Cefotaxime: A Reappraisal in Lower Respiratory Tract Infections

Empirical treatment with antibacterial agents can be useful to reduce mortality in such cases

The latest CAP guidelines released by the American Thoracic Society and Infectious Diseases Society of America recommend cefotaxime in combination with macrolides or doxycycline as one of the empiric antibiotics for the management of such infections.^13,14 Resistance to newly developed antibiotics has been documented globally. In the aforementioned context, the rational use of older, effective antimicrobial agents mentioned in several guidelines with no multidrug-resistance (MDR) could serve as a helpful alternative for the treatment of MDR bacterial pathogens.³ From this background, the present narrative review aims to revisit the basic science of old, commonly prescribed cephalosporins for respiratory infections like ceftriaxone/cefotaxime and their clinical applicability in some of the most common bacterial infections, LRTIs. This article highlights the need for looking back at well-established, cost-effective and non-resistant antibiotics for LRTI patients. Apart from S. pneumoniae, other bacteria responsible for LRTIs have been tabulated in Table 1.^15,16

Third-generation cephalosporins

Third-generation cephalosporins are generally prescribed for cases of bacterial infection, pneumonia and upper and lower respiratory tract infections. These cephalosporins are semisynthetic analogues with different chemical substitutions on the C7 acylamido chain and include ceftriaxone, cefdinir, cefixime, cefditoren, cefpodoxime, ceftazidime, cefoperazone, ceftizoxime, ceftibuten, cefotaxime and others. They are more active against Gram-negative bacteria and organisms resistant to first- and second-generation cephalosporins. Third-generation cephalosporins are used for empiric therapy in (i) acute LRTI due to community-acquired pneumonia (CAP) in adults and children; (ii) CAP patients requiring intensive care unit (ICU) admission; (c) suspected infection in Human Immunodeficiency Virus (HIV) patients (outpatients)¹⁸; and (d) patients with healthcare-associated and community-acquired SBP without hepatocellular carcinoma.^18,19 Some third-generation compounds, like ceftriaxone, ceftazidime, and cefotaxime are poorly absorbed in the gastrointestinal tract and are administered only intramuscularly (IM) or intravenously (IV).

The most useful third-generation cephalosporins, ceftriaxone and cefotaxime have been used as listed in an essential medicine list, also recommended by various guidelines along with dosages; a few are listed in Tables 2, 3 and 4. Cefotaxime is the most commonly used drug in neonatal early-onset sepsis due to its wider therapeutic index, superior cerebrospinal fluid penetration, and lower incidence of nephrotoxicity. Its molecular structure is presented in Figure 1.¹⁸

Figure 1. Structural formula of Cefotaxime.²⁷

Most prescribed antibiotics for LRTIs

Ceftriaxone is an antibiotic agent frequently used in paediatric hospital practice for the treatment of severe bacterial infections. Ceftriaxone is the most common cause of cholelithiasis in pediatric practice,²⁸ as well as nephrolithiasis due to the drug being excreted via biliary and renal routes. This medication is contraindicated in preterm infants up to 41 weeks of age and in full-term infants less than 28 days of age. Patients with hypersensitivity to cephalosporins may result in an anaphylactic reaction and ceftriaxone-induced encephalopathy symptoms feature limb weakness or numbness, and memory impairment; behavioural problems have been reported in a few cases and are more common in patients with end-stage renal disease (ESRD). Clinically, the symptoms manifest within one to seven days of antibiotic therapy and usually resolve within two to seven days after discontinuation of the medication.

Futagi et al., 2022 reported a case of an 84-year-old male patient with a single right kidney when started on IV ceftriaxone (CRO) (2 g, every 24 hours) for bacterial infection who had about one-tenth of total body clearance and one-third of the volume of distribution compared with healthy adults, and the elimination half-life was about three times longer. He developed tonic-clonic seizures of the left face and left upper extremity on the eighth day. The encephalopathy appeared to have been caused by the administration of CRO to a patient with a single kidney.²⁹

CRO-associated encephalopathy (CAE) develops at a dose of 1 g/day and may increase blood and cerebrospinal fluid ceftriaxone levels.³⁰ Neurotoxic symptoms such as psychosis, seizure, myoclonus, and choreoathetosis show no abnormalities in laboratory investigations, CT, or MRI. However, electro encephalogram (EEG) shows slow and generalized periodic discharge with triphasic morphology.³¹

Ceftriaxone-associated neurotoxicity occurred in a patient after pancreas-kidney transplantation, as reported by Hagiya et al. in 2017. Thus, a higher serum concentration of the drug can trigger neurotoxicity. Antibiotic-associated encephalopathy (AAE) is easily treatable by stopping the administration of the responsible drugs.³²

In another case, a 49-year-old female patient with symptoms of upper respiratory tract infection and fever for five days, for which she received ceftriaxone for two days, was admitted to the emergency department with pruritic skin rash in both upper and lower limbs and swollen lips for one day. The patient had a history of penicillin allergy and was also allergic to some foods. Many studies have reported antibiotic-induced leukocytoclastic vasculitis caused by ceftriaxone, which healed with withdrawal of antibiotic use for 2, 5, 14 and 30 days; however, there was only one study on cefotaxime by Cure et al., 2007 in which patients recovered after five days of antibiotic.^33,34 Resistance to ceftriaxone has been steadily increasing from 2015 to 2020. Therefore, the appropriate antibiotics should be selected based on susceptibility data.³⁵

Ceftriaxone causes more severe clinical courses and more fatal outcomes than other drugs responsible for DIIHA (Drug-induced immune hemolytic anaemia).³⁶ In a case where ceftriaxone was given for bilateral pneumonia to an 82-year-old male patient admitted to ICU, skin lesions formed after three days and led to the patient’s death due to acute and fatal cephalosporin-induced autoimmune haemolytic anaemia (CIIHA), due to strong agglutinating drug antibody effect. CIIHA is a rare and serious cause of livedo that should be suspected in patients exhibiting livedo and acute haemolytic anaemia within hours/days following cephalosporin administration.³⁷ The temporal relationship between changing platelet counts and starting and discontinuing ceftriaxone suggests the diagnosis of drug-induced thrombocytopenia.³⁸

The risk of third-generation cephalosporin (ceftriaxone) resistance is particularly high in nosocomially-acquired episodes of spontaneous bacterial peritonitis but also occurred in healthcare system-acquired cases.³⁹ Ceftriaxone was responsible for the highest number of deaths in one study (49 cases). Of 20,877 (5.8%) reports, 1205 were related to ceftriaxone; 357 reports (30%) were categorized as serious including cardiac arrest, anaphylactic and anaphylactoid reactions. The most frequently reported serious events with ceftriaxone were cardiac arrest, and anaphylactic and anaphylactoid reactions.⁴⁰

CIIHA is a potentially fatal complication.³³ The reported fatality rate of CIIHA is as high as 40%. Acute renal failure and cardiovascular decompensation are the most lethal complications in pediatric patients with CIIHA. A seven-year old child underwent cochlear implantation of the left ear under general anaesthesia, and was given 1 g of IV ceftriaxone intra-operatively and subsequently daily post-operation. The child developed CIIHA after seven days of daily ceftriaxone administration and presented with sudden abdominal pain, shivering, sweating, and dark tea-coloured urine. Ceftriaxone therapy was immediately discontinued whereas intravenous immunoglobulin was used after the episode of hemolysis; hemoglobinuria then ceased by itself.⁴¹

Establishment of cefotaxime over ceftriaxone

A pilot study was performed with intravenous ceftriaxone (1 g/24 h) or cefotaxime (1 g/8 h) for at least three days to assess the emergence of third-generation cephalosporin-resistant Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, toxigenic Clostridium difficile, and vancomycin-resistant Enterococci. No significant difference in the emergence of resistance was observed.⁴²

Also, cefotaxime and ceftriaxone have a comparable spectrum of antimicrobial activity, but differ in terms of pharmacokinetics. In an antimicrobial stewardship (AMS) program, ceftriaxone was replaced (64% reduction in application density from 2013 to 2019) with cefotaxime.⁴³

Clinical pharmacology

Like other cephalosporins, cefotaxime inhibits bacterial cell wall synthesis. Its beta-lactam rings bind to penicillin-binding proteins (PBPs) and inhibit transpeptidation in peptidoglycan cell wall synthesis of susceptible bacteria. This leads to the autolysis of the bacteria. The effect of cefotaxime on several organisms has been tabulated in Table 5.⁴⁴

Once administered, cefotaxime is metabolized in the liver and most of the molecule including its metabolites are renally excreted. Within the liver, cefotaxime converts to desacetylcefotaxime, which is further converted to desacetylcefotaxime lactone and subsequently to metabolites.⁴⁵ More than 80% of cefotaxime is recovered in the urine, with one third being in the form of desacetylcefotaxime (des-CTX). Although des-CTX is the primary metabolite of cefotaxime, its activity is eight-fold lower than cefotaxime itself. ^46,47 It is generally well-tolerated and hypersensitivity reactions such as rash, fever, and pruritus are uncommon.²⁷ Cefotaxime has not been associated with hypoprothrombinemia/coagulopathies, or disulfiram-like reactions, as with other cephalosporins and pseudocholelithiasis.^27,44

In an Indian study by Merchant et al., the incidence of nosocomial infection was documented at 1.8% in patients of general wards versus 16.7% in ICU patients. It reported cefotaxime (34%) as a commonly utilized antibiotic, followed by amikacin and gentamicin.⁴⁸ In adult in-patients with nonsevere CAP, the following empirical treatment regimens were recommended: combination therapy with a beta-lactam (ampicillin+sulbactam 1.5-3 g every 6 h, cefotaxime 1-2 g every 8 h, ceftriaxone 1–2 g daily, or ceftaroline 600 mg every 12 h) and a macrolide (azithromycin 500 mg daily or clarithromycin 500 mg twice daily; strong recommendation, high quality of evidence), or monotherapy with a respiratory fluoroquinolone (levofloxacin 750 mg daily, moxifloxacin 400 mg daily; strong recommendation, high quality of evidence). The third option for adults with CAP who have contraindications to both macrolides and fluoroquinolones is: combination therapy with beta-lactam (ampicillin+sulbactam, cefotaxime, ceftaroline, or ceftriaxone, doses as above) and doxycycline 100 mg twice daily.^13,14

Cefotaxime use in various conditions

Cefotaxime may also be used prophylactically before surgery to prevent surgical infections. Enterobacteriaceae is particularly sensitive to cefotaxime and thus the drug is capable of treating MDR strains of Enterobacteriaceae.⁴⁹ A favorable characteristic of cefotaxime, compared with the other cephalosporins, is that it does not cause a notable occurrence of coagulopathies and pseudocholelithiasis.⁴⁴ Cefotaxime can readily cross the blood-brain barrier when administered intravenously and may treat gram-negative infections resistant to previous generations of cephalosporins.⁵⁰

A study was performed on children aged 0-18 years admitted to the paediatric ICU who received intravenous cefotaxime (100-150 mg/kg/day, interval 6-8 h) as an antibiotic. The maximum cefotaxime doses (200 mg/kg/day, interval 6 h) proved adequate for MICs ≤0.5 mg/L across the whole age range against the majority of pathogens; these doses can be combined with therapeutic drug monitoring (TDM) to improve exposure after the start of treatment in critically ill children.⁵¹

A German study group led by Bruch and Kujath evaluated twice a day dosing of cefotaxime in patients with postoperative pneumonia. Of the 88 (n=88) patients without serious underlying diseases who received 1 g every 12 h dosage regimen in this study, all were clinically cured along with the eradication of all pathogens. In the cohort with severe infection/severe underlying disease receiving 2 g every 12-h of cefotaxime, the overall clinical success rate (cure plus improved) was 98.4%. Results supported the use of cefotaxime as a feasible alternative for empiric monotherapy to manage nosocomial pneumonia in surgical-service patients who were non-neutropenic or on long-term artificial ventilation.⁵² A similar study which evaluated twice-a-day daily dosing of cefotaxime (2 g every 12 h) in patients with severe nosocomial pneumonia documented this regimen of cefotaxime as adequate and appropriate. It was suggested that a combination of cefotaxime with aminoglycosides be reserved for cases with suspected multi-resistant Gram negative bacterial infections.⁵³

In a randomized, multicentric trial, use of cefotaxime and ceftriaxone in adult patients with nosocomial pneumonia was proven 80% clinically and 93% bacteriologically successful with cefotaxime compared to ceftriaxone.⁷ In terms of adverse events the ceftriaxone group reported a higher incidence of gall bladder sludge and diarrhoea.

One Canadian trial compared cefotaxime and ceftriaxone in patients with nosocomial LRTI. It was inferred that cefotaxime at 1 g IV every 8 h was noninferior to ceftriaxone at 1 g i.v. every 12 h, with a trend for a lower likelihood of side effects, reinfections, and superinfections.⁵⁴

In a multicentric clinical trial, adult patients diagnosed with nosocomial pneumonia and not receiving mechanical ventilation were treated randomly with monotherapy with cefotaxime or the antibiotic combination routinely used in a clinical set-up. The cure rate was 79% in the cefotaxime group and 71% in the group receiving antibiotic combinations; this difference was statistically significant (p ≤ 0.03). The trial concluded that monotherapy with cefotaxime is a regimen with better results, hinting at superiority of cefotaxime as an empirical therapy for nosocomial pneumonia.⁵⁵ One more study was conducted on 46 adults hospitalized with pneumococcal pneumonia in Spain. The common underlying diseases in these patients included heart disease, COPD/asthma and diabetes mellitus. When resistance pattern of the pneumococci to antibiotics was studied, it was reported to be 15%, 11% and 6% with penicillin, erythromycin and cefotaxime respectively.⁵⁶

Rylski conducted a study on 100 patients with respiratory infections like bronchopneumonia, acute bronchitis and chronic bronchitis who underwent fibre optic bronchoscopy. 48% of these patients tested positive for bacterial flora (aerobic, anaerobic and mixed bacterial flora). Cefotaxime was one of the antibiotics to which high sensitivity was reported in antibacterial susceptibility reports.⁵⁷

In another publication, Konishi et al. reported 129 patients with respiratory tract and other infections were treated with cefotaxime at a dose of 0.5 to 8 mg of daily through the intravenous route for two to 61 days. Cefotaxime was documented to be efficacious in 87.1% (108/124) of cases. The study concluded that cefotaxime is effective against LRTIs.⁵⁸ All the reported trials suggest that cefotaxime has the lowest resistance pattern towards pneumococci and is much safer as it doesn’t lead to encephalopathy, CIIHA, or cholelithiasis, and is much more effective in treating infections as it also has the potential to cross the blood-brain barrier.

Contraindications of cefotaxime

Cefotaxime administration and dosing require adjusting in geriatric populations, patients with decreased renal function, and hepatic dysfunction. CBC should also be monitored with cefotaxime use.²⁷ Cefotaxime is an FDA Pregnancy Category B drug. Cefotaxime use in pregnancy has not been studied clearly and should be used with caution. Toxicity may result in convulsions, dyspnea, hypothermia, cyanosis, reversible encephalopathy, and death. Mortality has occurred with dosages of 6000 mg/kg/day.⁴⁴