Ceftazidime for Gram-negative bacterial keratitis

Abstract

PURPOSE:

Empiric keratitis to treat Gram-negative infections is often fortified with tobramycin or monotherapy with fluoroquinolones. Ceftazidime is not generally administered, although it has found success in the past. In this in vitro study, we sought to understand the possible role of ceftazidime in the treatment of Gram-negative keratitis in comparison to other anti-infectives.

METHODS:

This was a retrospective study at an academic tertiary care ophthalmology department. The laboratory records of patients with culture-positive Gram-negative keratitis were evaluated for anti-infective susceptibility of Gram-negative bacteria to ceftazidime, tobramycin, ciprofloxacin, and polymyxin B. The median minimum inhibitory concentration (MICs μg/ml) of each Gram-negative bacterial group was compared to the established serum standards.

RESULTS:

Analysis of Pseudomonas aeruginosa isolates from 38 patients between January 1, 2020, and December 31, 2021, demonstrated median MICs for four antibiotics: ceftazidime (1.5 μg/ml), tobramycin (1.5 μg/ml), ciprofloxacin (0.094 μg/ml), and polymyxin B (1.75 μg/ml). Among 15 isolates from other Gram-negative isolates during the same period, the median MICs were: ceftazidime (0.19 μg/ml), tobramycin (1.0 μg/ml), ciprofloxacin (0.032 μg/ml), and polymyxin B (1.0 μg/ml). All median MIC values for P. aeruginosa and other Gram-negative bacteria were denoted as susceptible, as interpreted by the serum standards.

CONCLUSION:

Based on in vitro testing, our data suggest that ceftazidime may still be useful in the treatment of Gram-negative keratitis. Patient comfort, costs, and availability will dictate the role of ceftazidime in the treatment of Gram-negative keratitis.

INTRODUCTION

Infectious keratitis is a leading cause of ocular morbidity and visual impairment worldwide,[1] and prompt, effective treatment is of paramount importance.[1] Pseudomonas aeruginosa is a ubiquitous Gram-negative rod that is oxidase-positive, nonglucose fermenting, and is frequently implicated as a causative pathogen in severe infectious keratitis.[2] Given its rapid doubling time of 30 min, empirical antibiotic choice is of utmost importance.[3] While protocols often recommend fortified broad-spectrum antibiotics such as tobramycin and cefazolin for P. aeruginosa, data suggest that single-drug therapy with fluoroquinolones may be sufficient for most mild and moderately severe cases of Gram-negative keratitis.[4,5,6,7]

In this in vitro study, we investigated the anti-infective susceptibilities of Gram-negative bacteria isolated from infectious keratitis to ceftazidime, tobramycin, ciprofloxacin, and polymyxin B. Our hypothesis is that laboratory studies indicate no clear advantages for any specific anti-infective in the treatment of Gram-negative keratitis. Optimal treatment characteristics would be based on clinical improvement, patient comfort, dosing, price, and availability.

METHODS

The laboratory records were reviewed between January 1, 2020, and December 31, 2021, for cases of Gram-negative keratitis for anti-infective susceptibilities to ceftazidime, tobramycin, ciprofloxacin, and polymyxin B. This retrospective observational study involved a review of de-identified microbiological data without medical chart review. Institutional Review Board approval was not required for this study. This study adhered to the tenets of the Declaration of Helsinki.

At our center, suspected cases of bacterial keratitis had corneal samples cultured on trypticase soy agar supplemented with 5% sheep blood, chocolate agar, mannitol salt agar, and Sabouraud’s agar with gentamicin. Gram and Giemsa stains were performed on corneal scrapings to directly observe bacteria. Minimum inhibitory concentrations (MICs) were determined using E-tests (Liofilchem, Abruzzi, Italy) to determine anti-infective susceptibilities were tested to ceftazidime, tobramycin, ciprofloxacin, and polymyxin B. The median MICs for each anti-infective and Gram-negative group were interpreted using Clinical and Laboratory Standards Institute Standards (CLSI, Wayne, PA, USA), which were based on serum concentrations. There are no standards for assessing anti-infective susceptibility for topically administered anti-infectives.[8]

RESULTS

Table 1 provides the descriptive statistics of MICs of P. aeruginosa isolated from keratitis to ceftazidime, tobramycin, ciprofloxacin, and polymyxin B (January 1, 2020, through December 31, 2021). The median MICs (μg/ml) for the four anti-infectives were ceftazidime (1.5), tobramycin (1.5), ciprofloxacin (0.094), and polymyxin B (1.75). All median MIC values for P. aeruginosa and other Gram-negative bacteria were denoted as susceptible as compared to the serum standards.

Table 1.

The descriptive statistics of Minimum Inhibitory Concentrations of Pseudomonas aeruginosa isolated from keratitis to ceftazidime, tobramycin, ciprofloxacin, and polymyxin B (January 1, 2020 through December 31, 2021)

Pseudomonas aeruginosa (MIC=ug/mL)
Antibiotic	#	Minimum	Q1	Median	Q3	Maximum	MIC susceptible	MIC resistant
Ceftazidime	38	0.75	1.375	1.5	2	4	<8	>32
Tobramycin	38	0.38	1	1.5	2	6	<4	>16
Ciprofloxacin	38	0.017	0.064	0.094	0.125	1	<1	>4
Polymyxin B	38	0.75	1.5	1.75	2.25	6	<2	>8

Anti-infectives susceptibilities are based on serum concentrations and NOT concentrations achieved in the corneal tissue. #: Number of isolates tested, MIC: Minimum inhibitory concentrations

Table 2 provides the descriptive statistics of MICs of other Gram-negative bacteria isolated from keratitis to ceftazidime, tobramycin, ciprofloxacin, and polymyxin B (January 1, 2020, through December 31, 2021). The median MICs (μg/ml) for the four anti-infectives were ceftazidime (0.19), tobramycin (1.0), ciprofloxacin (0.032), and polymyxin B (1.0).

Table 2.

The descriptive statistics of minimum inhibitory concentrations of other Gram-negative bacteria isolated from keratitis to ceftazidime, tobramycin, ciprofloxacin, and polymyxin B (January 1, 2020 through December 31, 2021)

Other Gram-negative bacteria (MIC=ug/mL)
Antibiotic	#	Minimum	Q1	Median	Q3	Maximum	MIC susceptible	MIC resistant
Ceftazidime	14	0.064	0.125	0.19	1	3	<8	>32
Tobramycin	15	0.25	0.38	1	1.5	3	<4	>16
Ciprofloxacin	14	0.012	0.021	0.032	0.33	4	<1	>4
Polymyxin B	13	0	0.63	1	4.75	32	<2	>8

*Other Gram-negative bacteria: Stenotrophomonas, Proteus, Escherichia, Klebsiella, Acinetobacter, Haemophilus, Neisseria. Antibiotic susceptibilities are based on serum concentrations and NOT concentrations achieved in the corneal tissue. MIC: Minimum inhibitory concentrations, #: Number of isolates tested

Table 3 summarizes some of the properties of ophthalmic anti-infectives used for the treatment of Gram-negative keratitis.

Table 3.

Properties of ophthalmic anti-infectives used for the treatment of Gram-negative keratitis

Property	Ceftazidime	Tobramycin	Ciprofloxacin	Polymyxin B
Source	Pharmacy	Pharmacy	Commercial	Commercial
Concentration	50 mg/mL	14 mg/mL	3 mg/mL	10,000 units/mL
Intraocular penetration	Low	Low	High	Low-Moderate
Toxicity	Low	Moderate	Moderate-High	High
Costs	High	High	Low	Low

DISCUSSION

The American Academy of Ophthalmology’s Preferred Practice Pattern recommends single-drug therapy with fluoroquinolone in most cases, given its equivalence in various studies to fortified broad-spectrum antibiotics such as ceftazidime.[4] Several previous studies have shown a >99% in vitro susceptibility rate of P. aeruginosa to fluoroquinolones; however, resistant strains do present an ongoing challenge.[9,10,11,12] Earlier work from our laboratory indicated that Gram-positive ocular isolates had the lowest MICs to moxifloxacin, while ciprofloxacin had the lowest MICs for Gram-negative bacteria. It is important to note that moxifloxacin may not be the most potent anti-infective for treating ocular bacterial infections.[13,14,15]

Our data for P. aeruginosa and other Gram-negative bacteria demonstrate that the median MICs are lower than the serum standards for ceftazidime, ciprofloxacin, and polymyxin B. We believe that the ciprofloxacin data support the use of single-drug fluoroquinolone therapy in the appropriate clinical setting for Gram-negative keratitis, but it may not be the best option for treating Gram-positive bacteria, where moxifloxacin monotherapy would be more suitable. We excluded moxifloxacin from this study because there are no established standards for interpreting susceptibility for Gram-negative bacteria. It is important to note that while serum MIC standards are the only available benchmarks, topical fortified antibiotics achieve substantially higher corneal concentrations, which further supports the clinical efficacy of topical antibiotics even when serum-based thresholds are not met.

Table 3 highlights crucial factors that influence a clinician’s choice of anti-infective in a specific scenario. For instance, fortified antibiotics such as ceftazidime and tobramycin are generally more expensive and necessitate compounding compared to commercially available options such as polymyxin B and ciprofloxacin. However, they provide favorable coverage against Gram-positive bacteria and minimal epithelial toxicity. Notably, commercially available antibiotics such as polymyxin B and ciprofloxacin tend to have higher toxicity to the ocular surface, which should be considered. In addition, while tobramycin gained popularity for empirical use due to its bactericidal efficacy, as gentamicin became less preferred, it has poor epithelial penetration.[16] These factors certainly play a role in a clinician’s decision-making process for a specific treatment regimen. Another consideration is double-coverage or triple-coverage with multiple antibiotics. One advantage is the in vitro synergism of multiple drugs, which can lead to a more effective combination regimen.[17,18] Conversely, treatment with additional agents raises concerns about increased adverse side effects.[19]

Limitations of this investigation include its retrospective and observational nature. Given the necessity for in vitro rather than in vivo analysis of these microbial isolates, MIC values for each antibiotic guide treatment decisions. However, this limitation accurately reflects clinical practice, and the conclusions made in this investigation align with the global literature and practice patterns. Our data reveal similarly high rates of susceptibility to those published previously.[9,10]

CONCLUSION

Our data suggest that ceftazidime remains a viable option for managing patients with Gram-negative keratitis.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.