Latest Generation Cephalosporins: Which One Does What With regard to Pseudomonas, cUTI, and cIAI?

There has been an explosion of medical information lately that is destined to influence the content of the USMLE. It is critical to know important milestones in Pharmacology. Some drugs have such unique properties or attributes that one cannot help but predict their immediate relevance for the USMLE. In fact, you would be a fool not to prepare for something like this.

The properties of the first four generational cephalosporins and their spectrum of activity in clinical therapeutics are clearly known. To put it simplistically, going from first to fourth generation, there is increasing gram negative coverage and decreasing gram positive coverage. That implies that, conversely, there is decreasing gram negative coverage and increasing gram positive coverage from fourth to first generation.

The first-generation offers coverage against gram positive bacteria (including S. aureus) and basic gram-negative coverage. The second generation have diminished gram positive activity, improved gram-negative coverage compared to first generation, and some anaerobic coverage. The third generation offers further diminished gram-positive coverage, further improved gram-negative coverage compared to first and second generation; diminished gram-positive coverage and some with Pseudomonal coverage. This generation is the one that has excellent CSF penetration and can be used to treat meningitis.

The fourth generation have coverage that is the same as third generation plus coverage against Pseudomonas. Many can cross the blood-brain barrier and are effective in meningitis. They are also used against Pseudomonas aeruginosa. They have increased activity against gram-positive bugs.

The fifth generation is the group that students often struggle with the most. Although the three members have 'ceft' in the name, many third-generation drugs have that nomenclature as well. Furthermore, ceftabiprole's classification as 'fifth-generation' cephalosporin is not universally accepted and ceftaroline does not have the activity against Pseudomonas aeruginosa or vancomycin-resistant enterococci (VRE) that ceftobiprole has. This generation retains the activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria.

• Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance.
• Ceftaroline lacks the antipseudomonal or VRE coverage of ceftobiprole. It is indicated for the treatment of community-acquired pneumonia and acute bacterial skin infections. It is active against MRSA and Gram-positive bacteria. 
• Ceftolazone is excellent for gram-negative infections. It is indicated for the treatment of cUTI (complicated urinary tract infections) and cIAI (complicated intra-abdominal infections). Ceftolozane-tazobactam (Zerbaxa) is excellent for multidrug-resistant gram-negative bacilli, especially cUTI and cIAI. Tazobactam is obviously a β-lactamase inhibitor.

Anyway, check out one of the USMLE questions we have prepared on these concepts. This is one of the questions written by our experts that our students have to be able to answer during the USMLE Insider Prep Course for USMLE Step 1. Test yourself with this and let us see how you do. We will discuss the answer and offer explanations later.

1. A 33-year-old prisoner who has been incarcerated for the past 8 years is brought to the hospital with a 3-day history of fever, chills, pleuritic chest pain, malaise, and cough productive of sputum. At presentation, his temperature is 102.1ºF (38.9ºC) with all other vital signs normal. His chest radio­graph shows consolidation in the right lower lobe. His white blood cell count is 14,400/mm³, but all other laboratory values are normal. Gram's stain of a smear from a sputum sample demonstrates gram-positive cocci in clusters that is found to be resistant to methicillin and vancomycin. Which of the following is the most appropriate therapy for this patient?

A. Aztreonam
B. Cefepime
C. Ceftaroline
D. Ceftazidime
E. Ceftolozane
F. Gentamicin