] but it is not in the guidelines. There is a suggestion, not statistically significant (which like as not means it is not real as p was 0.06 and a real significant result should be 0.005, not 0.05 ([5 out of 4 Americans Do Not Understand Statistics](https://sciencebasedmedicine.org/5-out-of-4-americans-do-not-understand-statistics/))), that giving the macrolide first decreases mortality. [^80] I really doubt it but the literature is what it is. Or go with a respiratory quinolone. Of interest, using a quinolone may be more likely to select for subsequent resistant organisms. [^81] I increasingly think of quinolones as evil, since most evil is accomplished by those that think they are doing good. No recent antibiotics: [[moxifloxacin]], [[levofloxacin]], or gemifloxacin alone OR [[erythromycin]]), [[Azithromycin]], [[clarithromycin]] PLUS [[cefotaxime]] or [[ceftriaxone]]. I REALLY preferred the macrolide/beta-lactam combination, as do the guidleines. It probably decreases mortality. [^83] A meta-analysis [^88] suggests it is a waste of time to cover atypicals, but several studies have demonstrated combination therapy with a macrolide increases survival of patients with pneumococcal bacteremia. [^89] What kills people is the *Pneumococcus*, not the 'atypicals'. Usually. Some epidemiologic studies suggest that CAP mortality doubles if treatment for atypical pathogens is not given. [^90] Recent antibiotics: [[erythromycin]]), [[Azithromycin]], [[clarithromycin]] PLUS cefotaximeor [[ceftriaxone]] or [[moxifloxacin]], [[levofloxacin]], alone (regimen selected will depend on the nature of recent antibiotics). Suspected aspiration with infection: [[amoxicillin]]-clavulanate OR [[clarithromycin]] o rpenicillin/beta-lactamase inhibitors. I preferred [[amoxicillin]] OR  third-generation cephalosporins PLUS [[metronidazole]]). MRSA [[pneumonia]]: with [[vancomycin]] push the trough to 15 mcg/ml. Whether this is of benefit is questionable [^91] and whether one should add [[rifampin]]or change to another agent is unknown. Is [[linezolid]] superior to [[vancomycin]]? Data keeps going back and forth with a 2010 meta-analysis suggesting they are equally a piece of crap. [^92] As of 2012, the preponderance of data and the best clinical trial point to the slight superiority of [[linezolid]] for MRSA [[pneumonia]] with 10% higher cure rate but a similar 60 day mortality. [^94] But then a 2014 review suggests they are equal. [^95] Sigh. The trend suggests [[linezolid]] for [[pneumonia]] [^96] and the better outcomes may be due to suppression of toxins, at least in the mouse model. [^97]  Although not supported by data, I tend towards [[linezolid]] when the mic to [[vancomycin]] is >= 1.0, but I am hesitant for bacteremic MRSA infections off all sorts.  For patients that are STS, I have been giving ceftaroline and either [[clindamycin]] or [[linezolid]] based on a hope and a prayer, which is something for an atheist. How long to treat CAP? Shorter is better than longer, recent studies with a long-acting [[Azithromycin]] suggest a single dose will do. Usually, it is 5,7,10 or 14, mostly based on the number of fingers we have or the number of days in the week. I think if we had 8 fingers and 12 day weeks, that would determine most of the duration of antibiotic therapy. That being said, for CAP that is doing well clinically (afebrile, WBC normal, etc) 3 or 4 days of antibiotics is all that is needed, so saith the guidelines. Even severe CAP probably only needs 7 days of therapy. [^100] Five days likely sufficient for most non-ventilator hospital-acquired [[pneumonia]]. Despite the guidelines that suggest 5 days is all most people need, at least 70% will get an extended duration they do not need. How long. 10 days of course. People just can't resist the allure of counting fingers and basing the antibiotic duration on the result. [^93] In clinically stable CAP patients (apyrexia (temperature ≤37·8°C), heart rate below 100 beats per min, respiratory rate below 24 breaths per min, arterial oxygen saturation of 90% or higher, systolic blood pressure of 90 mm Hg or higher, and normal mental status) 3 days of a beta lactam is no worse than an 8 day course. [^98] Hospitalized mild [[pneumonia]] ([a low CURB65 score]()) can be treated with 5 days. [^99] In a meta-analysis mild to moderate disease, 5 days total therapy is probably enough.  [^101] The guidelines suggest at least 7 days for CAP from MRSA and [[Pseudomonas]]. Even if bacteremia with *S*. *pneumoniae*, it clinically stable ("cough and shortness of breath are improving, the patient is afebrile for at least 8 hours, the white blood cell count is normalizing, and oral intake and gastrointestinal tract absorption are adequate"), it is safe to change to oral. [^102] 5 days of [[levofloxacin]] is as good as 10 days. The only disease that has probably not been treated with steroids is Cushing's (probably), and CAP is no exception. In a Lancet study, 5 mg a day for 4 days decreased the length of hospitalization in nonimmunocompromised patients by one day but did not alter short term morbidity or mortality. Would I recommend it? Naw. The steroid group had more hyperglycemia and readmission. [^104] I would be more interested if dexamethasone decreased long term mortality.  Then again, 7 days of prednisone also shortens illness without increasing mortality. [^103]  A 2015 meta-analysis suggests > "For hospitalized adults with CAP, systemic corticosteroid therapy may reduce mortality by approximately 3%, need for mechanical ventilation by approximately 5%, and hospital stay by approximately 1 day." [^105] Another suggests   > "Corticosteroids treatment was associated with a decreased risk of adult respiratory distress syndrome (RR, 0.21; 95% CI, 0.08­0.59), and may reduce the lengths of the hospital and intensive care unit stay, the duration of intravenous antibiotic treatment, and the time to clinical stability. Corticosteroid was not associated with increased rates of adverse events."   [^105] Or [[pneumonia]] should maybe perhaps receive hydrocortisone 200 mg bolus followed by 10mg/hr for 4 days. It decreased mortality. [^109] So take your pick on studies and endpoints. For me giving steroids for CAP is an unnatural act and it is harder and harder to change as I age. #### Fine Risk Class III/IV CAP. If the [[pneumonia]] severity score](https://www.mdcalc.com/calc/33/psi-port-score-[[pneumonia]]-severity-index-cap) is less than 110, they only need 3 days of IV and need NOT go home on oral. [^106] But no one will do this. If the [[pneumonia]] severity score](https://www.mdcalc.com/calc/33/psi-port-score-[[pneumonia]]-severity-index-cap) is class IV or V (severe) and patient stable (defined as respiratory rate <25/min, oxygen saturation >90% or arterial oxygen pressure >55 mm Hg, hemodynamically stable, >1°C decrease in temperature in case of fever, absence of mental confusion, and the ability to take oral drugs) can change to oral therapy after 3 days. [^108] Regardless, when the patient is afebrile and vital signs are stable, time for discharge. It is way stupid to watch them on po for 24 hours as pharmacokinetically they are on IV for four half-lives, usually a day. And it is safe to do. [^107] If the cultures are negative I always recommend they be sent home on doxycyclineor [[amoxicillin]] as the vast majority of patients are cured at the time of discharge and the last thing they need is a prescription for an expensive quinolone or macrolide. #### Inpatients, ICU treatment A beta-lactam ([[cefotaxime]], [[ceftriaxone]], or [[ampicillin]]-sulbactam) plus either [[Azithromycin]] or a respiratory quinolone. For penicillin-allergic patients, a respiratory fluoroquinolone and [[aztreonam]] are recommended. The patient should receive a macrolide for its immunomodulatory effects whether or not the organism is susceptible to a macrolide; it decreases mortality. [^110] [[Clarithromycin]] in particular, perhaps due to immunomodulatory effects, [^111] at a dose of 1 gm a day for three days markedly decreases days on the ventilator and may decrease mortality. [^112] *[[Pseudomonas]]* infection is not an issue: cefotaximeor [[ceftriaxone]] or [[ampicillin]]-sulbactam (hah, a drug I still this is a Yugo: underpowered and overpriced) PLUS either [[erythromycin]]), [[Azithromycin]], [[clarithromycin]] or [[moxifloxacin]], [[levofloxacin]], or gemifloxacin. *[[Pseudomonas]]* infection is not an issue but the patient has a beta-lactam allergy: [[moxifloxacin]], [[levofloxacin]], or gemifloxacin, with or without [[clindamycin]]. Long term decrease in functional status is common. [^113] **[[Pseudomonas]] infection may be an issue** Either an antipseudomonal agent plus [[ciprofloxacin]], OR an antipseudomonal agent plus [[moxifloxacin]], [[levofloxacin]], OR [[erythromycin]], [[Azithromycin]], [[clarithromycin]] . *[[Pseudomonas]]* infection is an issue but the patient has a beta-lactam allergy: Either [[aztreonam]] PLUS [[levofloxacin]] (I prefer [[ciprofloxacin]]) OR [[aztreonam]] PLUS [[moxifloxacin]], or [[ciprofloxacin]].  How long to treat? Most of the time 8 days of IV. [^114] **Hospital-Acquired or Ventilator Acquired [[Pneumonia]]** [[Cefepime]] or [[Ceftazidime]] OR [[imipenem]] or [[meropenem]] OR [[Piperacillin]] /tazobactam  PLUS [[linezolid]] or [[vancomycin]] (if worried about MRSA, and who isn't) PLUS ([[Azithromycin]] or a quinolone (if worried about *[[Legionella]]*). [[Clarithromycin]] , perhaps due to immunomodulatory effects at a dose of 1 gm a day for three days markedly decreases days on the vent and may decrease mortality. [^115] As of 2019, the Concept of healthcare-associated [[pneumonia]] was abandoned in place of > "Emphasis on local epidemiology and validated risk factors to determine need for MRSA or P. aeruginosa coverage. Increased emphasis on deescalation of treatment if cultures are negative." About time. It was a stupid concept and led to the overuse of antibiotics. There is an oh so stupid 'rule' in medicine: once antibiotics are started they can't be stopped and once a class of antibiotics is started, it can't be changed. I call shenanigans. De-escalation of antibiotics is reasonable and safe. You can change from multiple antibiotics to a single antibiotic if *[[Pseudomonas]]* *aeruginosa* is not present (and most of the time you do not need to two antibiotics for *[[Pseudomonas]]*, shorten the therapy to < 5 days if the cultures are negative and there have been > 48 hours of defervescence, and change from a broad to a narrow antibiotic based on culture data. How long to treat? Most of the time 8 days of IV. [^116] However, and pay attention here, if the CPIS score on day three is < 6, antibiotics can be discontinued as the patient probably doesn't have [[pneumonia]]. [Click here to calculate a CPIS score](https://www.medcentral.com/calculators/pulmonology/clinical-pulmonary-infection-score-cpis). 1-3 days antibiotics are long enough in **suspected** VAP if > "daily minimum PEEP of ≤5 cm H2O and daily minimum FiO2 less than 40% for at least 3 days from the first day of antibiotics (and) may be suitable candidates for early antibiotic discontinuation." [^117] You can also drop the [[vancomycin]] if cultures negative, and/or, if you do not have cultures if the nasal swab for MRSA is negative [^119] and the [CPIS score](https://www.medcentral.com/calculators/pulmonology/clinical-pulmonary-infection-score-cpis) is less than 6. [^118] Stopping the anti-MRSA antibiotic in culture-negative patients does not change mortality but is associated with a shorter hospital LOS and lower incidence of AKI. [^120] And a curious literature, like Alice's curiouser and curiouser, that adjunctive [[clarithromycin]] for three days decreases mortality. This is not the only study to show such a benefit and perhaps has more to do with the immunomodulatory effects of [[clarithromycin]] than its antibacterial effects. [^121] **Nursing Home Receiving treatment in a nursing home** [[Moxifloxacin]], [[levofloxacin]], or gemifloxacin alone or [[amoxicillin]]-clavulanate PLUS [[erythromycin]]), [[Azithromycin]] or [[clarithromycin]] . **Hospitalized Nursing Home Patient** Same as for medical ward and ICU. **Special concerns** If *[[Pseudomonas]]* is a consideration. Which for some people is always. *[[Pseudomonas]]* is the modern equivalent of demons. Always lurking to cause problems. An anti-pneumococcal, antipseudomonal beta-lactam [[cefepime]], [[imipenem]], [[meropenem]], [[Piperacillin]]-tazobactam, [[aztreonam]] Remember: Double coverage is associated with increased mortality in a study when treating suspected *[[Pseudomonas]]*and CAP. [^82] If MRSA is a consideration, add [[vancomycin]] or [[linezolid]]. > "...in patients with CAP provide strong evidence that de-escalation of antibiotic therapy at 48 hours in accord with microbiological results that do not yield MRSA or *P. aeruginosa* is safe and reduces duration of antibiotic treatment, length of hospitalization, and complications of broad-spectrum therapy. " ### Pearls Empiric therapy for MRSA [[pneumonia]] offered no benefit but does more harm than good: > "empirical anti-MRSA therapy plus standard therapy was significantly associated with an increased adjusted risk of death, kidney injury, and secondary C difficile infections, [[vancomycin]]-resistant [[Enterococcus]] spp infections, and secondary gram-negative rod infections." [^122] Not all patients have a fever: > "Bacteremic [[pneumonia]] was present in ... 101 of 2149 (4.7%) afebrile patients" and increased risk of death." [^123] Why is the patient still febrile after antibiotics? From a 2014 NEJM Review: [^124] - Correct organism but inappropriate antibiotic choice or dose - Resistance of organism to selected antibiotic - Wrong dose (e.g., in a patient who is morbidly obese or has fluid overload) - Antibiotics not administered - Correct organism and correct antibiotic but infection is loculated (e.g., most commonly [[empyema]]) - Obstruction (e.g., lung cancer, foreign body) - Incorrect identification of causative organism - No identification of causative organism and empirical therapy directed toward wrong organism - Noninfectious cause - Drug-induced fever - Presence of an unrecognized, concurrent infection Older patients will often not recover completely, having accelerated functional decline. [^125] To quote another article) > "A year after hospitalization for community-acquired [[pneumonia]], moderate-to-severe impairment in multiple cognitive domains affected one-third of patients ≥ 65 years old and 20% of younger patients, and another third of survivors had mild cognitive impairment." [^126] Infections are short term and long term bad for people. Antibiotics do little for acute asthma except for increase cost and hospitalization. [^127] Cardiac events are common with CAP and more than doubles mortality. [^128] The risk of MI goes up with acute viral pneumonias as well. Influenza > RSV > other viri especially during the first week of infection. [^129] There is a > "small but strongly significant associations in the timing of respiratory infection (with HMPV, RSV, influenza, rhinovirus, and [[adenovirus]]) and MI or ischemic stroke hospitalizations in the elderly." [^130] Even if they survive their CAP, and most should, the risk of death is increased for a year after CAP and that death risk is increased for a decade after *Pneumococcal* [[pneumonia]]. Infections are bad for you. [^131] One third will have a cardiovascular event and it will increase mortality 5x. [^132] Amongst other complications, CAP is associated with an increased risk of CHF in the following year. [^133] Mortality from Pneumococcal [[pneumonia]] has not improved in 20 years despite all the hotshot interventions we have tried. [^134] Pleural effusions at admission are a risk for death and have a longer hospital stay (if they live). [^135] As for so many infections, prior use of NSAIDS increases like likelihood of badness compared to those who did not take NSAIDs: > "pleural [[empyema]] and lung cavitation (37.5% vs. 7%; ) and had a trend to more invasive disease, with a higher frequency of pleural [[empyema]] (25% vs. 5%, P=0.014) and bacteremia." [^136] Could try selective oropharyngeal decontamination with topical application of tobramycin, [[Colistin]], and [[Amphotericin B]] in the oropharynx and stomach for four days. Decreased mortality at 30 days by 2.9%. [^137] Overall, I was not a fan. Room air O2 saturation in CAP of < 92% have increased morbidity and mortality. [^138] If you should have to resort to [[Colistin]], adding inhaled to IV adds nothing for the treatment. [^139] There is always the urge to add inhaled antibiotics.  A 2016 meta-analysis suggests > "There is insufficient evidence for the use of inhaled antibiotic therapy as primary or adjuvant treatment of VAP or VAT." [^140] Not that insufficient evidence ever stops anyone.  Hell sufficient evidence shows acupuncture is nothing but placebo and people keep on using it. For severe [[pneumonia]], one meta-analysis suggests zinc supplementation will decrease mortality. [^141] ### Rants I tend to go on and on that infections are inflammatory, that inflammation is prothrombotic, and that every infection that has been evaluated has an increase in vascular events (stroke, MI or PE) in the months following the infection. It may be why people with hospitalized infections have higher death rates. But it is like the weather. Everyone complains about it but no one tries to change it. Well, now you can. 300 mg of aspirin a day for a month decreased cardiac events and deaths in patients with [[pneumonia]]. [^142] I suspect that in a decade, once the clinical trials are complete, that everyone with an acute infection will go home on ASA. But. NSAIDs during an acute respiratory infection increase MI risk 3.4x. [^143] What continues to flabber my gaster is how people order tests then ignore them  For [[pneumonia]] a negative procalcitonin combined with a postive viral PCR does not result in antibiotics being stopped. 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Which is something](http://www.pusware.com/PW10/IGotNothing.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop1146.mp3) [Journey or Destination](http://www.pusware.com/PW10/JourneyOrDestination.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop1134.mp3) [Meniscus of Pus Happens](http://www.pusware.com/PW8/Meniscus.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop956.mp3) ### Rationalizations [^1]: Ebell MH, Chupp H, Cai X, Bentivegna M, Kearney M. Accuracy of Signs and Symptoms for the Diagnosis of Community-acquired [[Pneumonia]]: A Meta-analysis. Acad Emerg Med. 2020 Jul;27(7):541-553. doi: 10.1111/acem.13965. Epub 2020 Apr 24. PMID: 32329557. [^2]: Miyashita N, Shimizu H, Ouchi K, Kawasaki K, Kawai Y, Obase Y, Kobashi Y, Oka M. Assessment of the usefulness of sputum Gram stain and culture for diagnosis of community-acquired [[pneumonia]] requiring hospitalization. Med Sci Monit. 2008 Apr;14(4):CR171-6. PMID: 18376343. [^3]: Hiroaki Ogawa, Georgios D Kitsios, Mitsunaga Iwata, Teruhiko Terasawa, Sputum Gram Stain for Bacterial Pathogen Diagnosis in Community-acquired [[Pneumonia]]: A Systematic Review and Bayesian Meta-analysis of Diagnostic Accuracy and Yield, _Clinical Infectious Diseases_, Volume 71, Issue 3, 1 August 2020, Pages 499–513, [https://doi.org/10.1093/cid/ciz876](https://doi.org/10.1093/cid/ciz876) [^4]: O'Horo JC, Thompson D, Safdar N. Is the gram stain useful in the microbiologic diagnosis of VAP? A meta-analysis. Clin Infect Dis. 2012 Aug;55(4):551-61. doi: 10.1093/cid/cis512. Epub 2012 Jun 7. PMID: 22677711. [^5]: Dubourg G, Abat C, Rolain JM, Raoult D. Correlation between sputum and bronchoalveolar lavage fluid cultures. J Clin Microbiol. 2015 Mar;53(3):994-6. doi: 10.1128/JCM.02918-14. Epub 2014 Dec 24. PMID: 25540405; PMCID: PMC4390670. [^6]: Claessens YE, Debray MP, Tubach F, Brun AL, Rammaert B, Hausfater P, Naccache JM, Ray P, Choquet C, Carette MF, Mayaud C, Leport C, Duval X. Early Chest Computed Tomography Scan to Assist Diagnosis and Guide Treatment Decision for Suspected Community-acquired [[Pneumonia]]. Am J Respir Crit Care Med. 2015 Oct 15;192(8):974-82. doi: 10.1164/rccm.201501-0017OC. PMID: 26168322. [^7]: Sacha F de Stoppelaar, Liza Pereverzeva, Bram Hafkamp, Nikki Lips, Floor Tielbeke, Linde Rustenburg, Caroline Hoogerheide-Wiegerinck, Koen de Heer, Diagnostic Value of Chest X-Ray in Patients With Suspected Infection and No Respiratory Signs or Symptoms, _Open Forum Infectious Diseases_, Volume 7, Issue 6, June 2020, ofaa221, [https://doi.org/10.1093/ofid/ofaa221](https://doi.org/10.1093/ofid/ofaa221) [^8]: Long L, Zhao HT, Zhang ZY, Wang GY, Zhao HL. Lung ultrasound for the diagnosis of [[pneumonia]] in adults: A meta-analysis. Medicine (Baltimore). 2017 Jan;96(3):e5713. doi: 10.1097/MD.0000000000005713. PMID: 28099332; PMCID: PMC5279077. [^9]: Sordé R, Falcó V, Lowak M, Domingo E, Ferrer A, Burgos J, Puig M, Cabral E, Len O, Pahissa A. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired [[pneumonia]] to guide antimicrobial therapy. Arch Intern Med. 2011 Jan 24;171(2):166-72. doi: 10.1001/archinternmed.2010.347. Epub 2010 Sep 27. PMID: 20876397. [^10]: Andreo F, Prat C, Ruiz-Manzano J, Lores L, Blanco S, Cuesta MA, Giménez M, Domínguez J. Persistence of [[Streptococcus]] pneumoniae urinary antigen excretion after pneumococcal [[pneumonia]]. Eur J Clin Microbiol Infect Dis. 2009 Feb;28(2):197-201. doi: 10.1007/s10096-008-0606-3. Epub 2008 Oct 2. PMID: 18830727. [^11]: Bellew S, Grijalva CG, Williams DJ, Anderson EJ, Wunderink RG, Zhu Y, Waterer GW, Bramley AM, Jain S, Edwards KM, Self WH. Pneumococcal and [[Legionella]] Urinary Antigen Tests in Community-acquired [[Pneumonia]]: Prospective Evaluation of Indications for Testing. Clin Infect Dis. 2019 May 30;68(12):2026-2033. doi: 10.1093/cid/ciy826. PMID: 30265290; PMCID: PMC7182343. [^12]: Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired [[pneumonia]]. Ann Intern Med. 2008 Sep 16;149(6):391-8. doi: 10.7326/0003-4819-149-6-200809160-00005. PMID: 18794558. [^13]: Trifirò G, Gambassi G, Sen EF, Caputi AP, Bagnardi V, Brea J, Sturkenboom MC. Association of community-acquired [[pneumonia]] with antipsychotic drug use in elderly patients: a nested case-control study. Ann Intern Med. 2010 Apr 6;152(7):418-25, W139-40. doi: 10.7326/0003-4819-152-7-201004060-00006. PMID: 20368647. [^14]: Trifirò G, Gambassi G, Sen EF, Caputi AP, Bagnardi V, Brea J, Sturkenboom MC. Association of community-acquired [[pneumonia]] with antipsychotic drug use in elderly patients: a nested case-control study. Ann Intern Med. 2010 Apr 6;152(7):418-25, W139-40. doi: 10.7326/0003-4819-152-7-201004060-00006. PMID: 20368647. [^15]: Onozuka D, Hashizume M, Hagihara A. Impact of weather factors on Mycoplasma pneumoniae [[pneumonia]]. Thorax. 2009 Jun;64(6):507-11. doi: 10.1136/thx.2008.111237. Epub 2009 Mar 23. PMID: 19318345. [^16]: Garcia-Vidal C, Labori M, Viasus D, Simonetti A, Garcia-Somoza D, Dorca J, Gudiol F, Carratalà J. Rainfall is a risk factor for sporadic cases of [[Legionella]] pneumophila [[pneumonia]]. PLoS One. 2013 Apr 16;8(4):e61036. doi: 10.1371/journal.pone.0061036. PMID: 23613778; PMCID: PMC3628787. [^17]: Assink-de Jong E, Douma M, Beishuizen A, Hoogewerf M, Debets-Ossenkopp YJ, de Waard MC, Girbes ARJ. Microbiological findings and adequacy of antibiotic treatment in the critically ill patient with drowning-associated [[pneumonia]]. Intensive Care Med. 2014 Feb;40(2):290-291. doi: 10.1007/s00134-013-3175-6. Epub 2013 Dec 6. PMID: 24310849. [^18]: Forshee-Hakala BA. [[Pneumonia]] cases following an EF-5 tornado. Am J Infect Control. 2015 Jul 1;43(7):682-5. doi: 10.1016/j.ajic.2015.02.027. Epub 2015 Apr 11. PMID: 25868649. [^19]: Nie, W., Zhang, Y., Jee, S.H. et al. Obesity survival paradox in [[pneumonia]]: a meta-analysis. BMC Med 12, 61 (2014). https://doi.org/10.1186/1741-7015-12-61 [^20]: Edelman EJ, Gordon KS, Crothers K, et al. Association of Prescribed Opioids With Increased Risk of Community-Acquired [[Pneumonia]] Among Patients With and Without [[HIV]]. _JAMA Intern Med._ 2019;179(3):297–304. doi:10.1001/jamainternmed.2018.6101 [^21]: Edelman EJ, Gordon KS, Crothers K, et al. Association of Prescribed Opioids With Increased Risk of Community-Acquired [[Pneumonia]] Among Patients With and Without [[HIV]]. JAMA Intern Med. 2019;179(3):297–304. doi:10.1001/jamainternmed.2018.6101 [^22]: Jason Frisbee, R Eric Heidel, Mark S Rasnake, Adverse Outcomes Associated With Potentially Inappropriate Antibiotic Use in Heart Failure Admissions, _Open Forum Infectious Diseases_, Volume 6, Issue 6, June 2019, ofz220, [https://doi.org/10.1093/ofid/ofz220](https://doi.org/10.1093/ofid/ofz220) [^23]: Dickson RP, Huffnagle GB. The Lung Microbiome: New Principles for Respiratory Bacteriology in Health and Disease. PLoS Pathog. 2015 Jul 9;11(7):e1004923. doi: 10.1371/journal.ppat.1004923. PMID: 26158874; PMCID: PMC4497592. [^24]: Dickson RP, Huffnagle GB. The Lung Microbiome: New Principles for Respiratory Bacteriology in Health and Disease. PLoS Pathog. 2015 Jul 9;11(7):e1004923. doi: 10.1371/journal.ppat.1004923. PMID: 26158874; PMCID: PMC4497592. [^25]: Cesario TC. Viruses associated with [[pneumonia]] in adults. Clin Infect Dis. 2012 Jul;55(1):107-13. doi: 10.1093/cid/cis297. Epub 2012 Mar 15. PMID: 22423119; PMCID: PMC7107903. [^26]: Holter, J.C., Müller, F., Bjørang, O. _et al._ Etiology of community-acquired [[pneumonia]] and diagnostic yields of microbiological methods: a 3-year prospective study in Norway. _BMC Infect Dis_ **15**, 64 (2015). https://doi.org/10.1186/s12879-015-0803-5 [^27]: Gadsby NJ, Russell CD, McHugh MP, Mark H, Conway Morris A, Laurenson IF, Hill AT, Templeton KE. Comprehensive Molecular Testing for Respiratory Pathogens in Community-Acquired [[Pneumonia]]. Clin Infect Dis. 2016 Apr 1;62(7):817-823. doi: 10.1093/cid/civ1214. Epub 2016 Jan 7. PMID: 26747825; PMCID: PMC4787606. [^28]: Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, Reed C, Grijalva CG, Anderson EJ, Courtney DM, Chappell JD, Qi C, Hart EM, Carroll F, Trabue C, Donnelly HK, Williams DJ, Zhu Y, Arnold SR, Ampofo K, Waterer GW, Levine M, Lindstrom S, Winchell JM, Katz JM, Erdman D, Schneider E, Hicks LA, McCullers JA, Pavia AT, Edwards KM, Finelli L; CDC EPIC Study Team. Community-Acquired [[Pneumonia]] Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015 Jul 30;373(5):415-27. doi: 10.1056/NEJMoa1500245. Epub 2015 Jul 14. PMID: 26172429; PMCID: PMC4728150. [^29]: Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, Reed C, Grijalva CG, Anderson EJ, Courtney DM, Chappell JD, Qi C, Hart EM, Carroll F, Trabue C, Donnelly HK, Williams DJ, Zhu Y, Arnold SR, Ampofo K, Waterer GW, Levine M, Lindstrom S, Winchell JM, Katz JM, Erdman D, Schneider E, Hicks LA, McCullers JA, Pavia AT, Edwards KM, Finelli L; CDC EPIC Study Team. Community-Acquired [[Pneumonia]] Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015 Jul 30;373(5):415-27. doi: 10.1056/NEJMoa1500245. Epub 2015 Jul 14. PMID: 26172429; PMCID: PMC4728150. [^30]: Saadi H, Pagnier I, Colson P, Cherif JK, Beji M, Boughalmi M, Azza S, Armstrong N, Robert C, Fournous G, La Scola B, Raoult D. First isolation of Mimivirus in a patient with [[pneumonia]]. Clin Infect Dis. 2013 Aug;57(4):e127-34. doi: 10.1093/cid/cit354. Epub 2013 May 24. PMID: 23709652. [^31]: Jennings LC, Anderson TP, Beynon KA, Chua A, Laing RT, Werno AM, Young SA, Chambers ST, Murdoch DR. Incidence and characteristics of viral community-acquired [[pneumonia]] in adults. Thorax. 2008 Jan;63(1):42-8. doi: 10.1136/thx.2006.075077. Epub 2007 Jun 15. PMID: 17573440. [^32]: Falsey AR, Becker KL, Swinburne AJ, Nylen ES, Formica MA, Hennessey PA, Criddle MM, Peterson DR, Baran A, Walsh EE. Bacterial complications of respiratory tract viral illness: a comprehensive evaluation. J Infect Dis. 2013 Aug 1;208(3):432-41. doi: 10.1093/infdis/jit190. Epub 2013 May 9. PMID: 23661797; PMCID: PMC3699009. [^33]: Widmer K, Zhu Y, Williams JV, Griffin MR, Edwards KM, Talbot HK. Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults. J Infect Dis. 2012 Jul 1;206(1):56-62. doi: 10.1093/infdis/jis309. Epub 2012 Apr 23. PMID: 22529314; PMCID: PMC3415933. [^34]: Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with [[pneumonia]] in Saudi Arabia. N Engl J Med. 2012 Nov 8;367(19):1814-20. doi: 10.1056/NEJMoa1211721. Epub 2012 Oct 17. Erratum in: N Engl J Med. 2013 Jul 25;369(4):394. PMID: 23075143. [^35]: Yosuke Karimata, Takeshi Kinjo, Gretchen Parrott, Ayako Uehara, Daijiro Nabeya, Shusaku Haranaga, Futoshi Higa, Masao Tateyama, Keiko Miyagawa, Tomoo Kishaba, Kanako Otani, Michiko Okamoto, Hidekazu Nishimura, Jiro Fujita, Clinical Features of Human Metapneumovirus [[Pneumonia]] in Non-Immunocompromised Patients: An Investigation of Three Long-Term Care Facility Outbreaks, The Journal of Infectious Diseases, Volume 218, Issue 6, 15 September 2018, Pages 868–875, https://doi.org/10.1093/infdis/jiy261 [^36]: Juthaporn Cowan, Thuy Linh Do, Sacha Desjardins, Karamchand Ramotar, Vicente Corrales-Medina, Donald William Cameron, Prevalence of Hypogammaglobulinemia in Adult Invasive Pneumococcal Disease, _Clinical Infectious Diseases_, Volume 66, Issue 4, 15 February 2018, Pages 564–569, [https://doi.org/10.1093/cid/cix836](https://doi.org/10.1093/cid/cix836) [^37]: Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, Albrecht V, Limbago B, Talan DA; EMERGEncy ID NET Study Group. Prevalence of methicillin-resistant [[Staphylococcus]] aureus as an etiology of community-acquired [[pneumonia]]. Clin Infect Dis. 2012 Apr;54(8):1126-33. doi: 10.1093/cid/cis022. PMID: 22438343. [^38]: Murdoch DR, Podmore RG, Anderson TP, Barratt K, Maze MJ, French KE, Young SA, Chambers ST, Werno AM. Impact of routine systematic polymerase chain reaction testing on case finding for Legionnaires' disease: a pre-post comparison study. Clin Infect Dis. 2013 Nov;57(9):1275-81. doi: 10.1093/cid/cit504. Epub 2013 Jul 29. PMID: 23899682. [^39]: Daniel M Musher, Sirus J Jesudasen, Joseph W Barwatt, Daniel N Cohen, Benjamin J Moss, Maria C Rodriguez-Barradas, Normal Respiratory Flora as a Cause of Community-Acquired [[Pneumonia]], Open Forum Infectious Diseases, Volume 7, Issue 9, September 2020, ofaa307, https://doi.org/10.1093/ofid/ofaa307 [^40]: Bolliger R, Neeser O, Merker M, Vukajlovic T, Felder L, Fiumefreddo R, Haubitz S, Koch D, Hammerer-Lercher A, Ottiger C, Fux CA, Mueller B, Schuetz P. Validation of a Prediction Rule for _[[Legionella]]_ [[Pneumonia]] in Emergency Department Patients. Open Forum Infect Dis. 2019 Jun 4;6(7):ofz268. doi: 10.1093/ofid/ofz268. PMID: 31281863; PMCID: PMC6602791. [^41]: Barbier, F., Bailly, S., Schwebel, C. _et al._ Infection-related ventilator-associated complications in ICU patients colonised with extended-spectrum β-lactamase-producing Enterobacteriaceae. _Intensive Care Med_ **44**, 616–626 (2018). https://doi.org/10.1007/s00134-018-5154-4 [^42]: Ishan S Kamat, Vignesh Ramachandran, Harish Eswaran, Danielle Guffey, Daniel M Musher, Procalcitonin to Distinguish Viral From Bacterial [[Pneumonia]]: A Systematic Review and Meta-analysis, Clinical Infectious Diseases, Volume 70, Issue 3, 1 February 2020, Pages 538–542, https://doi.org/10.1093/cid/ciz545 [^43]: La Combe B, Clermont O, Messika J, et al. [[Pneumonia]]-Specific [[Escherichia]] coli with Distinct Phylogenetic and Virulence Profiles, France, 2012–2014. _Emerging Infectious Diseases_. 2019;25(4):710-718. doi:10.3201/eid2504.180944. [^44]: David P Serota, Mary Elizabeth Sexton, Colleen S Kraft, Federico Palacio, Severe Community-Acquired [[Pneumonia]] due to Acinetobacter baumannii in North America: Case Report and Review of the Literature, Open Forum Infectious Diseases, Volume 5, Issue 3, March 2018, ofy044, https://doi.org/10.1093/ofid/ofy044 [^45]: Jung WJ, Kang YA, Park MS, Park SC, Leem AY, Kim EY, Chung KS, Kim YS, Kim SK, Chang J, Jung JY. Prediction of methicillin-resistant [[Staphylococcus]] aureus in patients with non-nosocomial [[pneumonia]]. BMC Infect Dis. 2013 Aug 9;13:370. doi: 10.1186/1471-2334-13-370. PMID: 23937553; PMCID: PMC3751064. [^46]: Diane M Parente, Cheston B Cunha, Eleftherios Mylonakis, Tristan T Timbrook, The Clinical Utility of Methicillin-Resistant [[Staphylococcus]] aureus (MRSA) Nasal Screening to Rule Out MRSA [[Pneumonia]]: A Diagnostic Meta-analysis With Antimicrobial Stewardship Implications, Clinical Infectious Diseases, Volume 67, Issue 1, 1 July 2018, Pages 1–7, https://doi.org/10.1093/cid/ciy024 [^47]: Baby N, Faust AC, Smith T, Sheperd LA, Knoll L, Goodman EL. Nasal Methicillin-Resistant [[Staphylococcus]] aureus (MRSA) PCR Testing Reduces the Duration of MRSA-Targeted Therapy in Patients with Suspected MRSA [[Pneumonia]]. Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02432-16. doi: 10.1128/AAC.02432-16. PMID: 28137813; PMCID: PMC5365699. [^48]: Diane M Parente, Cheston B Cunha, Eleftherios Mylonakis, Tristan T Timbrook, The Clinical Utility of Methicillin-Resistant [[Staphylococcus]] aureus (MRSA) Nasal Screening to Rule Out MRSA [[Pneumonia]]: A Diagnostic Meta-analysis With Antimicrobial Stewardship Implications, Clinical Infectious Diseases, Volume 67, Issue 1, 1 July 2018, Pages 1–7, https://doi.org/10.1093/cid/ciy024 [^49]: Gardner JG, Rueda AM, Musher DM. Acute Onset of Pneumococcal [[Pneumonia]] Following Instrumentation of the Respiratory Tract. Open Forum Infect Dis. 2018 Apr 2;5(4):ofy047. doi: 10.1093/ofid/ofy047. PMID: 29644245; PMCID: PMC5888258. [^50]: Lim YK, Kweon OJ, Kim HR, Kim TH, Lee MK. Impact of bacterial and viral coinfection in community-acquired [[pneumonia]] in adults. Diagn Microbiol Infect Dis. 2019 May;94(1):50-54. doi: 10.1016/j.diagmicrobio.2018.11.014. Epub 2018 Nov 24. PMID: 30578007; PMCID: PMC7126955. [^51]: Loughlin L, Hellyer TP, White PL, McAuley DF, Conway Morris A, Posso RB, Richardson MD, Denning DW, Simpson AJ, McMullan R. Pulmonary Aspergillosis in Patients with Suspected Ventilator-associated [[Pneumonia]] in UK ICUs. Am J Respir Crit Care Med. 2020 Oct 15;202(8):1125-1132. doi: 10.1164/rccm.202002-0355OC. PMID: 32609533; PMCID: PMC7560800. [^52]: Arvanitis M, Anagnostou T, Mylonakis E. Galactomannan and Polymerase Chain Reaction-Based Screening for Invasive Aspergillosis Among High-Risk Hematology Patients: A Diagnostic Meta-analysis. Clin Infect Dis. 2015 Oct 15;61(8):1263-72. doi: 10.1093/cid/civ555. Epub 2015 Jul 8. PMID: 26157047. [^53]: Ronny M. Schnabel, Catharina F. Linssen, Nele Guion, Walther N. van Mook, Dennis C. Bergmans, [[Candida]] [[Pneumonia]] in Intensive Care Unit?, Open Forum Infectious Diseases, Volume 1, Issue 1, Spring 2014, ofu026, https://doi.org/10.1093/ofid/ofu026 [^54]: Alpern JD, Bahr NC, Vazquez-Benitez G, Boulware DR, Sellman JS, Sarosi GA. Diagnostic Delay and Antibiotic Overuse in Acute Pulmonary Blastomycosis. Open Forum Infect Dis. 2016 Apr 19;3(2):ofw078. doi: 10.1093/ofid/ofw078. PMID: 27419155; PMCID: PMC4943562. [^55]: Musher DM, Rueda AM, Kaka AS, Mapara SM. The association between pneumococcal [[pneumonia]] and acute cardiac events. Clin Infect Dis. 2007 Jul 15;45(2):158-65. doi: 10.1086/518849. Epub 2007 Jun 6. PMID: 17578773. [^56]: Johansson N, Kalin M, Tiveljung-Lindell A, Giske CG, Hedlund J. Etiology of community-acquired [[pneumonia]]: increased microbiological yield with new diagnostic methods. Clin Infect Dis. 2010 Jan 15;50(2):202-9. doi: 10.1086/648678. PMID: 20014950; PMCID: PMC7107844. [^57]: Kallen AJ, Brunkard J, Moore Z, Budge P, Arnold KE, Fosheim G, Finelli L, Beekmann SE, Polgreen PM, Gorwitz R, Hageman J. [[Staphylococcus]] aureus community-acquired [[pneumonia]] during the 2006 to 2007 influenza season. Ann Emerg Med. 2009 Mar;53(3):358-65. doi: 10.1016/j.annemergmed.2008.04.027. Epub 2008 Jun 4. PMID: 18534715. [^58]: https://en.wikipedia.org/wiki/Ask_Dr._Science [^59]: Dragan V, Wei Y, Elligsen M, Kiss A, Walker SAN, Leis JA. Prophylactic Antimicrobial Therapy for Acute Aspiration Pneumonitis. Clin Infect Dis. 2018 Aug 1;67(4):513-518. doi: 10.1093/cid/ciy120. PMID: 29438467. [^60]: Salahuddin M, Karanth S, Ocazionez D, Estrada-Y-Martin RM, Cherian SV. Clinical Characteristics and Etiologies of Miliary Nodules in the US: A Single-Center Study. Am J Med. 2019 Jun;132(6):767-769. doi: 10.1016/j.amjmed.2018.12.030. Epub 2019 Jan 16. PMID: 30659816. [^61]: Huang HL, Liu CJ, Lee MR, Cheng MH, Lu PL, Wang JY, Chong IW. Surgical resection is sufficient for incidentally discovered solitary pulmonary nodule caused by nontuberculous mycobacteria in asymptomatic patients. PLoS One. 2019 Sep 12;14(9):e0222425. doi: 10.1371/journal.pone.0222425. PMID: 31513659; PMCID: PMC6742351. [^62]: Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, Cooley LA, Dean NC, Fine MJ, Flanders SA, Griffin MR, Metersky ML, Musher DM, Restrepo MI, Whitney CG. Diagnosis and Treatment of Adults with Community-acquired [[Pneumonia]]. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67. doi: 10.1164/rccm.201908-1581ST. PMID: 31573350; PMCID: PMC6812437. [^63]: Mortensen EM, Restrepo MI, Anzueto A, Pugh JA. Antibiotic therapy and 48-hour mortality for patients with [[pneumonia]]. Am J Med. 2006 Oct;119(10):859-64. doi: 10.1016/j.amjmed.2006.04.017. PMID: 17000217. [^64]: Frei CR, Restrepo MI, Mortensen EM, Burgess DS. Impact of guideline-concordant empiric antibiotic therapy in community-acquired [[pneumonia]]. Am J Med. 2006 Oct;119(10):865-71. doi: 10.1016/j.amjmed.2006.02.014. PMID: 17000218. [^65]: Frei CR, Restrepo MI, Mortensen EM, Burgess DS. Impact of guideline-concordant empiric antibiotic therapy in community-acquired [[pneumonia]]. Am J Med. 2006 Oct;119(10):865-71. doi: 10.1016/j.amjmed.2006.02.014. PMID: 17000218. [^66]: Bruns AH, Oosterheert JJ, Prokop M, Lammers JW, Hak E, Hoepelman AI. Patterns of resolution of chest radiograph abnormalities in adults hospitalized with severe community-acquired [[pneumonia]]. Clin Infect Dis. 2007 Oct 15;45(8):983-91. doi: 10.1086/521893. Epub 2007 Sep 12. PMID: 17879912. [^67]: Skalsky K, Yahav D, Lador A, Eliakim-Raz N, Leibovici L, Paul M. Macrolides vs. quinolones for community-acquired [[pneumonia]]: meta-analysis of randomized controlled trials. Clin Microbiol Infect. 2013 Apr;19(4):370-8. doi: 10.1111/j.1469-0691.2012.03838.x. Epub 2012 Apr 10. PMID: 22489673. [^68]: Postma DF, van Werkhoven CH, van Elden LJ, Thijsen SF, Hoepelman AI, Kluytmans JA, Boersma WG, Compaijen CJ, van der Wall E, Prins JM, Oosterheert JJ, Bonten MJ; CAP-START Study Group. Antibiotic treatment strategies for community-acquired [[pneumonia]] in adults. N Engl J Med. 2015 Apr 2;372(14):1312-23. doi: 10.1056/NEJMoa1406330. PMID: 25830421. [^69]: Blanc V, Mothes A, Smetz A, Timontin I, Guardia MD, Billiemaz A, Dellamonica J, Vassallo M, Néri D, Chadapaud S, Toyer AL, Del Guidice P, Fribourg A, Léotard S, Nicolle I, Roger PM. Severe community-acquired [[pneumonia]] and positive urinary antigen test for S. pneumoniae: [[amoxicillin]] is associated with a favourable outcome. Eur J Clin Microbiol Infect Dis. 2015 Dec;34(12):2455-61. doi: 10.1007/s10096-015-2503-x. Epub 2015 Oct 17. PMID: 26476549. [^70]: Asadi L, Sligl WI, Eurich DT, Colmers IN, Tjosvold L, Marrie TJ, Majumdar SR. Macrolide-based regimens and mortality in hospitalized patients with community-acquired [[pneumonia]]: a systematic review and meta-analysis. Clin Infect Dis. 2012 Aug;55(3):371-80. doi: 10.1093/cid/cis414. Epub 2012 Apr 16. PMID: 22511553. [^71]: Lee JS, Giesler DL, Gellad WF, Fine MJ. Antibiotic Therapy for Adults Hospitalized With Community-Acquired [[Pneumonia]]: A Systematic Review. JAMA. 2016 Feb 9;315(6):593-602. doi: 10.1001/jama.2016.0115. PMID: 26864413. [^72]: Postma DF, van Werkhoven CH, van Elden LJ, Thijsen SF, Hoepelman AI, Kluytmans JA, Boersma WG, Compaijen CJ, van der Wall E, Prins JM, Oosterheert JJ, Bonten MJ; CAP-START Study Group. Antibiotic treatment strategies for community-acquired [[pneumonia]] in adults. N Engl J Med. 2015 Apr 2;372(14):1312-23. doi: 10.1056/NEJMoa1406330. PMID: 25830421. [^73]: Schembri S, Williamson PA, Short PM, Singanayagam A, Akram A, Taylor J, Singanayagam A, Hill AT, Chalmers JD. Cardiovascular events after [[clarithromycin]] use in lower respiratory tract infections: analysis of two prospective cohort studies. BMJ. 2013 Mar 20;346:f1235. doi: 10.1136/bmj.f1235. PMID: 23525864.'' [^74]: Belforti RK, Lagu T, Haessler S, Lindenauer PK, Pekow PS, Priya A, Zilberberg MD, Skiest D, Higgins TL, Stefan MS, Rothberg MB. Association Between Initial Route of Fluoroquinolone Administration and Outcomes in Patients Hospitalized for Community-acquired [[Pneumonia]]. Clin Infect Dis. 2016 Jul 1;63(1):1-9. doi: 10.1093/cid/ciw209. Epub 2016 Apr 5. PMID: 27048748; PMCID: PMC4901867. [^75]: Kang CI, Song JH, Kim SH, Chung DR, Peck KR, Thamlikitkul V, Wang H, So TM, Hsueh PR, Yasin RM, Carlos CC, Van PH, Perera J; Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study Group. Association of [[levofloxacin]] resistance with mortality in adult patients with invasive pneumococcal diseases: a post hoc analysis of a prospective cohort. Infection. 2013 Feb;41(1):151-7. doi: 10.1007/s15010-012-0299-5. Epub 2012 Jul 22. PMID: 22821428. [^76]: Arnold FW, Lopardo G, Wiemken TL, Kelley R, Peyrani P, Mattingly WA, Feldman C, Gnoni M, Maurici R, Ramirez JA; Community-Acquired [[Pneumonia]] Organization (CAPO). Macrolide therapy is associated with lower mortality in community-acquired bacteraemic [[pneumonia]]. Respir Med. 2018 Jul;140:115-121. doi: 10.1016/j.rmed.2018.05.020. Epub 2018 Jun 5. PMID: 29957272. [^77]: Horita N, Otsuka T, Haranaga S, Namkoong H, Miki M, Miyashita N, Higa F, Takahashi H, Yoshida M, Kohno S, Kaneko T. Beta-lactam plus macrolides or beta-lactam alone for community-acquired [[pneumonia]]: A systematic review and meta-analysis. Respirology. 2016 Oct;21(7):1193-200. doi: 10.1111/resp.12835. Epub 2016 Jun 23. PMID: 27338144. [^78]: Pereira JM, Gonçalves-Pereira J, Ribeiro O, Baptista JP, Froes F, Paiva JA. Impact of antibiotic therapy in severe community-acquired [[pneumonia]]: Data from the Infauci study. J Crit Care. 2018 Feb;43:183-189. doi: 10.1016/j.jcrc.2017.08.048. Epub 2017 Sep 4. PMID: 28915392. [^79]: Teh B, Grayson ML, Johnson PD, Charles PG. [[Doxycycline]] vs. macrolides in combination therapy for treatment of community-acquired [[pneumonia]]. Clin Microbiol Infect. 2012 Apr;18(4):E71-3. doi: 10.1111/j.1469-0691.2011.03759.x. Epub 2012 Jan 27. PMID: 22284533. [^80]: Mark L Metersky, Aruna Priya, Eric M Mortensen, Peter K Lindenauer, Association Between the Order of Macrolide and Cephalosporin Treatment and Outcomes of [[Pneumonia]], Open Forum Infectious Diseases, Volume 4, Issue 3, Summer 2017, ofx141, https://doi.org/10.1093/ofid/ofx141 [^81]: Goldstein RC, Husk G, Jodlowski T, Mildvan D, Perlman DC, Ruhe JJ. Fluoroquinolone- and [[ceftriaxone]]-based therapy of community-acquired [[pneumonia]] in hospitalized patients: the risk of subsequent isolation of multidrug-resistant organisms. Am J Infect Control. 2014 May;42(5):539-41. doi: 10.1016/j.ajic.2014.01.005. PMID: 24773792. [^82]: Obodozie-Ofoegbu OO, Teng C, Mortensen EM, Frei CR. Antipseudomonal monotherapy or combination therapy for older adults with community-onset [[pneumonia]] and multidrug-resistant risk factors: a retrospective cohort study. Am J Infect Control. 2019 Sep;47(9):1053-1058. doi: 10.1016/j.ajic.2019.02.018. Epub 2019 Mar 21. PMID: 30904374; PMCID: PMC6710104. [^83]: Lodise TP, Kwa A, Cosler L, Gupta R, Smith RP. Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized Veterans Affairs patients with community-acquired [[pneumonia]]. Antimicrob Agents Chemother. 2007 Nov;51(11):3977-82. doi: 10.1128/AAC.00006-07. Epub 2007 Aug 20. PMID: 17709460; PMCID: PMC2151470. [^84]: D'Ignazio J, Camere MA, Lewis DE, Jorgensen D, Breen JD. Novel, single-dose microsphere formulation of [[Azithromycin]] versus 7-day [[levofloxacin]] therapy for treatment of mild to moderate community-acquired [[Pneumonia]] in adults. Antimicrob Agents Chemother. 2005 Oct;49(10):4035-41. doi: 10.1128/AAC.49.10.4035-4041.2005. PMID: 16189077; PMCID: PMC1251562. [^85]: Shorr AF, Khashab MM, Xiang JX, Tennenberg AM, Kahn JB. [[Levofloxacin]] 750-mg for 5 days for the treatment of hospitalized Fine Risk Class III/IV community-acquired [[pneumonia]] patients. Respir Med. 2006 Dec;100(12):2129-36. doi: 10.1016/j.rmed.2006.03.019. Epub 2006 May 26. PMID: 16730170. [^86]: Hayashi Y, Paterson DL. Strategies for reduction in duration of antibiotic use in hospitalized patients. Clin Infect Dis. 2011 May;52(10):1232-40. doi: 10.1093/cid/cir063. PMID: 21507920. [^87]: Hayashi Y, Paterson DL. Strategies for reduction in duration of antibiotic use in hospitalized patients. Clin Infect Dis. 2011 May;52(10):1232-40. doi: 10.1093/cid/cir063. PMID: 21507920. [^88]: Shefet D, Robenshtok E, Paul M, Leibovici L. Empirical atypical coverage for inpatients with community-acquired [[pneumonia]]: systematic review of randomized controlled trials. Arch Intern Med. 2005 Sep 26;165(17):1992-2000. doi: 10.1001/archinte.165.17.1992. PMID: 16186469. [^89]: Metersky ML, Ma A, Houck PM, Bratzler DW. Antibiotics for bacteremic [[pneumonia]]: Improved outcomes with macrolides but not fluoroquinolones. Chest. 2007 Feb;131(2):466-73. doi: 10.1378/chest.06-1426. PMID: 17296649. [^90]: Arnold FW, Summersgill JT, Lajoie AS, Peyrani P, Marrie TJ, Rossi P, Blasi F, Fernandez P, File TM Jr, Rello J, Menendez R, Marzoratti L, Luna CM, Ramirez JA; Community-Acquired [[Pneumonia]] Organization (CAPO) Investigators. A worldwide perspective of atypical pathogens in community-acquired [[pneumonia]]. Am J Respir Crit Care Med. 2007 May 15;175(10):1086-93. doi: 10.1164/rccm.200603-350OC. Epub 2007 Mar 1. PMID: 17332485. [^91]: Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose [[vancomycin]] therapy for methicillin-resistant [[Staphylococcus]] aureus infections: efficacy and toxicity. Arch Intern Med. 2006 Oct 23;166(19):2138-44. doi: 10.1001/archinte.166.19.2138. PMID: 17060545. [^92]: Walkey AJ, O'Donnell MR, Wiener RS. [[Linezolid]] vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant [[Staphylococcus]] aureus nosocomial [[pneumonia]]: a meta-analysis of randomized controlled trials. Chest. 2011 May;139(5):1148-1155. doi: 10.1378/chest.10-1556. Epub 2010 Sep 23. PMID: 20864609; PMCID: PMC3087458. [^93]: Sarah H Yi, Kelly M Hatfield, James Baggs, Lauri A Hicks, Arjun Srinivasan, Sujan Reddy, John A Jernigan, Duration of Antibiotic Use Among Adults With Uncomplicated Community-Acquired [[Pneumonia]] Requiring Hospitalization in the United States, _Clinical Infectious Diseases_, Volume 66, Issue 9, 1 May 2018, Pages 1333–1341, [https://doi.org/10.1093/cid/cix986](https://doi.org/10.1093/cid/cix986) [^94]: Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, McGee WT, Reisman A, Chastre J. [[Linezolid]] in methicillin-resistant [[Staphylococcus]] aureus nosocomial [[pneumonia]]: a randomized, controlled study. Clin Infect Dis. 2012 Mar 1;54(5):621-9. doi: 10.1093/cid/cir895. Epub 2012 Jan 12. PMID: 22247123. [^95]: Wang Y, Zou Y, Xie J, Wang T, Zheng X, He H, Dong W, Xing J, Dong Y. [[Linezolid]] versus [[vancomycin]] for the treatment of suspected methicillin-resistant [[Staphylococcus]] aureus nosocomial [[pneumonia]]: a systematic review employing meta-analysis. Eur J Clin Pharmacol. 2015 Jan;71(1):107-15. doi: 10.1007/s00228-014-1775-x. Epub 2014 Oct 30. PMID: 25355172. [^96]: Shorr AF, Puzniak LA, Biswas P, Niederman MS. Predictors of Clinical Success in the Treatment of Patients with Methicillin-Resistant [[Staphylococcus]] aureus (MRSA) Nosocomial [[Pneumonia]] (NP). PLoS One. 2015 Jul 21;10(7):e0131932. doi: 10.1371/journal.pone.0131932. PMID: 26196695; PMCID: PMC4510301. [^97]: Diep BA, Afasizheva A, Le HN, Kajikawa O, Matute-Bello G, Tkaczyk C, Sellman B, Badiou C, Lina G, Chambers HF. Effects of [[linezolid]] on suppressing in vivo production of staphylococcal toxins and improving survival outcomes in a rabbit model of methicillin-resistant [[Staphylococcus]] aureus necrotizing [[pneumonia]]. J Infect Dis. 2013 Jul;208(1):75-82. doi: 10.1093/infdis/jit129. Epub 2013 Mar 26. PMID: 23532096; PMCID: PMC3666136. [^98]: Discontinuing β-lactam treatment after 3 days for patients with community-acquired [[pneumonia]] in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial Dinh, AurélienATTAL-BEHAR, Julie et al. The Lancet, Volume 397, Issue 10280, 1195 - 1203 [^99]: Murray C, Shaw A, Lloyd M, Smith RP, Fardon TC, Schembri S, Chalmers JD. A multidisciplinary intervention to reduce antibiotic duration in lower respiratory tract infections. J Antimicrob Chemother. 2014 Feb;69(2):515-8. doi: 10.1093/jac/dkt362. Epub 2013 Sep 10. PMID: 24022067. [^100]: Choudhury G, Mandal P, Singanayagam A, Akram AR, Chalmers JD, Hill AT. Seven-day antibiotic courses have similar efficacy to prolonged courses in severe community-acquired [[pneumonia]]--a propensity-adjusted analysis. Clin Microbiol Infect. 2011 Dec;17(12):1852-8. doi: 10.1111/j.1469-0691.2011.03542.x. Epub 2011 Sep 15. PMID: 21919994. [^101]: Dimopoulos G, Matthaiou DK, Karageorgopoulos DE, Grammatikos AP, Athanassa Z, Falagas ME. Short- versus long-course antibacterial therapy for community-acquired [[pneumonia]] : a meta-analysis. Drugs. 2008;68(13):1841-54. doi: 10.2165/00003495-200868130-00004. PMID: 18729535. [^102]: Ramirez JA, Bordon J. Early switch from intravenous to oral antibiotics in hospitalized patients with bacteremic community-acquired [[Streptococcus]] pneumoniae [[pneumonia]]. Arch Intern Med. 2001 Mar 26;161(6):848-50. doi: 10.1001/archinte.161.6.848. PMID: 11268227. [^103]: Blum CA, Nigro N, Briel M, Schuetz P, Ullmer E, Suter-Widmer I, Winzeler B, Bingisser R, Elsaesser H, Drozdov D, Arici B, Urwyler SA, Refardt J, Tarr P, Wirz S, Thomann R, Baumgartner C, Duplain H, Burki D, Zimmerli W, Rodondi N, Mueller B, Christ-Crain M. Adjunct prednisone therapy for patients with community-acquired [[pneumonia]]: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015 Apr 18;385(9977):1511-8. doi: 10.1016/S0140-6736(14)62447-8. Epub 2015 Jan 19. PMID: 25608756. [^104]: Matthias Briel, Simone M C Spoorenberg, Dominic Snijders, Antoni Torres, Silvia Fernandez-Serrano, G Umberto Meduri, Albert Gabarrús, Claudine A Blum, Marco Confalonieri, Benjamin Kasenda, Reed AC Siemieniuk, Wim Boersma, Willem Jan W Bos, Mirjam Christ-Crain, Ovidius Study Group, Capisce Study Group and STEP Study Group, Corticosteroids in Patients Hospitalized With Community-Acquired [[Pneumonia]]: Systematic Review and Individual Patient Data Metaanalysis, Clinical Infectious Diseases, Volume 66, Issue 3, 1 February 2018, Pages 346–354, https://doi.org/10.1093/cid/cix801 [^105]: Siemieniuk RA, Meade MO, Alonso-Coello P, Briel M, Evaniew N, Prasad M, Alexander PE, Fei Y, Vandvik PO, Loeb M, Guyatt GH. Corticosteroid Therapy for Patients Hospitalized With Community-Acquired [[Pneumonia]]: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 Oct 6;163(7):519-28. doi: 10.7326/M15-0715. PMID: 26258555. [^106]: el Moussaoui R, de Borgie CA, van den Broek P, Hustinx WN, Bresser P, van den Berk GE, Poley JW, van den Berg B, Krouwels FH, Bonten MJ, Weenink C, Bossuyt PM, Speelman P, Opmeer BC, Prins JM. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired [[pneumonia]]: randomised, double blind study. BMJ. 2006 Jun 10;332(7554):1355. doi: 10.1136/bmj.332.7554.1355. PMID: 16763247; PMCID: PMC1479094. [^107]: Nathan RV, Rhew DC, Murray C, Bratzler DW, Houck PM, Weingarten SR. In-hospital observation after antibiotic switch in [[pneumonia]]: a national evaluation. Am J Med. 2006 Jun;119(6):512.e1-7. doi: 10.1016/j.amjmed.2005.09.012. PMID: 16750965. [^108]: Oosterheert JJ, Bonten MJ, Schneider MM, Buskens E, Lammers JW, Hustinx WM, Kramer MH, Prins JM, Slee PH, Kaasjager K, Hoepelman AI. Effectiveness of early switch from intravenous to oral antibiotics in severe community acquired [[pneumonia]]: multicentre randomised trial. BMJ. 2006 Dec 9;333(7580):1193. doi: 10.1136/bmj.38993.560984.BE. Epub 2006 Nov 7. PMID: 17090560; PMCID: PMC1693658. [^109]: Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, Meduri GU. Hydrocortisone infusion for severe community-acquired [[pneumonia]]: a preliminary randomized study. Am J Respir Crit Care Med. 2005 Feb 1;171(3):242-8. doi: 10.1164/rccm.200406-808OC. Epub 2004 Nov 19. PMID: 15557131. [^110]: Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ, Anzueto A. Impact of macrolide therapy on mortality for patients with severe [[Sepsis and Bacteremia]] due to [[pneumonia]]. Eur Respir J. 2009 Jan;33(1):153-9. doi: 10.1183/09031936.00054108. Epub 2008 Sep 3. PMID: 18768577. [^111]: Spyridaki A, Raftogiannis M, Antonopoulou A, Tsaganos T, Routsi C, Baziaka F, Karagianni V, Mouktaroudi M, Koutoukas P, Pelekanou A, Kotanidou A, Orfanos SE, van der Meer JW, Netea MG, Giamarellos-Bourboulis EJ. Effect of [[clarithromycin]] in inflammatory markers of patients with ventilator-associated [[pneumonia]] and [[Sepsis and Bacteremia]] caused by Gram-negative bacteria: results from a randomized clinical study. Antimicrob Agents Chemother. 2012 Jul;56(7):3819-25. doi: 10.1128/AAC.05798-11. Epub 2012 May 7. PMID: 22564837; PMCID: PMC3393410. [^112]: Giamarellos-Bourboulis EJ, Pechère JC, Routsi C, Plachouras D, Kollias S, Raftogiannis M, Zervakis D, Baziaka F, Koronaios A, Antonopoulou A, Markaki V, Koutoukas P, Papadomichelakis E, Tsaganos T, Armaganidis A, Koussoulas V, Kotanidou A, Roussos C, Giamarellou H. Effect of [[clarithromycin]] in patients with [[Sepsis and Bacteremia]] and ventilator-associated [[pneumonia]]. Clin Infect Dis. 2008 Apr 15;46(8):1157-64. doi: 10.1086/529439. PMID: 18444850. [^113]: Sangla F, Legouis D, Marti PE, Sgardello SD, Brebion A, Saint-Sardos P, Adda M, Lautrette A, Pereira B, Souweine B. One year after ICU admission for severe community-acquired [[pneumonia]] of bacterial, viral or unidentified etiology. What are the outcomes? PLoS One. 2020 Dec 14;15(12):e0243762. doi: 10.1371/journal.pone.0243762. PMID: 33315946; PMCID: PMC7735561. [^114]: Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, Clementi E, Gonzalez J, Jusserand D, Asfar P, Perrin D, Fieux F, Aubas S; PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated [[pneumonia]] in adults: a randomized trial. JAMA. 2003 Nov 19;290(19):2588-98. doi: 10.1001/jama.290.19.2588. PMID: 14625336. [^115]: Giamarellos-Bourboulis EJ, Pechère JC, Routsi C, Plachouras D, Kollias S, Raftogiannis M, Zervakis D, Baziaka F, Koronaios A, Antonopoulou A, Markaki V, Koutoukas P, Papadomichelakis E, Tsaganos T, Armaganidis A, Koussoulas V, Kotanidou A, Roussos C, Giamarellou H. Effect of [[clarithromycin]] in patients with [[Sepsis and Bacteremia]] and ventilator-associated [[pneumonia]]. Clin Infect Dis. 2008 Apr 15;46(8):1157-64. doi: 10.1086/529439. PMID: 18444850. [^116]: Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, Clementi E, Gonzalez J, Jusserand D, Asfar P, Perrin D, Fieux F, Aubas S; PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated [[pneumonia]] in adults: a randomized trial. JAMA. 2003 Nov 19;290(19):2588-98. doi: 10.1001/jama.290.19.2588. PMID: 14625336. [^117]: Klompas M, Li L, Menchaca JT, Gruber S; Centers for Disease Control and Prevention Epicenters Program. Ultra-Short-Course Antibiotics for Patients With Suspected Ventilator-Associated [[Pneumonia]] but Minimal and Stable Ventilator Settings. Clin Infect Dis. 2017 Apr 1;64(7):870-876. doi: 10.1093/cid/ciw870. PMID: 28034888. [^118]: Boyce JM, Pop OF, Abreu-Lanfranco O, Hung WY, Fisher A, Karjoo A, Thompson B, Protopapas Z. A trial of discontinuation of empiric [[vancomycin]] therapy in patients with suspected methicillin-resistant [[Staphylococcus]] aureus health care-associated [[pneumonia]]. Antimicrob Agents Chemother. 2013 Mar;57(3):1163-8. doi: 10.1128/AAC.01965-12. Epub 2012 Dec 17. PMID: 23254432; PMCID: PMC3591869. [^119]: Boyce JM, Pop OF, Abreu-Lanfranco O, Hung WY, Fisher A, Karjoo A, Thompson B, Protopapas Z. A trial of discontinuation of empiric [[vancomycin]] therapy in patients with suspected methicillin-resistant [[Staphylococcus]] aureus health care-associated [[pneumonia]]. Antimicrob Agents Chemother. 2013 Mar;57(3):1163-8. doi: 10.1128/AAC.01965-12. Epub 2012 Dec 17. PMID: 23254432; PMCID: PMC3591869. [^120]: Cowley MC, Ritchie DJ, Hampton N, Kollef MH, Micek ST. Outcomes Associated With De-escalating Therapy for Methicillin-Resistant [[Staphylococcus]] aureus in Culture-Negative Nosocomial [[Pneumonia]]. Chest. 2019 Jan;155(1):53-59. doi: 10.1016/j.chest.2018.10.014. Epub 2018 Oct 25. PMID: 30621854. [^121]: Tsaganos T, Raftogiannis M, Pratikaki M, Christodoulou S, Kotanidou A, Papadomichelakis E, Armaganidis A, Routsi C, Giamarellos-Bourboulis EJ. [[Clarithromycin]] Leads to Long-Term Survival and Cost Benefit in Ventilator-Associated [[Pneumonia]] and [[Sepsis and Bacteremia]]. Antimicrob Agents Chemother. 2016 May 23;60(6):3640-6. doi: 10.1128/AAC.02974-15. PMID: 27044546; PMCID: PMC4879428. [^122]: Jones BE, Ying J, Stevens V, et al. Empirical Anti-MRSA vs Standard Antibiotic Therapy and Risk of 30-Day Mortality in Patients Hospitalized for [[Pneumonia]]. JAMA Intern Med. 2020;180(4):552–560. doi:10.1001/jamainternmed.2019.7495 [^123]: Rate and Predictors of Bacteremia in Afebrile Community-Acquired [[Pneumonia]] Forstner, ChristinaDreher, M. et al. CHEST, Volume 157, Issue 3, 529 - 539 [^124]: https://www.nejm.org/doi/pdf/10.1056/NEJMra1312885 [^125]: Davydow DS, Hough CL, Levine DA, Langa KM, Iwashyna TJ. Functional disability, cognitive impairment, and depression after hospitalization for [[pneumonia]]. Am J Med. 2013 Jul;126(7):615-24.e5. doi: 10.1016/j.amjmed.2012.12.006. Epub 2013 Mar 14. PMID: 23499326; PMCID: PMC3690157. [^126]: Girard TD, Self WH, Edwards KM, Grijalva CG, Zhu Y, Williams DJ, Jain S, Jackson JC. Long-Term Cognitive Impairment after Hospitalization for Community-Acquired [[Pneumonia]]: a Prospective Cohort Study. J Gen Intern Med. 2018 Jun;33(6):929-935. doi: 10.1007/s11606-017-4301-x. Epub 2018 Jan 26. PMID: 29374359; PMCID: PMC5975139. [^127]: Stefan MS, Shieh MS, Spitzer KA, Pekow PS, Krishnan JA, Au DH, Lindenauer PK. Association of Antibiotic Treatment With Outcomes in Patients Hospitalized for an Asthma Exacerbation Treated With Systemic Corticosteroids. JAMA Intern Med. 2019 Mar 1;179(3):333-339. doi: 10.1001/jamainternmed.2018.5394. Retracted and republished in: JAMA Intern Med. 2021 Apr 1;181(4):569-570. doi: 10.1001/jamainternmed.2020.7599. PMID: 30688986; PMCID: PMC6439702. [^128]: Cilli A, Cakin O, Aksoy E, Kargin F, Adiguzel N, Karakurt Z, Ergan B, Mersin S, Bozkurt S, Ciftci F, Cengiz M. Acute cardiac events in severe community-acquired [[pneumonia]]: A multicenter study. Clin Respir J. 2018 Jul;12(7):2212-2219. doi: 10.1111/crj.12791. Epub 2018 Apr 17. PMID: 29570241. [^129]: Kwong JC, Schwartz KL, Campitelli MA, Chung H, Crowcroft NS, Karnauchow T, Katz K, Ko DT, McGeer AJ, McNally D, Richardson DC, Rosella LC, Simor A, Smieja M, Zahariadis G, Gubbay JB. Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection. N Engl J Med. 2018 Jan 25;378(4):345-353. doi: 10.1056/NEJMoa1702090. PMID: 29365305. [^130]: Ruth Blackburn, Honxin Zhao, Richard Pebody, Andrew Hayward, Charlotte Warren-Gash, Laboratory-Confirmed Respiratory Infections as Predictors of Hospital Admission for Myocardial Infarction and Stroke: Time-Series Analysis of English Data for 2004–2015, Clinical Infectious Diseases, Volume 67, Issue 1, 1 July 2018, Pages 8–17, https://doi.org/10.1093/cid/cix1144 [^131]: Bordon J, Wiemken T, Peyrani P, Paz ML, Gnoni M, Cabral P, Venero Mdel C, Ramirez J; CAPO Study Group. Decrease in long-term survival for hospitalized patients with community-acquired [[pneumonia]]. Chest. 2010 Aug;138(2):279-83. doi: 10.1378/chest.09-2702. Epub 2010 Apr 9. PMID: 20382718. [^132]: Violi F, Cangemi R, Falcone M, Taliani G, Pieralli F, Vannucchi V, Nozzoli C, Venditti M, Chirinos JA, Corrales-Medina VF; SIXTUS (Thrombosis-Related Extrapulmonary Outcomes in [[Pneumonia]]) Study Group. Cardiovascular Complications and Short-term Mortality Risk in Community-Acquired [[Pneumonia]]. Clin Infect Dis. 2017 Jun 1;64(11):1486-1493. doi: 10.1093/cid/cix164. Erratum in: Clin Infect Dis. 2017 Oct 15;65(8):1431-1433. doi: 10.1093/cid/cix563. PMID: 28205683. [^133]: Eurich DT, Marrie TJ, Minhas-Sandhu JK, Majumdar SR. Risk of heart failure after community acquired [[pneumonia]]: prospective controlled study with 10 years of follow-up. BMJ. 2017 Feb 13;356:j413. doi: 10.1136/bmj.j413. PMID: 28193610; PMCID: PMC5421448. [^134]: Cillóniz C, Liapikou A, Martin-Loeches I, García-Vidal C, Gabarrús A, Ceccato A, Magdaleno D, Mensa J, Marco F, Torres A. Twenty-year trend in mortality among hospitalized patients with pneumococcal community-acquired [[pneumonia]]. PLoS One. 2018 Jul 18;13(7):e0200504. doi: 10.1371/journal.pone.0200504. PMID: 30020995; PMCID: PMC6051626. [^135]: Dean NC, Griffith PP, Sorensen JS, McCauley L, Jones BE, Lee YC. Pleural Effusions at First ED Encounter Predict Worse Clinical Outcomes in Patients With [[Pneumonia]]. Chest. 2016 Jun;149(6):1509-15. doi: 10.1016/j.chest.2015.12.027. Epub 2016 Jan 16. PMID: 26836918; PMCID: PMC6026265. [^136]: Voiriot G, Dury S, Parrot A, Mayaud C, Fartoukh M. Nonsteroidal antiinflammatory drugs may affect the presentation and course of community-acquired [[pneumonia]]. Chest. 2011 Feb;139(2):387-394. doi: 10.1378/chest.09-3102. Epub 2010 Aug 19. PMID: 20724739. [^137]: de Smet AM, Kluytmans JA, Cooper BS, Mascini EM, Benus RF, van der Werf TS, van der Hoeven JG, Pickkers P, Bogaers-Hofman D, van der Meer NJ, Bernards AT, Kuijper EJ, Joore JC, Leverstein-van Hall MA, Bindels AJ, Jansz AR, Wesselink RM, de Jongh BM, Dennesen PJ, van Asselt GJ, te Velde LF, Frenay IH, Kaasjager K, Bosch FH, van Iterson M, Thijsen SF, Kluge GH, Pauw W, de Vries JW, Kaan JA, Arends JP, Aarts LP, Sturm PD, Harinck HI, Voss A, Uijtendaal EV, Blok HE, Thieme Groen ES, Pouw ME, Kalkman CJ, Bonten MJ. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med. 2009 Jan 1;360(1):20-31. doi: 10.1056/NEJMoa0800394. PMID: 19118302. [^138]: Majumdar SR, Eurich DT, Gamble JM, Senthilselvan A, Marrie TJ. Oxygen saturations less than 92% are associated with major adverse events in outpatients with [[pneumonia]]: a population-based cohort study. Clin Infect Dis. 2011 Feb 1;52(3):325-31. doi: 10.1093/cid/ciq076. Epub 2010 Dec 10. PMID: 21217179. [^139]: Kofteridis DP, Alexopoulou C, Valachis A, Maraki S, Dimopoulou D, Georgopoulos D, Samonis G. Aerosolized plus intravenous [[Colistin]] versus intravenous [[Colistin]] alone for the treatment of ventilator-associated [[pneumonia]]: a matched case-control study. Clin Infect Dis. 2010 Dec 1;51(11):1238-44. doi: 10.1086/657242. Epub 2010 Oct 25. PMID: 20973727. [^140]: Russell CJ, Shiroishi MS, Siantz E, Wu BW, Patino CM. The use of inhaled antibiotic therapy in the treatment of ventilator-associated [[pneumonia]] and tracheobronchitis: a systematic review. BMC Pulm Med. 2016 Mar 8;16:40. doi: 10.1186/s12890-016-0202-8. PMID: 26956371; PMCID: PMC4784295. [^141]: Wang L, Song Y. Efficacy of zinc given as an adjunct to the treatment of severe [[pneumonia]]: A meta-analysis of randomized, double-blind and placebo-controlled trials. Clin Respir J. 2018 Mar;12(3):857-864. doi: 10.1111/crj.12646. Epub 2017 May 31. PMID: 28488366. [^142]: Oz F, Gul S, Kaya MG, Yazici M, Bulut I, Elitok A, Ersin G, Abakay O, Akkoyun CD, Oncul A, Cetinkaya E, Gibson MC, Oflaz H. Does aspirin use prevent acute coronary syndrome in patients with [[pneumonia]]: multicenter prospective randomized trial. Coron Artery Dis. 2013 May;24(3):231-7. doi: 10.1097/MCA.0b013e32835d7610. PMID: 23283029. [^143]: Yao-Chun Wen, Fei-Yuan Hsiao, K. Arnold Chan, Zhen-Fang Lin, Li-Jiuan Shen, Cheng-Chung Fang, Acute Respiratory Infection and Use of Nonsteroidal Anti-Inflammatory Drugs on Risk of Acute Myocardial Infarction: A Nationwide Case-Crossover Study, _The Journal of Infectious Diseases_, Volume 215, Issue 4, 15 February 2017, Pages 503–509, [https://doi.org/10.1093/infdis/jiw603](https://doi.org/10.1093/infdis/jiw603) [^144]: Timbrook T, Maxam M, Bosso J. Antibiotic Discontinuation Rates Associated with Positive Respiratory Viral Panel and Low Procalcitonin Results in Proven or Suspected Respiratory Infections. Infect Dis Ther. 2015 Sep;4(3):297-306. doi: 10.1007/s40121-015-0087-5. Epub 2015 Sep 5. PMID: 26342921; PMCID: PMC4575297.