Dr Chu Quang Lien
Head of ICU Department,
Hong Ngoc General Hospital,
Hanoi, Vietnam

In the ever-evolving treatment landscape of hospital-acquired pneumonia (HAP), characterisation of the role of antibiotics has become paramount in the context of rising antimicrobial resistance. Levofloxacin is a widely used broad-spectrum antibiotic with a history spanning three decades since its approval in 1993 for medical use in Japan. It belongs to the fluoroquinolone class of medications and plays a crucial role in the treatment of bacterial infections, including HAP.^{1, 2} As such, it is increasingly important to consider and employ clinical strategies for maintaining its efficacy.

Dr Chu Quang Lien, from Vietnam, shares valuable insights on the resistance rates surrounding levofloxacin use, the balance between efficacy and tolerability that shapes the choice of antibiotics in the management of HAP, and current strategies for optimising antibiotic therapy in the context of emerging resistance.

Q1: Have you observed any significant changes in the resistance rates of levofloxacin in the treatment of patients with HAP in Vietnam over the past few years?

Multiple research studies conducted over the years have provided valuable data on the resistance rates of levofloxacin in the context of treating HAP in Vietnam.

In the EACRI multicenter study of the Vietnam Lung Association, there was a notable increase in the resistance rate of levofloxacin, increasing from 0% in 2010 to 20% in 2018.³ Another study, conducted by Pham Hong Nhung and colleagues at the Intensive Care Unit (ICU) and Respiratory Center of Bach Mai Hospital from the years 2012 to 2016, revealed varied sensitivities rates to levofloxacin among Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. While there were no data reported on the sensitivity rates of Pseudomonas aeruginosa and Acinetobacter baumannii to levofloxacin, Klebsiella pneumoniae showed a declining sensitivity, decreasing from over 60% to 30% over the years.⁴

The Ministry of Health’s collaborative report with an international project on antibiotic resistance, covering the situation in Vietnamese hospitals between 2008 and 2009, indicated that antibiotic resistance rates of Gram-negative bacteria remained relatively low with respect to third and fourth generation cephalosporin antibiotics, rates remained the same for aminoglycosides, and rates were higher for carbapenems. However, all reported resistance rates were below the 60% threshold.

A prospective observational study conducted by Duong Bich Thuy and colleagues at the Ho Chi Minh City Hospital for Tropical Diseases, Vietnam, from November 2014 to January 2016, assessed ICU-acquired colonisation and infections among adult patients with more than 48 hours of ICU stay, focusing on the five major pathogens: Staphylococcus aureus, Escherichia coli, Klebsiella spp., Pseudomonas spp. and Acinetobacter spp.⁵ The study found that Staphylococcus aureus, Acinetobacter spp. and Pseudomonas spp. exhibited antimicrobial resistance rates towards levofloxacin of 58.5%, 63.4% and 12.2%, respectively.⁵ There are no data reported on the antimicrobial resistance rates of Escherichia coli and Klebsiella spp. against levofloxacin.⁵

Giang et al. investigated the antibiotic resistance profile of patients with ventilator-associated pneumonia in the ICU setting at Nhan Dan Gia Dinh Hospital from 2014 to 2015. The study revealed that levofloxacin exhibited resistance rates as high as 72%.⁶

Collectively, these studies indicate a concerning trend of increasing levofloxacin resistance, especially evident during 2015 to 2016 when the resistance rates exceeded 70%. Notably, Klebsiella pneumoniae consistently demonstrated resistance rates around the 60% threshold. Furthermore, a study by Nhung et al. at the Bach Mai Hospital highlighted the gradual decrease between 2017 and 2018 with respect to levofloxacin sensitivity for Klebsiella pneumoniae.⁷

In summary, multiple research studies conducted in Vietnam, including those set in major hospitals like Cho Ray and Bach Mai Hospital, have consistently shown a significant decrease in levofloxacin sensitivity among various bacteria responsible for HAP.⁸

Q2: Are there any notable studies that compare the antibiotic resistance patterns between levofloxacin and other commonly used antibiotics in the treatment of patients with HAP? What were the key findings from these studies?
The Global Antibiotic Resistance Partnership (GARP)-Vietnam and the University of Oxford collaborated with the Vietnamese Ministry of Health (MoH) to establish a new antibiotic resistance surveillance program.⁹ In a cross-sectional study that took place between 2008 and 2009, in which antibiotic resistance and usage data were collected from 15 participating hospitals, found that Gram-negative bacteria exhibited resistance rates of 30–70% to third and fourth generation cephalosporins in 2009, while resistance rates were approximately 40–60% against aminoglycosides and fluoroquinolones.⁹ The surveillance data revealed alarmingly high carbapenem resistance in northern hospitals, with over 50% of Acinetobacter species found to be resistant to imipenem.⁹ Additionally, the study indicated that fluoroquinolone resistance among Klebsiella strains in southern hospitals exceeded 60%, highlighting a higher quinolone resistance compared to carbapenems during that period. ⁹

In a study conducted at Bach Mai Hospital from 2009 to 2011, focusing on the microbiological characteristics causing early and late nosocomial pneumonia in ventilated patients, the research indicated that nosocomial pneumonia associated with mechanical ventilation was primarily caused by Pseudomonas aeruginosaand Acinetobacter.¹⁰ Notably, these bacteria exhibited resistance to ciprofloxacin, although levofloxacin resistance was not specifically mentioned.¹⁰ The resistance rates to ciprofloxacin for Acinetobacter were between 50% and 75%.¹⁰ Furthermore, the study highlighted a significant increase in resistance to ciprofloxacin compared to carbapenems, the latter associated with a resistance rate of 58%.¹⁰

A study on antibiotic resistance involving Klebsiella pneumoniae, Pseudomonas, and Acinetobacter at the Department of Physiotherapy and Respiratory Center of Bach Mai Hospital between 2012 and 2016 revealed that sensitivity to antibiotics in the ICU had decreased compared to that in observed at the centre.⁴ However, there was a common trend of reduced sensitivity within the quinolone group, including levofloxacin. There was a relatively significant increase in sensitivity within the carbapenem and colistin groups. This suggests a growing resistance to quinolones, including levofloxacin, while resistance to carbapenems and colistin was previously low, although appeared to be increasing.

Collectively, these findings underscore the high and increasing resistance rates associated with levofloxacin and quinolones in general. In contrast, carbapenem and colistin, which were initially associated with lower resistance rates, are also showing signs of increasing resistance. Notably, in the absence of antibiogram results, the recommended first-line regimen involves a combination of carbapenem with levofloxacin or amikacin.

Q3: What are the factors that may have contributed to the changes in levofloxacin resistance rates over the years? Are there any specific patient populations or settings where resistance seems to be more prevalent, in Vietnam?
The changing landscape of levofloxacin resistance rates over the years can be attributed to several factors. Notably, the widespread use of levofloxacin, particularly in central-level hospitals and orthopaedic departments, has contributed significantly to the development of resistance. An analysis of antibiotic utilisation patterns for HAP in Yen Bai revealed that third-generation cephalosporin antibiotics and quinolones, including levofloxacin, were among the most commonly prescribed antibiotics.

Moreover, when examining the situation of antibiotic use in 15 hospitals in 2009, resistance rates were relatively consistent across hospitals, but central-level hospitals exhibited higher resistance rates compared to local hospitals, with institutions like Bach Mai displaying higher resistance rates than Saint Paul Hospital.⁹

Research conducted by Dang Ngoc Quy Hue and colleagues between 2014 and 2016 at Thong Nhat General Hospital, where patients were being treated for chronic gastritis, highlighted a noticeable increase in Helicobacter pylori resistance rates to levofloxacin (40.5%) compared to previous studies (18.4%).¹¹ This rise in resistance could be attributed to increased resistance rates to clarithromycin, prompting healthcare professionals to turn to levofloxacin as an alternative option for Helicobacter pylori eradication.

A study by Phan Trung Nam and colleagues at Hue University Hospital from 2012 to 2014 further emphasised this trend, reporting a Helicobacter pylori resistance rate to levofloxacin of 41.3%, with primary resistance at 35.6% and secondary resistance at 63.2%.¹² This suggests that the Helicobacter pylori bacterial population is increasingly becoming resistant to levofloxacin in patients with gastritis undergoing Helicobacter pylori eradication treatment, potentially contributing to the overall rise in antibiotic resistance among bacteria causing HAP.

Q4: Have you found that levofloxacin is still an effective option for treating patients with HAP despite the reported resistance rates? Are there any strategies you have employed to optimise its efficacy in the face of increasing antibiotic resistance?
Levofloxacin remains a viable option in our protocols for the treatment of HAP. However, it is never used as monotherapy but rather, is administered in combination with other antibiotic agents, in line with the recommendations outlined in the Surviving Sepsis Campaign 2020 guidelines. This approach aims to ensure a broad spectrum of antibiotic coverage capable of effectively targeting and inhibiting a wide range of bacteria. This strategy is implemented in the absence of specific data on the causative bacteria responsible for HAP, thus allowing for a comprehensive initial therapeutic approach.

Several studies conducted in various healthcare settings in Vietnam shed light on the effectiveness of levofloxacin in managing HAP:

1. A study conducted at the HSTC department of Quang Ninh Provincial General Hospital in 2017 indicated that levofloxacin demonstrated high sensitivity against common HAP-causing bacteria, including Klebsiella pneumoniae, Acinetobacter baumannii and Escherichia coli, with sensitivities of 100%, 25% and 25%, respectively.¹³
2. Another study conducted at Duc Giang General Hospital in 2014 assessed pneumonia related to mechanical ventilation at the ICU Department. The study reported varying rates of antibiotic resistance to levofloxacin among common bacteria, including Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae, with resistance rates of 75%, 41.7% and 27.3%, respectively.¹⁴
3. Research by Tran Minh Giang and colleagues at Gia Dinh People’s Hospital in Ho Chi Minh City during 2014 to 2015 indicated that levofloxacin and imipenem were the most frequently used antibiotics at the time of ICU admission, with resistance rates of 72% for levofloxacin.¹⁵
4. In a study by Vo Thi Ha and colleagues at Nhan Dan Gia Dinh Hospital, Ho Chi Minh City, in 2019, the resistance rate to levofloxacin for Pseudomonas aeruginosa was reported to be 32.4%.¹⁶

To optimise the efficacy of levofloxacin in the face of increasing antibiotic resistance, we take the following measures:

• Follow established treatment regimens.
• Implement pharmacokinetic/pharmacodynamic principles in antibiotic selection and dosing, considering factors such as loading doses, high-dose strategies, continuous infusions and interval adjustments.
• Adjust antibiotic therapies promptly, based on clinical response and antibiogram results.
• Adhere to the “4D guarantee” approach, which emphasises drug selection, dose optimisation, duration of treatment and de-escalation when necessary.¹⁷

Q5: Based on the available data and your clinical experience, how important is ‘tolerability’ when choosing an antibiotic regimen for HAP treatment? Are there cases where the choice of antibiotic might be influenced more by tolerability than by consideration of antimicrobial resistance?
The concept of antibiotic tolerability, particularly in the context of HAP, has not been extensively studied. While there are definitions that distinguish tolerability from antibiotic resistance and persistence, existing data primarily consists of in vitro studies, mainly focusing on Escherichia coli, and lacks comprehensive research on antibiotic tolerability within the HAP domain.

It is worth noting that tolerance and persistence are closely linked to persistent infections and the potential for treatment relapse. Additionally, tolerance and persistence are considered precursors to the development of antibiotic resistance in bacteria. Therefore, there is a need for more comprehensive research on the concept of antibiotic tolerability, particularly in the context of HAP. Such research would aid in selecting appropriate antibiotic regimens, especially as antibiotic resistance continues to pose a significant clinical challenge in the 21^st century.

As antibiotic resistance is believed to have arisen from drug tolerance, the treatment selection process should prioritise the antibiotic resistance profile of pathogenic bacteria. Nevertheless, the patient’s clinical condition continues to be a crucial factor when deciding between existing resistance patterns and the potential for antibiotic tolerance with the chosen antibiotic. In certain situations, particularly with critically ill patients, the choice of antibiotic regimen may be influenced primarily by the patient’s immediate clinical needs and the tolerability of the selected antibiotic.

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