INTRODUCTION

Lower respiratory tract infections (LRTIs) represent the most frequent infectious diseases diagnosed and treated in the context of clinical practice worldwide. Several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are main causes of LRTIs. The targeted selection of treatment regimen has a cardinal role in positive outcomes1,2. Importantly, several lines of evidence during COVID-19 pandemic demonstrated that irrational implementation of antibiotics might not only be ineffective but also lead to adverse events. For instance, azithromycin was not only ineffective in COVID-19 but also increased the odds ratio for arrhythmias3. Based on the above, identifying the causative pathogens of respiratory tract infections seems to be of paramount importance for avoiding the irrational use of broad-spectrum antibiotics. This narrative review aims to highlight recent evidence for LRTIs exerting major burden, including community-acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), hospital-acquired pneumonia (HAP), and COVID-19.

COMMUNITY-ACQUIRED PNEUMONIA (CAP)

Pneumonia represents a common cause of respiratory infection resulting at least to 0.8 million hospital admissions per year based on the American registry. CAP is a lung infectious disease acquired outside the setting of a hospital. CAP represents one of the most frequent causes of hospitalization and mortality among infectious diseases. Based on the annual recording in the US, 650 adults per 100000 population are hospitalized due to CAP every year, corresponding to 1.5 million CAP hospitalizations per year. Almost one in ten patients with CAP will experience a subsequent readmission4. The most frequent symptoms are fever, cough, dyspnea, exhaustion, and loss of appetite. Uncommon symptoms including headache, confusion, nausea, and abdominal pain, appear in children and the elderly. Awareness of local bacteria and their sensitivity/resistance profile is the key to effective pharmacological selection and treatment of pneumonia1.

Etiology

The microbial etiology of CAP is quite often unspecified in clinical practice. Population-based studies for the etiology and incidence are currently lacking. Frequently identified bacteria in CAP are the following: 1) Streptococcus pneumoniae, 2) Haemophilus influenzea, and 3) Moraxella catarrhalis5. Other pathogens frequently encountered are Staphylococcus aureus. Gram-negative bacteria (Pseudomonas spp, Enterobacteriaceae), Group A streptococci, anaerobes (especially in adults with bad oral cavity hygiene), and micro-aerophilic bacteria may also cause CAP. Pseudomonas spp represent characteristic pathogens of patients with bronchiectatic lesions of the lung and end-stage Chronic Obstructive Pulmonary Disease. ‘Atypical’ bacteria, including Mycoplasma pneumoniae and Legionella spp, represent relatively common causes of CAP. Influenza A and B viruses, Human Bocaviruses, Parainfluenza viruses, Coronaviruses, Adenoviruses, Rhinoviruses, and Human Metapneumovirus represent leading causes of CAP5,6.

Risk stratification

Pneumonia risk stratification scores, including CURB and PSI, guide management based on the 30-day mortality risk. PSI discriminates individuals with CAP into 5 groups with different 30-day mortality risk. The score is based on 20 clinical, radiographic, and laboratory parameters7.

CURB score is a clinical prediction tool able to stratify patients with CAP based on mortality risk and is an important tool to discriminate between patients that require outpatient versus inpatient treatment. The criteria included in the CURB score are confusion, elevated BUN above 20 mg/dL, respiratory rate above 30/min, and diastolic blood pressure below 60 mmHg. These criteria did not include one of the most critical risk factors of mortality, such as age8. A multivariate analysis led to the modified CURB-65 score, in which age >65 years was added as a criterion. The modified CURB-65 further increased the prognostic accuracy of this widely used score. Patients presenting with ≥3 positive criteria are classified as severe CAP and need hospital admission9.

PSI has higher prognostic accuracy with regard to mortality compared to the CURB-65 score since it considers a formal assessment of hypoxemia; yet PSI is majorly weighted by age and thus overestimates the risk of mortality in elderly male subjects with a history of active cancer (<6 months following diagnosis), irrespective of etiology. To this end, it is less valuable at extremes of age and invalid in children9. A main advantage of CURB-65 is the fact that it is simple and thus can provide prognostic information and guide treatment decisions in a fast manner, even in the emergency department.

While prognostic tools can provide valuable information to aid physicians in decision-making, their role is supplementary and they cannot replace clinical evaluation. For instance, although oxygen saturation is not included into the CURB 65 score, it may still be a crucial factor with regard to management decisions. Furthermore, patients with low PSI scores but no comorbidities may still require ICU care, while those with a high PSI score due to chronic illness may not. Ultimately, decisions regarding hospital admission should be also based on physician’s medical expertise and clinical judgment considering the limitations of these tools in the context of individual patient care7.

Diagnosis-procalcitonin

CAP is usually diagnosed following evaluation of clinical and radiologic findings. In the context of symptoms, CAP is characterized by shortness of breath of varying severity, productive (and sometimes non-productive) cough and systemic features including fever, rigors, and/or drills coupled with general fatigue and malaise. A clinical examination might reveal crackles or bronchial breath sounds as well as tachypnea, use of accessory respiratory muscles, and cyanosis10. CAP can also be defined as new radiographic findings in chest imaging coupled with compatible clinical findings. These may include consolidative areas, bilateral perihilar opacities, loss of the typical cardiac, diaphragmatic, and/or mediastinal silhouette, as well as interstitial infiltrates, for which there is no other explanation11. Regarding bacterial infections, lab tests including complete blood count and regular biochemical tests should be done. Influenza testing is strongly recommended during the winter season, as viral superinfections can be commonly encountered. In case of availability, a molecular test for respiratory viruses using nasopharyngeal swabs methods could also be performed4.

Procalcitonin represents one of the most important prognostic and theragnostic biomarkers in the context of pneumonia. Its use was widely spread, based on mechanistic evidence showing that pathogens induce the upregulation of the CALC-1 gene of innate immune cells such as macrophages, which subsequently results in the increased production of procalcitonin. More specifically, procalcitonin’s production occurs in the pulmonary parenchyma, in the liver, as well as in the intestine. It is secreted within 120–180 min, while the maximum concentration is identified approximately at 6 hours12. A main advantage of procalcitonin is the fact that it exhibits higher sensitivity and specificity in bacterial infections as well as favorable kinetics compared to C-reactive protein (CRP) due to its earlier increase, thus allowing timely interventions. In addition, its high negative predictive value was established in several cohorts mainly of adults with sepsis and septic shock. To this end, procalcitonin can limit irrational antibiotic usage, as it can reduce the duration of an antibiotic course and allow clinicians to de-escalate antibiotic regimens. Negative procalcitonin values in the appropriate clinical setting can reduce the implementation of broad-spectrum antibiotics. Based on that, procalcitonin might be a tool to avoid the danger of a substantial increase in health-related budgets following advent of novel, expensive antibiotics13.

While PCT seems to be a reliable biomarker for the reduction of antibiotic therapy duration, it cannot be utilized to determine the initiation of therapy. Serial monitoring of PCT levels can safely guide the reduction of antibiotic therapy duration for patients with severe ICU infections, including those with CAP, as observed in several large multicenter studies11.

Empiric treatment of CAP in adults

IDSA/ATS guidelines for CAP, with regard to outpatient adults without comorbidities, recommend the use of empiric antibiotic treatment that includes amoxicillin (1 g administered/ eight hours) or doxycycline (100 mg administered/twelve hours) or a macrolide, if the resistance of Streptococcus pneumoniae to macrolides is less than 25% (azithromycin 500 mg as initial dose followed by half dose per day after day 1 or clarithromycin 500 mg every 12 hours)14. It is important to mention that monotherapy using macrolides is not an option for treating CAP in Greece due to the high incidence of S. pneumoniae resistance15.

Isolation of S. pneumoniae resistant to second-generation cephalosporins precludes the use of cefuroxime as treatment and thus, third generation cephalosporins should be preferred, including cefditoren, a cephalosporin with the lowest MIC for S. pneumoniae 14. Additionally, based on the ATS and IDSA guidelines for CAP outpatient treatment of adults with a history of alcoholism or comorbidities such as chronic heart disease, chronic lung diseases, renal dysfunction, liver abnormalities, diabetes mellitus, cancer or asplenia, the recommended treatment regimen includes a combination of amoxicillin/clavulanate (500125 mg every eight hours or 875/125 mg every twelve hours or 2000/125 mg every twelve hours), or a cephalosporin (i.e. cefuroxime 500 mg/twelve hours) with a macrolide (in the dosage previously described), or doxycycline (100 mg every twelve hours). Alternatively, monotherapy with a respiratory fluoroquinolone (mainly moxifloxacin 400 mg or levofloxacin 750 mg every twenty-four hours) is highly recommended, particularly in outpatients presenting with several comorbidities and a history of previous hospitalization within the past 6 months4 (Table 1). Evaluation of epidemiological data of resistance against specific agents, search for prescription of specific antibiotics during the last 6 months and consideration of allergic reactions to drugs, history of cardiac arrhythmia (i.e. for avoidance of macrolides) and vascular disease (for avoidance of fluoroquinolones) are strongly recommended prior the choice of the antibiotic4,15.

Table 1

Initial treatment strategies for outpatients with community-acquired pneumonia

Standard regimenTreatmentc
No comorbidities or risk factors for MRSA or Pseudomonas aeruginosaaAmoxicillin or doxycycline or macrolide (if local pneumococcal resistance is <25%)
With comorbiditiesbCombination therapy with amoxicillin/clavulanate or cephalosporin AND macrolide or doxycycline or monotherapy with respiratory fluoroquinolone

a Risk factors include prior respiratory isolation of MRSA or P. aeruginosa or recent hospitalization and receipt of parenteral antibiotics (in the last 90 d).

b Comorbidities include chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancy; or asplenia.

c Amoxicillin 1 g three times daily, doxycycline 100 mg twice daily, azithromycin 500 mg on first day then 250 mg daily, clarithromycin 500 mg twice daily, or clarithromycin ER 1000 mg daily. Amoxicillin/clavulanate 500 mg/125 mg three times daily, amoxicillin/clavulanate 875 mg/125 mg twice daily, 2000 mg/125 mg twice daily, cefpodoxime 200 mg twice daily, or cefuroxime 500 mg twice daily and azithromycin 500 mg on first day then 250 mg daily, clarithromycin 500 mg twice daily, clarithromycin ER 1000 mg daily, or doxycycline 100 mg twice daily. Levofloxacin 750 mg daily, moxifloxacin 400 mg daily, or gemifloxacin 320 mg daily.

Furthermore, for inpatient adults with non-severe CAP, without risk factors for MRSA or Pseudomonas Aeruginosa, the empiric treatment includes a combination therapy with a b-lactam (ampicillin-sulbactam 1.5–3 g four times per day, ceftaroline 600 mg twice daily, cefotaxime 1–2 g thrice per day or ceftriaxone 1–2 g daily) and a macrolide (azithromycin 500 mg every twenty-four hours or clarithromycin 500 mg every twelve hours), or even monotherapy with a fluoroquinolone (same dosage as described above)14. Awareness that the elimination half-life of azithromycin following multiple dosing is almost 68 hours is crucial; thus, meticulous evaluation of patients receiving azithromycin is needed. If there are contraindications to quinolones and macrolides use, the indicated treatment is a combination of b-lactam and doxycycline. It is suggested that hospitalized individuals with severe CAP without risk factors for P. aeruginosa or MRSA should receive a regimen comprising a b-lactam antibiotic and a macrolide or a b-lactam antibiotic plus a fluoroquinolone4.

Antibiotics for anaerobic coverage should not be routinely included for suspected aspiration pneumonia unless lung abscess or empyema is suspected. An aspiration represents a common event in adults, especially during sleep when gastric contents cause aspiration pneumonitis. Many of these cases resolve within 1 to 2 days simply following supportive treatment16.

Antibiotic coverage for P. aeruginosa or MRSA in individuals with CAP must be considered in case risk factors for these bacteria are identified17. Empiric treatment options for MRSA include linezolid (600 mg every twelve hours) and vancomycin (15–20 mg/kg every twelve hours following modification according to trough levels), and for P. aeruginosa regimens include piperacillin-tazobactam (4.5 g every six hours), cefepime (2 g every eight hours), ceftazidime (2 g every eight hours), aztreonam (2 g every eight hours), meropenem (1 or 2 g every eight hours), or imipenem (500 mg every six hours). With regard to vancomycin, adjusting dosage following measurement of trough levels at least before the fourth dose is strongly recommended4.

The most important risk factors for infection with P. aeruginosa or MRSA are the following: 1) previous isolation of these microorganisms (especially from the respiratory tract), 2) recent hospitalization, and 3) exposure to parenteral antibiotics. De-escalation of antibiotic therapy is safer 48 hours after negative cultures for MRSA or P. aeruginosa4,18.

Individuals with CAP tested positive for Influenza should receive oseltamivir (75 mg bid), independent of the time of onset of symptoms. The treatment is preferred to be initiated within 48 hours following symptom initiation or hospitalization, although there could be some benefits when the treatment starts 4 or 5 days after symptoms begin19. In the outpatient setting, the anti-influenza agents have higher efficacy if received within 2 days following the onset of symptoms. Patients (outpatient or inpatient) with clinical and radiological features of CAP and positive Influenza testing should receive antibacterial and anti-influenza treatment, considering the high rates of concomitant infections (almost 30%)20. The mortality of patients hospitalized for Influenza and bacterial pneumonia is nearly 10%, mainly attributed to their complications. The most frequent bacteria related to influenza pneumonia are S. aureus, S. pneumoniae, group A Streptococcus and H. influenzae group A Streptococcus21-23 (Table 2). Treatment with corticosteroids for adults with CAP is not recommended. A seminal double-blind, randomized controlled trial by Blum et al.24 showed that administration of prednisolone for 7 days shortened clinical recovery in CAP without increasing complications; yet more data are needed to support this concept and to this end, corticosteroids do not currently belong to the standard of care in CAP.

Table 2

Initial treatment strategies for inpatients with community-acquired pneumonia

Standard regimenPrior respiratory isolation of MRSAPrior respiratory isolation of Pseudomonas aeruginosaRecent hospitalization and parenteral antibiotics and locally validated risk factors for MRSARecent hospitalization and parenteral antibiotics and locally validated risk factors for P. aeruginosa
Non severe inpatient pneumoniaβ-Lactam-macrolide-or respiratory fluroquinoloneAdd MRSA coverage and obtain cultures/nasal PCR to allow de-escalation or confirmation of need for continued therapyAdd coverage for P. aeruginosa and obtain cultures to allow de-escalation or confirmation of need for continued therapyObtain cultures but withhold MRSA coverage unless culture results are positive. If rapid nasal PCR is available, withhold additional empiric therapy against MRSA if rapid testing is negative or add coverage if PCR is positive and obtain culturesObtain cultures but initiate coverage for P. aeruginosa only if culture results are positive
Severe inpatient pneumoniaβ-Lactam-macrolide or β-lactam-fluroquinoloneAdd MRSA coverage and obtain cultures/nasal PCR to allow de-escalation or confirmation of need for continued therapyAdd coverage for P. aeruginosa and obtain cultures to allow de-escalation or confirmation of need for continued therapyAdd MRSA coverage and obtain nasal PCR and cultures to allow de-escalation or confirmation of need for continued therapyAdd coverage for P. aeruginosa and obtain cultures to allow de-escalation or confirmation of need for continued therapy

The appropriate duration of antibiotic treatment

The duration of antibiotic therapy is related to the patient’s clinical stability. It should be continued for at least 5 days until a substantial improvement in the patient is achieved. In case of other complications such as endocarditis or colonization with less-frequent pathogens (e.g. fungi or Burkholderia pseudomallei) longer courses of treatment are recommended. The duration of antibiotics can be shortened based on procalcitonin levels13,14.

VENTILATOR-ASSOCIATED PNEUMONIA (VAP)

VAP represents a typical complication in mechanically ventilated patients and exerts a dramatic impact on their survival rates. VAP is characterized by new pulmonary infiltrations at least 48 hours after intubation. Approximately 30% of patients who receive mechanical ventilation will develop VAP. The risk factors of VAP are many, such as aspiration of oral and gastric secretions, and colonization of nosocomial pathogens to the endotracheal tube or oropharynx25.

Diagnosis of VAP

IDSA/ATS guidelines suggest that the diagnosis of VAP requires new pulmonary infiltrations on chest imaging, increasing oxygen requirements, leukocytosis, fever, and increasing sputum production. In patients with suspected VAP, blood or sputum cultures should be obtained. Also, PCR testing can be used, especially during the influenza period, and measuring serum procalcitonin for separate bacterial and viral infections26.

Empirical treatment of clinically suspected VAP

Initially, all hospitals should have a local antibiogram, according to the pathogen population of their ICU and their susceptibility profile.

If VAP is suspected, it is strongly recommended to use empirical antibiotic treatment covering bacteria such as S. aureus and P. aeruginosa. The following conditions are suggestive of empirical treatment for MRSA: 1) individuals having risk factors for antimicrobial resistance, 2) units where methicillin-resistant S. aureus is isolated >10–20% of the cases, and 3) units with an unknown prevalence of MRSA resistance. Typically, MRSA is <10–20% of S. aureus, which is isolated in ICUs27.

If there are indications for MRSA empirical coverage, either vancomycin or linezolid should be given, while for MSSA (and not MRSA) empirical treatment, it is suggested piperacillin-tazobactam, respiratory fluoroquinolones, cefepime or carbapenems. When MSSA is proven as the causal pathogen of VAP, the preferred agents are oxacillin, nafcillin, or cefazolin27.

Furthermore, antipseudomonal empirical treatment from different classes should be given in patients suspected of VAP with any of the following criteria: a risk factor for antimicrobial resistance, units with isolation >10% of gram-negative pathogens that are resistant to a compound used as single-therapy, and patients with unknown antimicrobial susceptibility in ICU28 (Table 3). Aminoglycosides or colistin should be avoided if there are alternative agents against gram-negative pathogens in individuals with suspected VAP26 (Table 4). The duration of treatment is suggested to be a 7-day course, and the antibiotic therapy should be de-escalated according to the antibiogram. There are some exceptions in the duration of the treatment. These include patients with VAP owing to glucose-non-fermenting gram-negative bacteria that lead to an increased risk for recurrent infections if the treatment duration is only 7–8 days. Clinical criteria and serum procalcitonin levels should guide the discontinuation of antibiotic treatment27,28. Taken together, despite the devastating impact of VAP, a considerable proportion of patients receiving the appropriate regimen can be extubated after the onset of VAP.

Table 3

Risk factors for multidrug-resistant pathogens

Risk factors for MDR VAP
Prior intravenous antibiotic use with 90 d
Septic shock at time of VAP
ARDS preceding VAP
Five or more days of hospitalization prior to the occurrence of VAP
Acute renal replacement therapy prior to VAP onset
Risk factors for MDR HAP
Prior intravenous antibiotic use within 90 d
Risk factors for MRSA VAP/HAP
Prior intravenous antibiotic use within 90 d
Risk factors for MDR Pseudomonas VAP/HAP
Prior intravenous antibiotic use within 90 d

[i] ARDS: acute respiratory distress syndrome. HAP: hospital-acquired pneumonia. MDR: multidrug resistant. MRSA: methicillin-resistant Staphylococcus aureus. VAP: ventilator-associated pneumonia.

Table 4

Suggested empirical treatment options for clinically suspected VAP in Units where empirical MRSA coverage and double antipseudomonal/gram-negative coverage are appropriate

A. Gram-positive antibiotics with MRSA activityB. Gram-negative antibiotics with antipseudomonal activity: β-lactam based agentsC. Gram-negative antibiotics with antipseudomonal activity: non-β-lactam based agents
Glycopeptidesa
Vancomycin 15 mg/kg IV q8-12h (consider a loading dose of 25–30 mg/kg ×1 for severe illness)
or
Oxazolidinones
Linezolid 600 mg IV q12h
Antipseudomonal penicillinsb
Piperacillin-tazobactam 4.5 g IV q6hb
or
Cephalosporinsb
Cefepime 2 g IV q8h
Ceftazidime 2 g IV q8h
or
Cjarbapenemesb
Imipenem 500mg IV q6hd
Meropenem 1g IV q8h
or
Monobactamsf
Aztreonam 2 g IV q8h
Fluoroquinolones
Ciprofloxacin 400 mg IV q8h
Levofloxacin 750 mg IV q24h
or
Aminoglycosidesa,c
Amikacin 15–20 mg/kg IV q24h
Gentamicin 5–7 mg/kg IV q24h
Tobramycin 5–7 mg/kg IV q24h
or
Polymyxinsa,e
Colistin 5 mg/kg IV × 1 (loading dose)
followed by 2.5 mg × (1.5 × CrCl +30) IV q12h (maintenance dose)
Polymyxin B 2.5–3.0 mg/kg/d divided in 2 daily IV doses

Choose one gram-positive option from column A, one gram-negative option from column B, and one gram-negative option from column C. Note that the initial doses suggested in this table may need to be modified for patients with hepatic or renal dysfunction. CrCl: creatinine clearance. IV: intravenous. MRSA: methicillin-resistant Staphylococcus aureus.

a Drug levels and adjustment of doses and/or intervals required.

b Extended infusions may be appropriate.

c On meta-analysis, aminoglycoside regimens were associated with lower clinical response rates with no differences in mortality.

d The dose may need to be lowered in patients weighing <70 kg to prevent seizures.

e Polymyxins should be reserved for settings where there is a high prevalence of multidrug resistance and local expertise in using this medication. Dosing is based on colistin-base activity (CBA), for example: one million IU of colistin is equivalent to about 30 mg of CBA which corresponds to about 80 mg of the prodrug colistimethate. Polymyxin B (1 mg – 10000 units).

f In the absence of other options, it is acceptable to use aztreonam as an adjunctive agent with another β-lactam-based agent because it has different targets within the bacterial cell wall.

HOSPITAL-ACQUIRED PNEUMONIA (HAP)

HAP represents a lower respiratory tract infection which did not exist at the time of hospitalization and is shown at least 48 hours after that time point.

In case HAP is suspected (non-VAP), patients are treated according to the microbiological profile. Respiratory samples for culture can be obtained via multiple ways, including spontaneous expectoration or sputum induction. Hospitals in their entirety should regularly produce a local antibiogram, ideally based on their HAP population. Therefore, the empirical antibiotic regimens are tailored to the local pathogens’ distribution and susceptibility profile29.

The empirical management of clinically suspected HAP (Non-VAP)

With regard to individuals who are treated empirically for HAP, it is suggested to use an antibiotic against S. aureus, P. aeruginosa and other gram-negative bacilli. On the contrary, in case that patients with HAP are receiving empirical treatment and present with risk factors for MRSA infection (such as: 1. previous intravenous antibiotic use within 90 days; 2. hospitalization in a unit where methicillin-resistant S. aureus accounts for over 20% of isolates; 3. in case the prevalence of MRSA is unknown; and 4. when there is a high risk of mortality), healthcare providers are advised to administer an antibiotic with MRSA activity (vancomycin or linezolid)30.

For patients with HAP who are not at high risk of MRSA infection or high risk of mortality, the treatment should include an established anti-MSSA antibiotic such as piperacillin-tazobactam, levofloxacin, cefepime, meropenem or imipenem. In the context of MSSA specifically, the preferred treatment includes oxacillin, nafcillin, or cefazolin. However, one of the above medications does not need to be used. Patients with HAP under empirical treatment that have factors increasing the possibility of P. aeruginosa or other gram (-) bacilli infection (such as prior iv antibiotic treatment in the past 90 days) or high risk of mortality must be treated with 2 compounds of different categories with established activity against P. aeruginosa. An aminoglycoside should not be used as the only antipseudomonal agent27,29 (Table 5). The duration of antibiotic therapy for HAP should be approximately 7 days. The exact regimen and duration are typically decided on a case-by-case basis27.

Table 5

Recommended initial empirical antibiotic therapy for hospital-acquired pneumonia (non-ventilator associated pneumonia)

Not at high risk of mortalitya and no factors increasing the likelihood of MRSAb,cNot at high risk of mortalitya but with factors increasing the likelihood of MRSAb,cHigh risk of mortality or receipt of intravenous antibiotics during the prior 90 daysa,c
One of the following:
Piperacillin-tazobactamd 4.5 g IV q6h
or
Cefepimed 2g IV q8h
or
Levofloxacin 750 mg IV daily
or
Imipenemd 500 mg IV q6h
Meropenemd 1 g IV q8h
One of the following:
Piperacillin-tazobactamd 4.5 g IV q6h
or
Cefepimed or ceftazidimed 2 g IV q8h
or
Levofloxacin 750 mg IV daily
Ciprofloxacin 400 mg IV q8h
or
Imipenemd 500 mg IV q6h
Meropenemd 1 g IV q8h
or
Aztreonam 2 g IV q8h


Plus:
Vancomycin 15 mg/kg IV q8-12h with goal to target 15–20 mg/mL trough level (consider a loading dose of 25–30 mg/kg × 1 for severe illness)
or
Linezolid 600 mg IV q12h
Two of the following, avoid 2 β-lactams:
Piperacillin-tazobactamd 4.5 g IV q6h
or
Cefepimed or ceftazidimed 2 g IV q8h
or
Levofloxacin 750 mg IV daily
Ciprofloxacin 400 mg IV q8h
or
Imipenemd 500 mg IV q6h
Meropenemd 1 g IV q8h
or
Amikacin 15–20 mg/kg IV q24h
Gentamicin 5–7 mg/kg IV q24h
Tobramycin 5–7 mg/kg IV q24h
or
Aztreoname 2 g IV q8h


Plus:
Vancomycin 15 mg/kg IV q8-12h with goal to target 15–20 mg/mL trough level (consider a loading dose of 25–30 mg/kg × 1 for severe illness)
or
Linezolid 600 mg IV q12h

If MRSA coverage is not going to be used, include coverage for MSSA.
Options include:
Piperacillin-tazobactam, cefepime, levofloxacin, imipenem, meropenem. Oxacillin, nafcillin, and cefazolin are preferred for the treatment of proven MSSA, but would ordinarily not be used in an empiric regimen for HAP.

If patient has severe penicillin allergy and aztreonam is going to be used instead of any β-lactam based antibiotic, include coverage for MSSA. HAP: hospital acquired pneumonia. IV: intravenous. MRSA: methicillin resistant Staphylococcus aureus. MSSA methicillin sensitive Staphylococcus aureus.

a Risk factors for mortality include need for ventilatory support due to pneumonia and septic shock.

b Indications for MRSA coverage include intravenous antibiotic treatment during the prior 90 days, and treatment in a Unit where the prevalence of MRSA among S. aureus isolates is not known or is >20%. Prior detection of MRSA by culture or non-culture screening may also increase the risk of MRSA. The 20% threshold was chosen to balance the need for effective initial antibiotic therapy against the risks of excessive antibiotic use, hence individual units can elect to adjust the threshold in accordance with local values and preferences. If MRSA coverage is omitted, the antibiotic regimen should include coverage for MSSA.

c If patient has factors increasing the likelihood of gram-negative infection, 2 antipseudomonal agents are recommended. If patient has structural lung disease increasing the risk of gram-negative infection (i.e. bronchiectasis or cystic fibrosis), 2 antipseudomonal agents are recommended. A high-quality gram stain from a respiratory specimen with numerous and predominant gram-negative bacilli provides further support for the diagnosis of a gram-negative pneumonia, including fermenting and non-glucose fermenting microorganisms.

d Extended infusions may be appropriate. Meropenem dosage usually is 2 g tid, even if meropenem is still used at a regimen of 1 g tid in some countries, including the US.

e In the absence of other options, it is acceptable to use aztreonam as an adjunctive agent with another β-lactam based agent because it has different targets within the bacterial cell wall.

COVID-19

Therapeutic algorithm for non-hospitalized patients

All outpatient individuals with mild to moderate COVID-19 require symptoms management. Palliative treatment including adequate hydration, use of antipyretics, antitussives, or analgesics on a case-by-case basis and depending on the symptoms is encouraged. Monitoring of temperature and oxygen saturation is highly recommended31.

With regard to patients at high risk of progression to severe COVID-19, antiviral compounds such as ritonavir-nirmatrelvir (Paxlovid) and remdesivir can reduce the risk of death or hospitalization32. Particular attention should be paid to the use of nirmatrelvir/ritonavir, given that its combination is contraindicated with drugs that are potent CYP3A inducers. Alternative therapies include bebtelovimab and molnupiravir33. Antiviral compounds have shown far higher efficacy if implemented as early as possible. Treatment should be initiated immediately or at least seven days after symptom onset34. Especially for nirmatrelvir/ritonavir, treatment initiation within the first 3 days of symptoms is crucial, given that administration during this window reduces the risk for COVID-19 related hospitalization or death by 89%32. Evaluation of the risk of disease progression is important to decide whether to prescribe an antiviral drug to patients that have been vaccinated. The risk is linearly associated with the underlying comorbidome. Patients of older age, immunocompromised individuals, as well as patients with substantial latency time since the most recent COVID-19 vaccine dose (i.e. >4–6 months) are among the groups that are more likely to benefit from antiviral compounds35.

Except the treatment of COVID-19 per se, meticulous evaluation for co-infection is needed even if the coexistence is not that common. Concomitant viral infections in the setting of COVID-19 are generally rare (1–2%)36. Community-acquired bacterial pneumonia can also exist, but it is uncommon, as it can be identified in 4–6% of the subjects with SARS-CoV-2 infection2. Antibiotics are not generally recommended unless additional evidence for bacterial pneumonia is observed36.

Therapeutic algorithm for hospitalized patients

Hospitalized patients for a different reason than COVID-19 not requiring supplementary oxygen

Patients with mild to moderate illness from COVID-19 at high risk of progression may benefit from the administration of remdesivir. Τhose who are at greater risk of getting seriously ill from COVID-19, are patients with cancer, cerebrovascular disease, chronic lung diseases such as COPD, liver diseases, renal failure, cystic fibrosis, disabilities, diabetes mellitus, HIV (human immunodeficiency virus), chronic heart conditions, mental health disorders, neurological conditions limited to dementia, tuberculosis, solid organ or hematopoietic cell transplantation, primary immunοdeficiencies, obesity (BMI: >30 kg/m2), pregnancy, smokers, patients with limited physical inactivity, and patients using corticosteroids or other immunosuppressive medications. An age >65 years remains the strongest risk factor for severe disease37.

Hospitalized patients for COVID-19 not in need of supplementary oxygen

Implementation of remdesivir is recommended for patients not in need of supplementary oxygen that have increased risk of progression to severe COVID-1935. It is not recommended to use dexamethasone for the management of COVID-19 in patients not requiring supplementary oxygen. In case there is no indication for therapeutic anticoagulation, a prophylactic dose of heparin is typically recommended38.

Hospitalized patients for COVID-19 who require conventional oxygen

The use of remdesivir without corticosteroids is recommended if the needs for oxygen supplementation are minimal. For individuals who require conventional oxygen, administration of dexamethasone plus remdesivir is suggested. If dexamethasone is unavailable in medical care, an equivalent dose of another corticosteroid category may be used. If remdesivir is not available, the use of dexamethasone alone is suggested38-40. For non-pregnant patients requiring conventional oxygen with D-dimer levels exceeding the upper limit of normal and without an increased risk of bleeding, administration of a therapeutic dose of heparin is suggested. Patients not meeting the criteria for therapeutic heparin, including pregnant individuals, should be given a prophylactic dose of heparin, unless this is not recommended due to contraindications in pregnancy41. Patients have increased bleeding risk with any of the following: 1) bleeding within the past 30 days, 2) need of dual antiplatelet therapy, 3) Hgb <8 g/dL, 4) platelet count <50×109 per L, 5) history of a bleeding disorder, or 6) acquired bleeding disorder42. In patients with rapidly progressive disease, a second immunomodulatory compound (e.g. the IL-6R antagonist denominated tocilizumab or the Janus Kinase 1/2 inhibitor denominated baricitinib) should be added to dexamethasone43,44. Several studies have shown clinical improvement and improved survival in hospitalized patients treated for COVID-19 with tocilizumab and other monoclonal antibodies43.

Hospitalized patients for COVID-19 requiring support with non-invasive ventilation or high-flow nasal cannula oxygen

For this group of patients, the guidelines suggest the administration of dexamethasone plus either per os baricitinib or tocilizumab iv. Our group conducted an open-label, randomized-controlled trial in patients with severe COVID-19, which showed non-inferiority of baricitinib to tocilizumab for mechanical ventilation or death and the time to discharge45. If baricitinib and tocilizumab are not available, tofacitinib and sarilumab can be implemented instead, respectively. If none is available, the use of dexamethasone alone is recommended. Remdesivir should also be included in the treatment regimen for this group of patients. The treatment should typically include a prophylactic dose of heparin as well. A therapeutic or intermediate dose of anticoagulation for VTE prophylaxis should not be administered42.

Patients who are hospitalized for COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

With regard to patients who need mechanical ventilation or ECMO, the administration of dexamethasone plus tocilizumab or baricitinib is suggested. If baricitinib, tocilizumab, sarilumab and tofacitinib are not available, it is recommended to use dexamethasone alone. For patients progressing to invasive mechanical ventilation or ECMO, despite having started remdesivir, it is suggested to continue remdesivir until the treatment course is completed. A prophylactic dose of heparin should be typically administered as well. Patients who were given a therapeutic dose of heparin in a hospital ward without evidence of thromboembolism and then transferred to the ICU, should continue a prophylactic dose42,46,47.

Finally, the Greek guidelines for COVID-19 in hospitalized patients are worth mentioning. According to these guidelines, patients with mild disease who do not require supplementary oxygen should not receive any specific medication. In patients with risk factors for disease progression, oxygen therapy is administered within hospital early treatment to avoid progression to severe disease. Risk factors include an age >65 years, obesity BMI >35 kg/m2, immunosuppression, hemodialysis, chronic heart disease, chronic obstructive pulmonary disease, chronic respiratory deficiency under oxygen therapy, idiopathic pulmonary fibrosis, diabetes mellitus, hemoglobinopathies, 3rd trimester pregnancy. Non-vaccination, or an interval >6 months since vaccination, increases additionally the risk posed by the individual risk factors. For hospitalized patients who require conventional oxygen and do not exhibit symptoms or signs of severe disease such as oxygen saturation <90% on room air (or <94% but rapidly worsening), signs of severe respiratory distress (>30 breaths/min, inability to complete sentences, use of accessory respiratory muscles), extensive infiltrates (>50%) on chest imaging, or laboratory combination (lymphocytes <1000/μL, ferritin >1000 mg/mL, CRP >75 mg/L with normal value <5 mg/L), remdesivir plus a prophylactic dose of heparin should be administered. With regard to patients with increasing oxygen needs, dexamethasone should be implemented38,39. Anakinra can be administered to patients with pneumonia who have a high risk of respiratory failure, as determined by serum levels of soluble urokinase plasminogen activator receptor (suPAR) ≥6 ng/mL48. Antibiotics are administered for documented or suspected bacterial pneumonia based on clinical, imaging, or laboratory findings, following the guidelines of the Hellenic Society of Infectious Diseases for community-acquired pneumonia. Remdesivir, dexamethasone plus a prophylactic dose of heparin should be administered to patients on high-flow oxygen supply on non-invasive ventilation, or those exhibiting symptoms and signs of severe disease. Baricitinib or tocilizumab should be added in non-improving patients with increased markers of inflammation43-45. Anakinra may be used for patients with pneumonia receiving high levels of oxygen supply and who are at serious risk of respiratory failure, as determined by serum levels of soluble urokinase plasminogen activator receptor (suPAR) ≥6 ng/mL48. Additionally, the patient should be positioned in a prone position. The administration of antibiotics for bacterial pneumonia, either documented or suspected, is based on clinical, imaging, or laboratory findings, and follows the guidelines established by the Hellenic Society of Infectious Diseases for community-acquired pneumonia36. If patients are on mechanical ventilation or ECMO and have not received or completed a 10-day course of dexamethasone, or if tocilizumab has not already been administered and there are no contraindications, the patient should be given the appropriate medication. To ensure optimal treatment, remdesivir should be administered only as part of a treatment regimen and for the complete 5-day duration. Additionally, all patients should receive a prophylactic dose of low molecular weight heparin41.

CONCLUSION

Respiratory tract infections represent a major cause of morbidity and mortality, and the emergence of SARS-CoV-2 has led to unprecedented global health and economic consequences. In the context of personalized medicine, targeted therapeutic strategies are needed to optimize patient outcomes. Thus, there is a growing consensus in favor of treatment regimens based on guidelines rather than the indiscriminate use of broad-spectrum antibiotics. Local guidelines are crucial for the evidence-based management of infections, given the variable resistance profiles observed worldwide. Such guidelines are essential complements to international guidelines in the effort to promote rational antimicrobial use and combat antimicrobial resistance.