Dr Ho Thanh Lich

Head of Intensive Care Unit, Emergency Department
Nam Sai Gon International Hospital, Vietnam

Hospital-acquired pneumonia (HAP) refers to any pneumonia contracted by a patient in a hospital at least 48 hours after hospital admission and is typically caused by bacteria, especially aerobic Gram-negative bacilli.¹ The epidemiologic data on HAP in Asia are limited, but various Asian healthcare institutions have reported incidences ranging from 1 to 21 per 1,000 hospital admissions, while intensive care unit (ICU)–acquired respiratory infections range from 9% to 23%. Despite the availability of effective antibiotics, the mortality associated with HAP is high²; the mortality rate of HAP/ventilator-associated pneumonia (VAP) ranges from 26 to 28% (reported in Thailand) up to 58% (reported in Pakistan).³

Dr Ho Thanh Lich, based in Vietnam, shares his clinical experience regarding the management of patients with HAP and discusses the role of fluoroquinolones such as levofloxacin for this indication.

Q1: What are your recommendations and strategies for empirical anti-infective therapy in patients with HAP? What are the key considerations including patient factors when selecting antibiotics?

HAP is caused by a wide range of bacteria. HAP may be polymicrobial and is rarely the result of viral or fungal pathogens in immunocompetent hosts. Pathogens commonly responsible for HAP include aerobic Gram-negative bacilli, such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Acinetobacter.^4,5 The incidence of infections due to Gram-positive cocci, such as Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), has been increasing.⁶ Patients with diabetes mellitus or head trauma and those hospitalised in ICUs are at increased risk for pneumonia owing to S. aureus. HAP caused by fungal and viral infections are more commonly seen in immunocompromised patients.

Prompt and appropriate use of empiric antimicrobial therapy is the key clinical strategy for patients with suspected HAP. There is consistent research evidence that delaying the initiation of appropriate antibiotic therapy for patients with HAP increases the risk of mortality in these patients.¹ When selecting an initial antibiotic therapy for patients with HAP, clinicians typically take into account risk factors for specific pathogens, modified by knowledge of local patterns of antibiotic resistance and the prevalence of causative organisms.¹ Treatment of HAP is then modified on the basis of the patient’s clinical response to the initial empiric antibiotic regimen and the results of cultures of lower respiratory tract secretions obtained on days 2 and 3 of treatment.⁷ The decision to use empiric antimicrobial therapy for HAP depends on the timing of onset (early versus late) of the disease and whether the patient has risk factors for multidrug-resistant (MDR) organisms.¹

Q2: According to guideline recommendations, which patients with HAP should be prioritised for the use of fluoroquinolones?

Current treatment guidelines recommend levofloxacin monotherapy, among other agents, as an empiric treatment for patients with HAP and with no risk factors for MRSA.¹ For patients with HAP at risk of infection with MRSA and high risk of mortality, the use of combination therapy (levofloxacin or ciprofloxacin plus another antipseudomonal agent [cephalosporin, carbapenem or β-lactam/ β-lactamase inhibitor] and vancomycin or linezolid if MRSA is suspected) is recommended.¹ The use of levofloxacin in combination therapy offers several advantages, including: (1) broad-spectrum coverage for infections caused by intracellular pathogens; (2) an alternative to more toxic antimicrobial agents (e.g. aminoglycosides) for patients with renal dysfunction and those at risk for renal insufficiency; and (3) better antibiotic tolerance in cases of severe systemic response to infection (septic shock).⁸

Q3a: What are the pharmacokinetic and pharmacodynamic features of fluoroquinolones such as levofloxacin that make it advantageous for the treatment of HAP in comparison to other fluoroquinolones?

Levofloxacin is characterised by excellent oral bioavailability and rapid absorption, with a mean ± standard deviation (SD) peak plasma concentration (C_max) of approximately 6.2±1.0 μg/mL after a 500 mg dose infused over 60 minutes, and 11.5±4.0 μg/mL after a 750 mg dose infused over 90 minutes following a single intravenous (IV) dose of levofloxacin to healthy volunteers.⁹ Levofloxacin also has a long half-life, allowing for once-daily dosing and facilitating convenient outpatient therapy for patients with HAP.¹⁰

The pharmacokinetics of levofloxacin exhibit linearity and predictability following single or multiple dosing regimens via both oral and IV administration routes. Steady-state conditions are achieved within 48 hours when administering either a 500 mg or 750 mg once-daily dose.⁹

After multiple once-daily oral dosage regimens, the mean ± SD peak and trough plasma concentrations for the 500 mg doses are approximately 5.7±1.4 and 0.5±0.2 μg/mL, respectively; for the 750 mg doses, the mean ± SD peak and trough plasma concentrations are approximately 8.6±1.9 and 1.1±0.4 μg/mL, respectively.⁹ Similarly, following multiple once-daily IV regimens, the mean ± SD peak and trough plasma concentrations for the 500 mg doses are approximately 6.4±0.8 and 0.6±0.2 μg/mL, respectively, while for the 750 mg doses they are approximately 12.1±4.1 and 1.3±0.71 μg/mL, respectively.⁹

The bioavailability of orally administered levofloxacin is minimally affected by food intake, indicating that absorption is not significantly altered when taken with a meal.¹⁰ Oral and IV administration of levofloxacin have similar plasma concentration–time profiles, when equal doses (mg/mg) are administered.⁹

Furthermore, levofloxacin is widely distributed throughout the body; the mean volume of distribution generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses.⁹. Drug concentrations of levofloxacin in lung tissue and epithelial lining fluid are generally higher than those in plasma, which is important for achieving therapeutic concentrations at the site of infection.¹⁰ However, levofloxacin has relatively poor penetration into cerebrospinal fluid (a concentration of approximately 16% of simultaneous plasma values).¹⁰

In vitro, levofloxacin is approximately 24 to 38% bound to serum plasma proteins (primarily albumin) over a clinically relevant range (1 to 10 μg/mL) of serum/plasma drug concentrations; serum protein binding is independent of serum drug concentrations.⁹ The plasma elimination half-life (t1/2β) ranges from 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously in individuals with normal renal function.⁹

Q3b: Based on the abovementioned features of levofloxacin, what are your opinions on a high-dose (750 mg) regimen with levofloxacin for the empiric therapy of HAP, while taking into account the emergence of resistance?

In the 2016 American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines for the treatment of HAP, a recommendation for the use of levofloxacin 750 mg/day is included in relation to initial empiric therapy for patients with HAP who are at risk for infection with P. aeruginosa.¹ The guidelines state that when using an antipseudomonal fluoroquinolone for initial empiric therapy, it is important to consider local susceptibility patterns and to ensure that adequate dosing is achieved.¹ The guidelines also note that the use of fluoroquinolones as monotherapy should be avoided in patients with severe illness or those at risk for infection with MDR pathogens.¹ Considering the emerging antibiotic resistance patterns in hospital settings, it is crucial to evaluate the potential efficacy of all antimicrobial agents, including levofloxacin, in treating severe infections caused by resistant Gram-negative organisms in the future.

A multicentre, open-label study has been conducted in which 438 adult patients with nosocomial pneumonia were randomised to levofloxacin 750 mg once-daily given IV for a minimum of 24 hours, then orally for 7 to 15 days, or imipenem/cilastatin 500 mg to 1,000 mg IV every 6 to 8 hours, followed by oral ciprofloxacin 750 mg every 12 hours for 7 to 15 days.¹¹ This study found that levofloxacin (750 mg) was at least as effective and well tolerated as imipenem/cilastatin in adult patients with nosocomial pneumonia, as demonstrated by comparable clinical and microbiologic success rates. A subgroup analysis from the same study suggested that levofloxacin (750 mg once-daily given IV every 24 hours, followed by an oral dosage regimen) represents a once-daily alternative for the treatment of VAP.¹²

Q4: What is the safety and tolerability profile of levofloxacin? Based on your clinical experience, how would you manage any side effects of levofloxacin seen in your patients? Are there any differences between the side effects seen in patients on high-dose levofloxacin versus those receiving a conventional dose?

According to available research, levofloxacin is generally safe and has a low rate of associated hepatic abnormalities (1/650,000).¹³ However, some central nervous system (CNS) events have been associated with fluoroquinolones, including dizziness, convulsions, psychosis and insomnia.¹³ Of the fluoroquinolones currently available, levofloxacin, ofloxacin and moxifloxacin reportedly have the lowest potential of inducing CNS adverse events.¹³ Cardiovascular problems were observed in only 1 of 15 million levofloxacin prescriptions compared with a 1 to 3% incidence of QTc prolongation of greater than 500 milliseconds in patients receiving sparfloxacin.¹³ Moxifloxacin was also associated with QTc prolongation when compared with non-fluoroquinolone comparators.¹³ The most common adverse drug reactions (ADRs) associated with levofloxacin are nausea, vomiting and diarrhoea.¹³ However, the ADR rate for levofloxacin is still relatively low at 2%, compared with 2 to 10% for other fluoroquinolones.¹³ Overall, levofloxacin has a good tolerability profile.

Clinical trials for levofloxacin have not found evidence that the incidence of any specific adverse event is related to dose (i.e. 500 mg versus 750 mg).¹⁴ In a study by Preston et al., logistic regression analyses revealed no relationship between exposure to levofloxacin (i.e. peak and trough concentrations, AUC) and the incidence of treatment-emergent adverse events involving the gastrointestinal tract, skin or CNS (including psychiatric disturbances).¹⁵

To manage side effects of levofloxacin effectively, patients are advised to follow these guidelines:

• Prior to initiating treatment with levofloxacin, patients should disclose a comprehensive medication list, health history and any known allergies to their healthcare provider.
• Levofloxacin should be stored under appropriate conditions to maintain efficacy. Levofloxacin should be stored at room temperature (under 30°C) and away from intense ultraviolet light.
• Levofloxacin tablets should be swallowed whole, and the liquid form should be taken exactly as prepared and according to the instructions provided by the healthcare provider.
• Patients should avoid taking levofloxacin with antacids, dairy products and high-fat meals, as they may reduce the medication’s efficacy.

References

1. Kalil AC, et al. Clin Infect Dis 2016;63:e61-111.
2. Zaragoza R, et al. Crit Care 2020;24:383.
3. Chawla R. Am J Infect Control 2008;36(4 Suppl):S93-100.
4. Jones RN. Clin Infect Dis 2010;51(Suppl 1):S81-87.
5. Weiner LM, et al. Infect Control Hosp Epidemiol 2016;37:1288-1301.
6. Siddiqui AH, Koirala J. Citing websites: Methicillin Resistant Staphylococcus Aureus. Available at: https://www.ncbi.nlm.nih.gov/books/NBK482221/. Accessed 5 April 2023.
7. Torres A, et al. Eur Respir J 2017;50:1700582.
8. Alvarez-Lerma F, et al. Clin Microbiol Infect 2006;12(Suppl 3):81-92.
9. MIMS Pte. Ltd. Citing websites: Cravit Full Prescribing Information. Available at: https://www.mims.com/singapore/drug/info/cravit?type=full. Accessed 18 April 2023.
10. Fish DN, Chow AT. Clin Pharmacokinet 1997;32:101-119.
11. West M, et al. Clin Ther 2003;25:485-506.
12. Shorr AF, et al. Clin Infect Dis 2005;40(Suppl 2):S123-129.
13. Carbon C. Chemotherapy 2001;47(Suppl 3):9-14.
14. Khashab MM, et al. Curr Med Res Opin 2006;22:1997-2006.
15. Preston SL, et al. JAMA 1998;279:125-129.