Managing Sepsis at a Cellular Level

I want to begin this article with a scenario: say sepsis due to MRSA (methicillin-resistant Staphylococcus aureus) is documented by the clinician and ICD-10-CM code A41.02 is captured by the coder. Assume that there are no secondary diagnoses or procedures. This leads to the assignment of MS-DRG (Medicare Severity Diagnosis-Related Group) 872 with a relative weight of 1.0283 and APR-DRG (All Patient Refined Diagnosis-Related Group) 720 with SOI (severity of illness) of 2, ROM (risk of mortality) of 1, and relative weight of 0.7191. 

The concepts and algorithms of DRGs are complex. In a similar fashion, the molecular and cellular processes underlying sepsis are complicated. A synopsis of these processes will provide insight into the challenges inherent in managing the protean manifestations of sepsis and will facilitate navigation through the medical record, generation of queries, and dialogue with clinicians, with respect to capturing sepsis as a principal or secondary diagnosis.

Sepsis arises due to a dysregulated immune response. PAMPs (pathogen associated molecular patterns), such as peptidoglycan and lipoteichoic acid (from gram-positive bacteria) and lipopolysaccharide (from gram-negative bacteria) incite the immune system by binding to PRRs (pattern recognition receptors), including TLRs (toll-like receptors) expressed on the surface of macrophages. This leads to pro-inflammatory and anti-inflammatory cytokine cascades with ensuing organ dysfunction and failure characteristic of sepsis, severe sepsis, and septic shock, as well as the SOFA and qSOFA scores.

Associated with these factors is a discussion regarding the administration of antibiotics for the management of sepsis. Depending on the causal organisms and the possibility of multi-drug resistance, different classes of antibiotics are initially prescribed for sepsis and cover a wide range of aerobic, anaerobic, gram-positive, and gram-negative bacteria. Based on culture and sensitivity studies, the regimen can be narrowed to one antibiotic. If the patient’s clinical status does not improve or worsens, new classes of antibiotics should be added to the regimen, or the entire regimen may need to be modified.

There are specific rationale regarding the use of several classes of antibiotics prescribed for sepsis: Zosyn, Vancocin, Avelox, and Flagyl.

Zosyn is comprised of piperacillin and tazobactam. Piperacillin is a fourth-generation ureidopenicillin that contains a β-lactam ring that binds DD-transpeptidase, a penicillin-binding protein. This inhibits cross-linking of peptidoglycans and cell wall synthesis, leading to bacteria cell wall lysis. Several bacteria strains possess β-lactamase, which destroys the β-lactam ring and neutralizes piperacillin. In order to circumvent this problem, tazobactam prevents the degradation of piperacillin by inhibiting the action of β-lactamase.

While Zosyn can treat many types of infections, it has limited efficacy against MRSA (methicillin-resistant Staphylococcus aureus). The mecA gene of MRSA encodes for penicillin-binding protein 2a, which does not bind the β-lactam ring and confers resistance to piperacillin.

This explains why Vancocin (vancomycin) is prescribed with Zosyn.  Vancocin is a glycopeptide antibiotic that does not possess a β-lactam ring and destroys MRSA via a mechanism distinct from Zosyn. Vancocin binds the terminal D-alanyl-D-alanine amino acid sequence of NAM (N-acetylmuramic acid) and NAG (N-acetylglucosamine), which comprise the backbone of the cell wall. By preventing the formation of the NAM and NAG polymers, Vancocin disrupts the integrity of the cell wall.

Avelox (moxifloxacin) is a fourth-generation fluoroquinolone that is used effectively against many strains of gram-positive and gram-negative bacteria. Avelox inhibits DNA gyrase and topoisomerase IV. DNA gyrase is an enzyme that relieves the strain caused by helicase, as it unwinds the DNA during bacteria replication. Topoisomerase IV is an enzyme that unlinks DNA following replication and also relieves the strain caused by helicase. Together, DNA gyrase and topoisomerase IV generate double-stranded DNA breaks to relieve the strain of the positive DNA supercoils and therefore allow DNA polymerase to replicate the strands of bacteria DNA. The binding of Avelox to DNA gyrase and topoisomerase IV creates complexes termed “topoisomerase poisons” that cleave the bacterial DNA into fragments, resulting in cell death. Since the mechanism of action of Avelox is distinct from Zosyn and Vancocin, Avelox can target strains of bacteria that may be resistant to Zosyn or Vancocin.

Flagyl (metronidazole) belongs to the nitroimidazole class of antibiotics and can treat sepsis caused by anaerobic bacteria, such as Bacteroides fragilis and Clostridium perfringens. In anaerobic bacteria, Flagyl is reduced by pyruvate: ferredoxin oxidoreductase to free radicals. The free radicals, in turn, cause DNA strand breakage, DNA helix destabilization, and death of anaerobic bacteria. Since the pyruvate-ferredoxin oxidoreductase  reaction typically does not take place in aerobic bacteria, Flagyl has minimal effect on aerobic bacteria.

In short, an appreciation of the mechanism of action of different classes of antibiotics can shed light on the complexity in managing sepsis.